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When a canary sings, it maintains a memory trace of the notes produced in the previous five to 10 seconds, a process that allows the bird to produce songs with long-range rules or syntactic structure, according to a new study co-written by a neuroscientist at the University of Oregon's Phil and Penny Knight Campus for Accelerating Scientific Impact.

Thalamus eyed as potential treatment target for schizophrenia's working memory deficits

Long assumed to be a mere "relay," an often-overlooked egg-like structure in the middle of the brain also turns out to play a pivotal role in tuning-up thinking circuity. A trio of studies in mice funded by the National Institutes of Health revealed that the thalamus sustains the ability to distinguish categories and hold thoughts in mind.

NIH-funded study in mice suggests loss of mossy cells plays a critical role in both

A small group of cells in the brain can have a big effect on seizures and memory in a mouse model of epilepsy. According to a new study in Science, loss of mossy cells may contribute to convulsive seizures in temporal lobe epilepsy (TLE) as well as memory problems often experienced by people with the disease. The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

NIH study reinforces theory for how neurons process information

Studies could lead to new ways to enhance memory for those with traumatic brain injury or Alzheimer's disease.

The MIT professor takes a mathematical approach to exploring memory, navigation, and other neural functions.

NIH-funded research reveals novel method for transferring genetic material between neurons

Two independent teams of scientists from the University of Utah and the University of Massachusetts Medical School have discovered that a gene crucial for learning, called Arc, can send its genetic material from one neuron to another by employing a strategy commonly used by viruses. The studies, both published in Cell, unveil a new way that nervous system cells interact.

Collaboration between NIH and Tetra Discovery Partners leads to development of treatment that may affect cognition

DetectCID to focus on methods for use in primary care and other everyday clinical settings

The steering committee for The Consortium for Detecting Cognitive Impairment, Including Dementia (DetectCID), recently held its kickoff meeting. The goal of the consortium is to establish, test, and validate methods for detecting cognitive impairment in the general public, including health disparities populations.

Studies of epilepsy patients uncover clues to how the brain remembers

In a pair of studies, scientists at the National Institutes of Health explored how the human brain stores and retrieves memories. One study suggests that the brain etches each memory into unique firing patterns of individual neurons. Meanwhile, the second study suggests that the brain replays memories faster than they are stored.

Pages

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memory | National Institute of Neurological Disorders and Stroke

# data[].attributes.attachment_link.description
When a canary sings, it maintains a memory trace of the notes produced in the previous five to 10 seconds, a process that allows the bird to produce songs with long-range rules or syntactic structure, according to a new study co-written by a neuroscientist at the University of Oregon's Phil and Penny Knight Campus for Accelerating Scientific Impact.

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Many older adults worry about their memory and other thinking abilities. For example, they might be concerned about taking longer than before to learn new things, or they may sometimes forget to pay a bill. These changes are usually signs of mild forgetfulness - often a normal part of aging - not serious memory problems.

What's normal forgetfulness and what's not?

What's the difference between normal, age-related forgetfulness and a serious memory problem? It's normal to forget things once in a while as we age, but serious memory problems make it hard to do everyday things like driving, using the phone, and finding your way home.

Talk with your doctor to determine whether memory and other cognitive problems, such as the ability to clearly think and learn, are normal and what may be causing them.

Signs that it might be time to talk to a doctor include:

Asking the same questions over and over again

Getting lost in places a person knows well

Having trouble following recipes or directions

Becoming more confused about time, people, and places

Not taking care of oneself -eating poorly, not bathing, or behaving unsafely

Tips for dealing with forgetfulness

People with some forgetfulness can use a variety of techniques that may help them stay healthy and deal with changes in their memory and mental skills. Here are some tips:

Learn a new skill.

Follow a daily routine.

Plan tasks, make to-do lists, and use memory tools such as calendars and notes.

Put your wallet or purse, keys, phone, and glasses in the same place each day.

Stay involved in activities that can help both the mind and body.

Volunteer in your community, at a school, or at your place of worship.*

Spend time with friends and family.*

Get enough sleep, generally seven to eight hours each night.

Exercise and eat well.

Prevent or control high blood pressure.

Don't drink a lot of alcohol.

Get help if you feel depressed for weeks at a time.

Mild cognitive impairment

Some older adults have a condition called mild cognitive impairment, or MCI, meaning they have more memory or other thinking problems than other people their age. People with MCI can usually take care of themselves and do their normal activities. MCI may be an early sign of Alzheimer's disease, but not everyone with MCI will develop Alzheimer's.

Signs of MCI include:

Losing things often

Forgetting to go to important events or appointments

Having more trouble coming up with desired words than other people of the same age

If you have MCI, visit your doctor every six to 12 months to track changes in memory and other thinking skills over time. There may be habits and behaviors you can change and activities you can do to help you maintain memory and thinking skills.

Dementia and aging

Read and share this infographic to learn whether forgetfulness is a normal part of aging.

Dementia is not a normal part of aging. It includes the loss of cognitive functioning - thinking, remembering, learning, and reasoning - and behavioral abilities to the extent that it interferes with a person's quality of life and activities. Memory loss, though common, is not the only sign of dementia. People with dementia may also have problems with language skills, visual perception, or paying attention. Some people have personality changes.

While there are different forms of dementia, Alzheimer's disease is the most common form in people over age 65. The chart below explains some differences between normal signs of aging and Alzheimer's.

Normal aging

Alzheimer's disease

Making a bad decision once in a while

Making poor judgments and decisions a lot of the time

Missing a monthly payment

Problems taking care of monthly bills

Forgetting which day it is and remembering it later

Losing track of the date or time of year

Sometimes forgetting which word to use

Trouble having a conversation

Losing things from time to time

Misplacing things often and being unable to find them

When to visit the doctor for memory loss

If you, a family member, or friend has problems remembering recent events or thinking clearly, talk with a doctor. He or she may suggest a thorough checkup to see what might be causing the symptoms. You may also wish to talk with your doctor about opportunities to participate in research on cognitive health and aging.

At your doctor visit, he or she can perform tests and assessments, which may include a brain scan, to help determine the source of memory problems. Your doctor may also recommend you see a neurologist, a doctor who specializes in treating diseases of the brain and nervous system.

Memory and other thinking problems have many possible causes, including depression, an infection, or medication side effects. Sometimes, the problem can be treated, and cognition improves. Other times, the problem is a brain disorder, such as Alzheimer's disease, which cannot be reversed.

Finding the cause of the problems is important for determining the best course of action. Once you know the cause, you can make the right treatment plan. People with memory problems should make a follow-up appointment to check their memory every six to 12 months. They can ask a family member, friend, or the doctor's office to remind them if they're worried they'll forget.

Learn more about cognitive health and Alzheimer's and related dementias.

A note about unproven treatments

Some people are tempted by untried or unproven "cures" that claim to make the brain sharper or prevent dementia. Be cautious of pills, supplements, brain training computer games, or other products that promise to improve memory or prevent brain disorders. These might be unsafe, a waste of money, or both. They might even interfere with other medical treatments. Currently there is no drug or treatment that prevents Alzheimer's or related dementias.

However, there are currently several drugs available by prescription to safely treat the symptoms of early and mid-stage Alzheimer's. If you have been diagnosed with dementia, your doctor may suggest that you take one of them.

How to protect yourself and others from unproven treatments:

Beware if the product claim seems too promising and if it conflicts with what you've heard from your health care provider.

Question any product that claims to be a "scientific breakthrough." Companies marketing these products often take advantage of people when they are most vulnerable and looking for a miracle cure.

Check with your doctor or health care professional before buying any product, including those labeled as dietary supplements, that promises to improve your memory or prevent dementia.

Report any products or supplements being advertised as a treatment for Alzheimer's or other diseases on the U.S. Food and Drug Administration's website.

Read about this topic in Spanish. Lea sobre este tema en español.

For more information about memory loss and forgetfulness

NIA Alzheimer's and related Dementias Education and Referral (ADEAR) Center
800-438-4380
adear@nia.nih.gov
www.nia.nih.gov/alzheimers
The NIA ADEAR Center offers information and free print publications about Alzheimer's and related dementias for families, caregivers, and health professionals. ADEAR Center staff answer telephone, email, and written requests and make referrals to local and national resources.

Alzheimers.gov
www.alzheimers.gov
Explore the Alzheimers.gov website for information and resources on Alzheimer's and related dementias from across the federal government.

This content is provided by the NIH National Institute on Aging (NIA). NIA scientists and other experts review this content to ensure it is accurate and up to date.

Many older adults worry about their memory and other thinking abilities. For example, they might be concerned about taking longer than before to learn new things, or they may sometimes forget to pay a bill. These changes are usually signs of mild forgetfulness - often a normal part of aging - not serious memory problems.

What's normal forgetfulness and what's not?

What's the difference between normal, age-related forgetfulness and a serious memory problem? It's normal to forget things once in a while as we age, but serious memory problems make it hard to do everyday things like driving, using the phone, and finding your way home.

Talk with your doctor to determine whether memory and other cognitive problems, such as the ability to clearly think and learn, are normal and what may be causing them.

Signs that it might be time to talk to a doctor include:

Asking the same questions over and over again

Getting lost in places a person knows well

Having trouble following recipes or directions

Becoming more confused about time, people, and places

Not taking care of oneself -eating poorly, not bathing, or behaving unsafely

Tips for dealing with forgetfulness

People with some forgetfulness can use a variety of techniques that may help them stay healthy and deal with changes in their memory and mental skills. Here are some tips:

Learn a new skill.

Follow a daily routine.

Plan tasks, make to-do lists, and use memory tools such as calendars and notes.

Put your wallet or purse, keys, phone, and glasses in the same place each day.

Stay involved in activities that can help both the mind and body.

Volunteer in your community, at a school, or at your place of worship.*

Spend time with friends and family.*

Get enough sleep, generally seven to eight hours each night.

Exercise and eat well.

Prevent or control high blood pressure.

Don't drink a lot of alcohol.

Get help if you feel depressed for weeks at a time.

Mild cognitive impairment

Some older adults have a condition called mild cognitive impairment, or MCI, meaning they have more memory or other thinking problems than other people their age. People with MCI can usually take care of themselves and do their normal activities. MCI may be an early sign of Alzheimer's disease, but not everyone with MCI will develop Alzheimer's.

Signs of MCI include:

Losing things often

Forgetting to go to important events or appointments

Having more trouble coming up with desired words than other people of the same age

If you have MCI, visit your doctor every six to 12 months to track changes in memory and other thinking skills over time. There may be habits and behaviors you can change and activities you can do to help you maintain memory and thinking skills.

Dementia and aging

Read and share this infographic to learn whether forgetfulness is a normal part of aging.

Dementia is not a normal part of aging. It includes the loss of cognitive functioning - thinking, remembering, learning, and reasoning - and behavioral abilities to the extent that it interferes with a person's quality of life and activities. Memory loss, though common, is not the only sign of dementia. People with dementia may also have problems with language skills, visual perception, or paying attention. Some people have personality changes.

While there are different forms of dementia, Alzheimer's disease is the most common form in people over age 65. The chart below explains some differences between normal signs of aging and Alzheimer's.

Normal aging

Alzheimer's disease

Making a bad decision once in a while

Making poor judgments and decisions a lot of the time

Missing a monthly payment

Problems taking care of monthly bills

Forgetting which day it is and remembering it later

Losing track of the date or time of year

Sometimes forgetting which word to use

Trouble having a conversation

Losing things from time to time

Misplacing things often and being unable to find them

When to visit the doctor for memory loss

If you, a family member, or friend has problems remembering recent events or thinking clearly, talk with a doctor. He or she may suggest a thorough checkup to see what might be causing the symptoms. You may also wish to talk with your doctor about opportunities to participate in research on cognitive health and aging.

At your doctor visit, he or she can perform tests and assessments, which may include a brain scan, to help determine the source of memory problems. Your doctor may also recommend you see a neurologist, a doctor who specializes in treating diseases of the brain and nervous system.

Memory and other thinking problems have many possible causes, including depression, an infection, or medication side effects. Sometimes, the problem can be treated, and cognition improves. Other times, the problem is a brain disorder, such as Alzheimer's disease, which cannot be reversed.

Finding the cause of the problems is important for determining the best course of action. Once you know the cause, you can make the right treatment plan. People with memory problems should make a follow-up appointment to check their memory every six to 12 months. They can ask a family member, friend, or the doctor's office to remind them if they're worried they'll forget.

Learn more about cognitive health and Alzheimer's and related dementias.

A note about unproven treatments

Some people are tempted by untried or unproven "cures" that claim to make the brain sharper or prevent dementia. Be cautious of pills, supplements, brain training computer games, or other products that promise to improve memory or prevent brain disorders. These might be unsafe, a waste of money, or both. They might even interfere with other medical treatments. Currently there is no drug or treatment that prevents Alzheimer's or related dementias.

However, there are currently several drugs available by prescription to safely treat the symptoms of early and mid-stage Alzheimer's. If you have been diagnosed with dementia, your doctor may suggest that you take one of them.

How to protect yourself and others from unproven treatments:

Beware if the product claim seems too promising and if it conflicts with what you've heard from your health care provider.

Question any product that claims to be a "scientific breakthrough." Companies marketing these products often take advantage of people when they are most vulnerable and looking for a miracle cure.

Check with your doctor or health care professional before buying any product, including those labeled as dietary supplements, that promises to improve your memory or prevent dementia.

Report any products or supplements being advertised as a treatment for Alzheimer's or other diseases on the U.S. Food and Drug Administration's website.

Read about this topic in Spanish. Lea sobre este tema en español.

For more information about memory loss and forgetfulness

NIA Alzheimer's and related Dementias Education and Referral (ADEAR) Center
800-438-4380
adear@nia.nih.gov
www.nia.nih.gov/alzheimers
The NIA ADEAR Center offers information and free print publications about Alzheimer's and related dementias for families, caregivers, and health professionals. ADEAR Center staff answer telephone, email, and written requests and make referrals to local and national resources.

Alzheimers.gov
www.alzheimers.gov
Explore the Alzheimers.gov website for information and resources on Alzheimer's and related dementias from across the federal government.

This content is provided by the NIH National Institute on Aging (NIA). NIA scientists and other experts review this content to ensure it is accurate and up to date.

# data[].attributes.attachment_link.title
Memory, Forgetfulness, and Aging: What's Normal and What's Not?

# data[].attributes.attachment_link.description
Many older adults worry about their memory and other thinking abilities. For example, they might be concerned about taking longer than before to learn new things, or they may sometimes forget to pay a bill.

# data[].attributes.attachment_link.description
Learn how to tell the difference between normal age-related memory loss and signs of a more serious problem like mild cognitive impairment or dementia. Sometimes, forgetfulness is caused by a treatable health condition.

# data[].attributes.attachment_link.provider_name
National Institute of Mental Health (NIMH)

# data[].attributes.attachment_link.readable_text
Working Memory is the active maintenance and flexible updating of goal/task relevant information (items, goals, strategies, etc.) in a form that has limited capacity and resists interference. These representations: may involve flexible binding of representations; may be characterized by the absence of external support for the internally maintained representations; and are frequently temporary, though this may be due to ongoing interference. It involves active maintenance, flexible updating, limited capacity, and interference control.

# data[].attributes.attachment_link.description
Working Memory is the active maintenance and flexible updating of goal/task relevant information (items, goals, strategies, etc.) in a form that has limited capacity and resists interference. These representations: may involve flexible binding of representations; may be characterized by the absence of external support for the internally maintained representations; and are frequently temporary, though this may be due to ongoing interference.

# data[].attributes.attachment_link.readable_text
As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health.
Learn more: PMC Disclaimer | PMC Copyright Notice

Abstract

One of the key goals of memory research is to develop a basic understanding of the nature and characteristics of memory processes and systems. Another important goal is to develop useful applications of basic research to everyday life. This editorial considers two lines of work that illustrate some of the prospects for applying memory research to everyday life: interpolated quizzing to enhance learning in educational settings, and specificity training to enhance memory and associated functions in individuals who have difficulties remembering details of their past experiences.

Keywords: memory, memory specificity, episodic simulation, neuroimaging, online learning, interpolated testing, mind wandering

The study of memory lias progressed rapidly over the past few decades, and as illustrated by the papers in the current issue, it remains a thriving endeavor with many exciting new discoveries and ideas. But memory is not only a target for laboratory study; it is also fundamentally important in many domains of everyday life. This point is nicely illustrated by several articles in this volume addressing memory changes in neurological and psychiatric conditions that can have a profound impact on an individual's ability to function in daily life. Memory research has also been applied extensively in legal settings, where such issues as how to construct effective lineups and how to deal with the inaccuracy of eyewitness testimony are of paramount importance.1,2 In this editorial, I discuss briefly some recent applications of memory research in educational and clinical settings that show promise for providing meaningful benefits in everyday life.

Enhancing attention and memory in educational settings

During the past several years, a rapidly expanding number of studies have attempted to apply principles and methods of cognitive psychology to educational settings. For example, one basic question concerns whether memory research can be used to increase the effectiveness with which students study for exams. In a recent comprehensive review, Dunlosky and colleagues3 evaluated the effectiveness of ten different study methods, and characterized each one as being of either high, moderate, or low utility based on available research. Some of the popular methods commonly embraced by students-including rereading, summarizing, and highlighting-received low utility assessments. Only two techniques, both supported by data from numerous laboratory studies, received high utility assessments: distributed study, which involves spreading out study activities so that more time intervenes between repetitions of the to-be-learned information (as opposed to mass study or "cramming"), and practice testing, where students are intermittently given brief quizzes about what they have learned prior to taking a formal test.

The beneficial effects of practice testing for students are based mainly on studies demonstrating that the act of retrieving information can be a highly effective means of strengthening memory for the retrieved information.4 Recent work in my laboratory has used a variant of the practice testing technique in an attempt to enhance attention and memory during video recorded lectures.5 Students frequently experience lapses of attention both during classroom6 and video7 lectures. For example, when probed during either a classroom or online lecture regarding whether they are attending to the lecture or mind wandering to other topics, students indicated on approximately 40% of probes that they were mind wandering; not surprisingly, the extent of mind wandering was negatively correlated with retention of lecture content.6-8

Our study5 focused on video recorded lectures because they are a key element in online education, which has exploded during recent years, partly as a result of the development of massive open online courses (MOOCs). Consequently, understanding how to enhance learning from video lectures could have important implications for online education. Participants watched a 21-minute video recorded statistics lecture divided into four equal segments. After each lecture segment, all participants did math problems for a minute, after which the tested group received brief quizzes on each lecture segment that took about 2 minutes each; the nontested group continued to work on math problems for an additional 2 minutes and only received a test for the final segment; and the restudy group was shown, but not tested on, the same material as the tested group for each of the segments preceding the final segment. After the final lecture segment, all three groups received a quiz for that segment, and a few minutes later they also received a final test for the entire lecture. At random times during the lecture, participants in all groups were probed about whether they were paying attention to the lecture or mind wandering off to other topics.

Participants in the nontested and re-study groups indicated that they were mind wandering in response to about 40% of the probes, but the incidence of mind wandering was cut in half, to about 20%, in the tested group. Moreover, participants in the tested group retained significantly more information from the final segment of the lecture than did participants in the other two groups, and they also retained significantly more information on the final test of the entire lecture than did the other groups. While it is encouraging that interpolated quizzing can dramatically reduce the incidence of mind wandering and increase retention, the results reported must be treated with some caution, both because they were obtained only with a single lecture on a single topic, and also because it is unclear whether the benefits of interpolated quizzing persist across multiple lectures or in actual online (or live) classes. There is reason for optimism, however, because other kinds of practice testing have produced increased learning in classroom settings.9

Increasing the specificity of memory

Consider next some recent research concerning a phenomenon that has been associated with a variety of troublesome symptoms in depressed individuals: reduced specificity of autobiographical memories. Several studies have shown that when asked to recall memories of everyday life experiences, depressed individuals tend to provide less specific detail about what happened during those experiences than do nondepressed controls.10 This reduced specificity has been linked with problems such as excessive rumination and difficulties handling everyday interpersonal situations.10-12 In light of these findings, a natural question concerns whether it is possible to increase memory specificity in depressed individuals, and whether such increases are associated with improvements in any of the problematic symptoms that had been linked with reduced memory specificity in previous research.

Recent studies13,14 have addressed this question by demonstrating that several sessions of training that attempts to boost the specificity of memory retrieval in depressed patients (ie, practice with feedback in generating detailed, specific memories) increases the posttraining specificity of patients' autobiographical memories, even when controlling for associated improvements in depression. Neshat-Doost et al13 reported that the gains from specificity training were maintained at a 2-month follow-up, and no improvements were evident in a control group. Raes et al14 showed that increases in memory specificity after training were associated with improvements in everyday social problem solving and rumination. Although further research needs to be carried out to pinpoint exactly what features of memory specificity training are responsible for the observed improvements, the results to date are encouraging, and highlight how basic knowledge of the memory characteristics of a clinical population can be used to formulate an effective intervention.

Targeting autobiographical memory specificity seems especially useful because a growing number of studies have emphasized that autobiographical or episodic memory is used not just as a basis for remembering past experiences, but also for imagining possible future experiences15 and related functions such as personal and social problem solving.16-19 Consistent with these findings, recent research in our lab provides evidence that an induction aimed at increasing memory specificity in young and old adults had beneficial effects on both groups' performance of subsequent tasks that required either remembering past experiences or imagining possible future experiences.20 Importantly, the effects of the induction were selective in two ways. First, the specificity induction (compared with a control induction) produced increases in the number of episodic details (eg, who, what, where, when) that participants remembered or imagined, but had no effect on the number of remembered or imagined semantic details (eg, general facts, commentary, impressions). Second, the influence of the specificity induction was restricted to memory and imagination tasks; it had no effect on a task that required participants to describe a picture of an everyday scene. These findings suggest that the induction targeted episodic memory in particular, and more generally, that specificity inductions can be used as experimental tools to distinguish among cognitive processes and representations that contribute to memory and related functions.

Concluding comments

The research reviewed in the preceding sections highlights ways in which memory research can be applied to educational and clinical settings. An important next step for this kind of research will be to investigate the neural mechanisms that mediate the observed effects on cognitive processes. How can we characterize the neural changes associated with improved attention and memory as a result of interpolated quizzing during lectures? What kinds of changes in brain activity are associated with the improvements produced by memory specificity training and how can they help to pinpoint the specific processes that are affected? Recent work in the domain of cognitive control has revealed that extensive training on a video game that requires multitasking skills led not only to improved cognitive performance in individuals ranging in age from their 20s to their 70s, but also to associated changes in brain activity that were predictive of cognitive improvements 6 months later.21 Moreover, the study also yielded evidence that training served to remediate age-related deficits in neural markers of cognitive control. Applying such a cognitive neuroscience approach to the phenomena considered here should enhance our understanding of both theoretical and applied aspects of memory function.

REFERENCES

2. Semrnler C., Brewer N. Eyewitness memory. In: Brown J, Campbell E, eds. . [ The Cambridge Handbook of Forensic Psychology. Cambridge, UK: Cambridge University Press; 2010:49-57. Google Scholar]

20. Madore KP., Gaesser B., Schacter DL. Constructive episodic simulation: Dissociable effects of a specificity induction on remembering, imagining, and describing in young and older adults. . [[ J Exp Psychol: Learn Mem Cogn. In press. PMC free article] [ PubMed] Google Scholar]

Articles from Dialogues in Clinical Neuroscience are provided here courtesy of Taylor & Francis

# data[].attributes.attachment_link.title
Memory: from the laboratory to everyday life

# data[].attributes.attachment_link.description
One of the key goals of memory research is to develop a basic understanding of the nature and characteristics of memory processes and systems. Another important goal is to develop useful applications of basic research to everyday life. This editorial ...

# data[].attributes.attachment_link.readable_text
NIH scientists discover that the resting brain repeatedly replays compressed memories of what was just practiced.

In a study of healthy volunteers, National Institutes of Health researchers have mapped out the brain activity that flows when we learn a new skill, such as playing a new song on the piano, and discovered why taking short breaks from practice is a key to learning. The researchers found that during rest the volunteers' brains rapidly and repeatedly replayed faster versions of the activity seen while they practiced typing a code. The more a volunteer replayed the activity the better they performed during subsequent practice sessions, suggesting rest strengthened memories.

"Our results support the idea that wakeful rest plays just as important a role as practice in learning a new skill. It appears to be the period when our brains compress and consolidate memories of what we just practiced," said Leonardo G. Cohen, M.D., senior investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published in Cell Reports. "Understanding this role of neural replay may not only help shape how we learn new skills but also how we help patients recover skills lost after neurological injury like stroke."

The study was conducted at the NIH Clinical Center. Dr. Cohen's team used a highly sensitive scanning technique, called magnetoencephalography, to record the brain waves of 33 healthy, right-handed volunteers as they learned to type a five-digit test code with their left hands. The subjects sat in a chair and under the scanner's long, cone-shaped cap. An experiment began when a subject was shown the code "41234" on a screen and asked to type it out as many times as possible for 10 seconds and then take a 10 second break. Subjects were asked to repeat this cycle of alternating practice and rest sessions a total of 35 times.

During the first few trials, the speed at which subjects correctly typed the code improved dramatically and then leveled off around the 11th cycle. In a previous study, led by former NIH postdoctoral fellow Marlene Bönstrup, M.D., Dr. Cohen's team showed that most of these gains happened during short rests, and not when the subjects were typing. Moreover, the gains were greater than those made after a night's sleep and were correlated with a decrease in the size of brain waves, called beta rhythms. In this new report, the researchers searched for something different in the subjects' brain waves.

"We wanted to explore the mechanisms behind memory strengthening seen during wakeful rest. Several forms of memory appear to rely on the replaying of neural activity, so we decided to test this idea out for procedural skill learning," said Ethan R. Buch, Ph.D., a staff scientist on Dr. Cohen's team and leader of the study.

To do this, Leonardo Claudino, Ph.D., a former postdoctoral fellow in Dr. Cohen's lab, helped Dr. Buch develop a computer program which allowed the team to decipher the brain wave activity associated with typing each number in the test code.

The program helped them discover that a much faster version - about 20 times faster - of the brain activity seen during typing was replayed during the rest periods. Over the course of the first eleven practice trials, these compressed versions of the activity were replayed many times - about 25 times - per rest period. This was two to three times more often than the activity seen during later rest periods or after the experiments had ended.

Interestingly, they found that the frequency of replay during rest predicted memory strengthening. In other words, the subjects whose brains replayed the typing activity more often showed greater jumps in performance after each trial than those who replayed it less often.

"During the early part of the learning curve we saw that wakeful rest replay was compressed in time, frequent, and a good predictor of variability in learning a new skill across individuals," said Dr. Buch. "This suggests that during wakeful rest the brain binds together the memories required to learn a new skill."

As expected, the team discovered that the replay activity often happened in the sensorimotor regions of the brain, which are responsible for controlling movements. However, they also saw activity in other brain regions, namely the hippocampus and entorhinal cortex.

"We were a bit surprised by these last results. Traditionally, it was thought that the hippocampus and entorhinal cortex may not play such a substantive role in procedural memory. In contrast, our results suggest that these regions are rapidly chattering with the sensorimotor cortex when learning these types of skills," said Dr. Cohen. "Overall, our results support the idea that manipulating replay activity during waking rest may be a powerful tool that researchers can use to help individuals learn new skills faster and possibly facilitate rehabilitation from stroke."

This study was supported by the NIH Intramural Research Program at the NINDS.

NINDS is the nation's leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
NIH...Turning Discovery Into Health®
###

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Study shows how taking short breaks may help our brains learn new skills

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NIH scientists discover that the resting brain repeatedly replays compressed memories of what was just practiced.

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from research organizations

Adolescence, like infancy, has been said to include distinct sensitive periods during which brain plasticity is heightened; but in a review of the neuroscience literature published on September 23 in Trends in Cognitive Sciences, University College London (UCL) researchers saw little evidence for this claim. However, a small number of studies do support that memory formation, social stress, and drug use are processed differently in the adolescent brain compared to other periods of life.

"Conclusively proving that adolescent sensitive periods exist will require studies comparing children, adolescents, and adults and will need to take into account individual differences in adolescent development," says Delia Fuhrmann, a PhD student in UCL's Institute of Cognitive Neuroscience Developmental Group. "Adolescents are much more likely than children to choose their own environments and choose what they want to experience."

Humans retain some plasticity--changes in brain and behavior in response to environmental demands, experiences, and physiological changes--throughout life. However, during sensitive periods plasticity is heightened and the brain "expects" to be exposed to a particular stimulus. For example, the brains of infants are primed to process visual input and language.

The ability to form memories seems to be augmented during adolescence, one example for how it may be a sensitive period. Memory tests in different cultures show a "reminiscence bump"; at 35 or later, we are more likely to recall autobiographic memories from ages 10 to 30 years than memories prior or subsequent. The recall of music, books, films, and public events from adolescence is also superior compared with that from other periods.

Further, they point out that simple aspects of working memory or ongoing information processing may reach maturity in childhood, while more complex, self-organized working memory abilities continue to improve during early adolescence and recruit frontal brain regions that are still developing. "Working memory can be trained in adolescents, but we don't know how these training effects differ from other age groups," Fuhrmann says. "Such data would be useful for planning curricula because it would tell us what to teach when."

Many mental illnesses have their onset in adolescence and early adulthood, possibly triggered by stress exposure. The UCL team explored studies indicating that both social stress and social exclusion have a disproportionate impact during adolescence. They also argue that adolescence may be a vulnerable period for recovery from these negative experiences.

"Adolescents are slower to forget frightening or negative memories," says Fuhrmann. "This might mean that some treatments for anxiety disorders, which are based on controlled exposure to whatever a patient is afraid of, might be less effective in adolescents and alternative treatments might be needed."

Finally, studies showed that adolescence is also a time of heightened engagement in risky health behaviors, such experimenting with alcohol and other drugs. Young adolescents seem to be particularly susceptible to peer influence on risk perception and risk taking compared with other age groups. Research in rodents also supports that adolescent brains might have an increased sensitivity to marijuana.
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Journal Reference:

Fuhrmann et al. Adolescence as a Sensitive Period of Brain Development. Trends in Cognitive Sciences, September 2015 DOI: 10.1016/j.tics.2015.07.008

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teen health; children's health; mental health research; psychology research; memory; intelligence; psychology; mental health

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Adolescent brain may be especially sensitive to new memories, social stress, and drug use

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Adolescence, like infancy, has been said to include distinct sensitive periods during which brain plasticity is heightened; but in a review of the neuroscience literature saw little evidence for this claim. However, a small number of studies do support that memory formation, social stress, and drug use are processed differently in the adolescent brain compared to other periods of life.

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Cognitive Development

Cognitive development refers to the development of the ability to think and reason.

Children (typically 6 to 12 years old) develop the ability to think in concrete ways (concrete operations), such as how to combine (addition), separate (subtract or divide), order (alphabetize and sort), and transform (5 pennies = 1 nickel) objects and actions. These processes are called concrete because they are performed in the presence of the objects and events being thought about.

Adolescence marks the beginning development of more complex thinking processes (also called formal logical operations) including abstract thinking (thinking about possibilities), the ability to reason from known principles (form own new ideas or questions), the ability to consider many points of view according to varying criteria (compare or debate ideas or opinions), and the ability to consider the process of thinking.

During adolescence (between 12 and 18 years of age), the developing teenager acquires the ability to think systematically about all logical relationships within a problem. The transition from concrete thinking to formal logical operations occurs over time.

Every adolescent progresses at varying rates in developing his / her ability to think in more complex ways. Each adolescent develops his / her own view of the world. Some adolescents may be able to apply logical operations to school work long before they are able to apply them to personal dilemmas.

When emotional issues arise, they often interfere with an adolescent's ability to think in more complex ways. The ability to consider possibilities, as well as facts, may influence decision making, in either positive or negative ways.

Some common features indicating a progression from more simple to more complex cognitive development include the following:

Early Adolescence

During early adolescence, the use of more complex thinking is focused on personal decision making in school and home environments, including the following:

Middle Adolescence

With some experience in using more complex thinking processes, the focus of middle adolescence often expands to include more philosophical and futuristic concerns, including the following:

Often questions and analyzes more extensively

Often analyzes more extensively

Thinks about and begins to form his / her own code of ethics (i.e., What do I think is right?)

Thinks about different possibilities and begins to develop own identity (i.e., Who am I?)

Thinks about and begins to systematically consider possible future goals (i.e., What do I want?)

Thinks about and begins to make his / her own plans

Begins to think long term

Use of systematic thinking to influence relationships with others

Late Adolescence

During late adolescence, complex thinking processes are used to focus on less self-centered concepts as well as personal decision making, including the following:

Increased thoughts about more global concepts such as justice, history and politics

Develops idealistic views on specific topics or concerns; debates and develops intolerance of opposing views

Begins to focus thinking on making career decisions

Begins to focus thinking on emerging role in adult society

The following suggestions will help to encourage positive and healthy cognitive development in the adolescent:

Assist adolescents in obtaining adequate sleep, hydration, and nutrition.

Include adolescents in discussions about a variety of topics, issues, and current events.

Encourage adolescents to share ideas and thoughts with adults.

Encourage adolescents to think independently and develop their own ideas.

Assist adolescents in setting their own goals.

Stimulate adolescents to think about possibilities of the future.

Compliment and praise adolescents for well-thought-out decisions.

Assist adolescents in re-evaluating poorly made decisions for themselves.

Cincinnati Children's has primary care services at locations in Avondale, Hopple Street, Fairfield, Hughes STEM High School, Rockdale Academy, South Avondale and Batesville & Greensburg, Ind.

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cognitive development thoughts processes conrete objects subjects children child teens teenagers future present past reasoning abstract thinking opinions emotions pediatrics health age cincinnati children's hospital medical center

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Cognitive development refers to the development of the ability to think and reason. Children (typically 6 to 12 years old) develop the ability to think in concrete ways (concrete operations), such as how to combine (addition), separate (subtract or divide), order (alphabetize and sort), and transform (5 pennies = 1 nickel) objects and actions.

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If you find it harder to focus your attention and absorb information as you age, you're not imagining it. Normal aging leads to gradual changes in many skills associated with thinking and memory. In fact, research shows that memory loss begins as early as age 45.

The slowdown in processing can lead to a bottleneck of information entering your short-term memory, reducing the amount of information that can be acquired and encoded into long-term memory.

The good news is that you can improve focus and attention. Try these four strategies to help you tune out distractions and improve your ability to focus in daily life:

1. When someone is talking to you, look at the person and listen closely. If you missed something that was said, ask the person to repeat it or to speak more slowly.

2. Paraphrase what was said to make sure you understand it and reinforce the information. For example, if someone says, "We can see the movie either at Loews Theater at 7:30 or at the Paramount at 7:50," you might respond, "Which would you prefer, 7:30 at Loews or 7:50 at the Paramount?"

3. If you find that you tend to become distracted during conversations, try getting together with people in quiet environments. For example, you could suggest meeting at someone's home instead of at a noisy restaurant. When you do meet people at a restaurant, sit at a table near a wall. If your companions sit against the wall and you sit facing them, you'll be able to focus on them without having your attention wander to other diners.

4. You can improve your ability to focus on a task and screen out distractions if you do one thing at a time. Try to avoid interruptions. For example, if someone asks you something while you're in the middle of reading or working, ask if the person can wait until you're finished. Don't answer the phone until you've finished what you're doing - let voice mail take the call.

For more on how to learning how to improve your memory, buy Improving Memory: Understanding age-related memory loss, a SHR from Harvard Medical School.

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4 ways to improve focus and memory - Harvard Health

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Normal aging leads to gradual changes in many skills associated with thinking and memory. But the following 4 strategies can help with improving your focus and ability to attend to the information presented to you.

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Memory loss: 7 tips to improve your memory

Try these simple ways to improve your memory.
By Mayo Clinic Staff
Can't find your car keys? Forget your grocery list? Can't remember the name of the personal trainer you liked at the gym? You're not alone. Everyone forgets things occasionally. Still, memory loss is nothing to take lightly.

Although there are no guarantees when it comes to preventing memory loss or dementia, certain activities might help. Consider seven simple ways to sharpen your memory - and know when to seek help for memory loss.

1. Include physical activity in your daily routine

Physical activity increases blood flow to your whole body, including your brain. This might help keep your memory sharp.

For most healthy adults, the Department of Health and Human Services recommends at least 150 minutes a week of moderate aerobic activity, such as brisk walking, or 75 minutes a week of vigorous aerobic activity, such as jogging - preferably spread throughout the week. If you don't have time for a full workout, squeeze in a few 10-minute walks throughout the day.

2. Stay mentally active

Just as physical activity helps keep your body in shape, mentally stimulating activities help keep your brain in shape - and might keep memory loss at bay. Do crossword puzzles. Play bridge. Take alternate routes when driving. Learn to play a musical instrument. Volunteer at a local school or community organization.

3. Socialize regularly

Social interaction helps ward off depression and stress, both of which can contribute to memory loss. Look for opportunities to get together with loved ones, friends and others - especially if you live alone.

4. Get organized

You're more likely to forget things if your home is cluttered and your notes are in disarray. Jot down tasks, appointments and other events in a special notebook, calendar or electronic planner.

You might even repeat each entry out loud as you jot it down to help cement it in your memory. Keep to-do lists current and check off items you've completed. Set aside a place for your wallet, keys, glasses and other essentials.

Limit distractions and don't do too many things at once. If you focus on the information that you're trying to retain, you're more likely to recall it later. It might also help to connect what you're trying to retain to a favorite song or another familiar concept.

5. Sleep well

Sleep plays an important role in helping you consolidate your memories, so you can recall them down the road. Make getting enough sleep a priority. Most adults need seven to nine hours of sleep a day.

6. Eat a healthy diet

A healthy diet might be as good for your brain as it is for your heart. Eat fruits, vegetables and whole grains. Choose low-fat protein sources, such as fish, beans and skinless poultry. What you drink counts, too. Too much alcohol can lead to confusion and memory loss. So can drug use.

7. Manage chronic conditions

Follow your doctor's treatment recommendations for medical conditions, such as depression, high blood pressure, high cholesterol, diabetes, obesity and hearing loss. The better you take care of yourself, the better your memory is likely to be. In addition, review your medications with your doctor regularly. Various medications can affect memory.

When to seek help for memory loss

If you're worried about memory loss - especially if memory loss affects your ability to complete your usual daily activities or if you notice your memory getting worse - talk to your doctor. He or she will likely do a physical exam, as well as check your memory and problem-solving skills.

Sometimes other tests are needed as well. Treatment will depend on what's contributing to your memory loss.

Show references

See more In-depth

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Memory loss: 7 tips to improve your memory

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Try these simple ways to improve your memory. By Mayo Clinic Staff Can't find your car keys? Forget your grocery list? Can't remember the name of the personal trainer you liked at the gym? You're not alone. Everyone forgets things occasionally. Still, memory loss is nothing to take lightly.

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Did you forget where you put your keys? It’s normal to forget things, but it can be a sign of memory problems. Read more on memory and memory loss.

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Abstract

Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings characterize sleep as a brain state optimizing memory consolidation, in opposition to the waking brain being optimized for encoding of memories. Consolidation originates from reactivation of recently encoded neuronal memory representations, which occur during SWS and transform respective representations for integration into long-term memory. Ensuing REM sleep may stabilize transformed memories. While elaborated with respect to hippocampus-dependent memories, the concept of an active redistribution of memory representations from networks serving as temporary store into long-term stores might hold also for non-hippocampus-dependent memory, and even for nonneuronal, i.e., immunological memories, giving rise to the idea that the offline consolidation of memory during sleep represents a principle of long-term memory formation established in quite different physiological systems.

I. INTRODUCTION

The capability to form memory is critical to the strategic adaptation of an organism to changing environmental demands. Observations indicating that sleep benefits memory date back to the beginning of experimental memory research, and since then have been fitted with quite different concepts. This review targets this field of "sleep and memory" research, which has experienced a unique renaissance during the last three decades. Although we have aimed at comprehensively covering the field, we might have missed out or overlooked some aspects, owing to the vast progress achieved in the last years. Before we begin, we will briefly introduce the core concepts of sleep and memory, respectively.

A. Sleep

Sleep is defined as a natural and reversible state of reduced responsiveness to external stimuli and relative inactivity, accompanied by a loss of consciousness. Sleep occurs in regular intervals and is homeostatically regulated, i.e., a loss or delay of sleep results in subsequently prolonged sleep ( 113). Sleep deprivation and sleep disruptions cause severe cognitive and emotional problems ( 142, 634, 1243), and animals deprived of sleep for several weeks show temperature and weight dysregulation and ultimately die of infections and tissue lesions ( 973). Sleep probably occurs in all vertebrates, including birds, fishes, and reptiles, and sleeplike states are similarly observed in invertebrates like flies, bees, and cockroaches ( 209).

Sleep in mammals consists of two core sleep stages: slow-wave sleep (SWS) and rapid-eye-movement (REM) sleep, which alternate in a cyclic manner (). In human nocturnal sleep, SWS is predominant during the early part and decreases in intensity and duration across the sleep period, whereas REM sleep becomes more intense and extensive towards the end of the sleep period. SWS is hallmarked by slow high-amplitude EEG oscillations (slow wave activity, SWA), whereas REM sleep (also termed paradoxical sleep) is characterized by wakelike fast and low-amplitude oscillatory brain activity. In addition, REM sleep is characterized by phasic REMs and by muscle atonia. Almost 50% of sleep in adult humans is marked by a lighter form of non-REM sleep (stage "N2") that is characterized by the occurrence of distinct (waxing and waning) sleep spindles and K-complexes in the EEG, but minor SWA. Sleep stage N2 is not discriminated from SWS in rodents.

B. Memory

1. Memory processes

To form and retrieve memories is a fundamental ability of any living organism, enabling it to adapt its behavior to the demands of an ever-changing environment, and allowing it to appropriately select and improve the behaviors of a given repertoire. Memory functions comprise three major subprocesses, i.e., encoding, consolidation, and retrieval. During encoding, the perception of a stimulus results in the formation of a new memory trace, which is initially highly susceptible to disturbing influences and decay, i.e., forgetting. During consolidation, the labile memory trace is gradually stabilized possibly involving multiple waves of short and long-term consolidation processes ( 803), which serve to strengthen and integrate the memory into preexisting knowledge networks. During retrieval, the stored memory is accessed and recalled. This review discusses sleep's critical role in the consolidation of memory. We assume that whereas the waking brain is optimized for the acute processing of external stimuli that involves the encoding of new information and memory retrieval, the sleeping brain provides optimal conditions for consolidation processes that integrate newly encoded memory into a long-term store. Encoding and consolidation might be mutually exclusive processes inasmuch they draw on overlapping neuronal resources. Thus sleep as a state of greatly reduced external information processing represents an optimal time window for consolidating memories.

At the neuronal level, memory formation is thought to be based on the change in the strength of synaptic connections in the network representing the memory. Encoding induces synaptic long-term potentiation (LTP) or long-term depression (LTD) as major forms of learning-induced synaptic plasticity ( 222, 527, 616, 629, 1209). Activity reverberating in the neuronal representation following encoding is thought to promote two kinds of consolidation processes, termed "synaptic consolidation" and "systems consolidation" ( 330). Synaptic consolidation leads to the remodeling of the synapses and spines of the neurons contributing to a memory representation, eventually producing enduring changes in the efficacy of the participating synapses (e.g., Refs. 555, 616, 977). System consolidation builds on synaptic consolidation and refers to processes in which reverberating activity in newly encoded representations stimulate a redistribution of the neuronal representations to other neuronal circuitries for long-term storage ( 418).

2. Memory systems

In neuropsychology, declarative and nondeclarative memory systems are distinguished depending on the critical involvement of medial temporal lobe regions, particularly of the hippocampus, in the acquisition of memory ( 1134). Declarative memory encompasses 1) episodic memories for events that are embedded in a spatiotemporal context (including autobiographical memories) and 2) semantic memories for facts that are stored independently of contextual knowledge ( 1218). Declarative memories can be encoded intentionally or unintentionally, but are typically explicitly (i.e., with awareness) accessible by active recall attempts. Episodic memories are learned very quickly, i.e., in one trial, but are also subject to fast forgetting ( 1332). Semantic memories can be regarded as a result of the repeated encoding or activation of overlapping episodic memories ( 1327). Integrity of hippocampal circuitry is a prerequisite for retaining an episode as well as spatial and temporal context information in memory for more than 15 min ( 231, 418).

In contrast to declarative memories, nondeclarative memories can be acquired without involvement of medial temporal lobe structures ( 1134). Nondeclarative memory encompasses quite different memory systems that rely on different areas of the brain. It includes procedural memories for motor skills (motor areas, striatum, cerebellum) and perceptual skills (sensory cortices), certain forms of conditioning and implicit learning (priming), etc. Nondeclarative memories can be implicitly (i.e., without awareness) acquired and recalled, and learning is slow, usually requiring multiple training trials. It is of note that experimentally disentangling nondeclarative from declarative memory processing is often complicated by the fact that these memory systems interact during acquisition of new knowledge in the healthy brain. Thus acquisition of skills like language learning and finger sequence tapping, especially at the initial stages, incorporates declarative in addition to procedural components ( 910).

II. OVERVIEW OF APPROACHES AND CONCEPTS

In this section, we review evidence from behavioral studies in support of the notion that sleep benefits memory consolidation. Key experiments for the different theoretical accounts and concepts will be described in more or less chronological order, thus complementing previous reviews of studies on sleep and memory ( 23, 49, 99, 116, 121, 125, 199, 200, 226, 246, 251, 293, 297, 319, 348, 377, 379, 411, 475, 524, 537, 538, 734, 765, 782, 807, 883, 894, 910, 915, 928, 957, 958, 967, 984, 988, 1001, 1025, 1092, 1094, 1096, 1098, 1149, 1151, 1152, 1156, 1202, 1242, 1279- 1281, 1283, 1289- 1291, 1305, 1321).

A. Sleep Acts by Passively Protecting Memory From Retroactive Interference

Memory research in the first half of the 20th century was preoccupied with the cause of forgetting. Two concepts were proposed, i.e., the "decay" account, assuming that memory traces decay over time resulting in time-dependent forgetting ( 1188), and the "interference" account, assuming that forgetting results from learning of new information which (retroactively) interferes and overwrites the old memory traces ( 806). In a classic study, Jenkins and Dallenbach ( 603) compared (in two participants, which were repeatedly examined every day and night over a period of almost 2 mo) the retention of nonsense syllables across 1-, 2-, 4-, and 8-h retention periods that were filled either with sleep or wakefulness (FIGURE 2 ). Sleep after learning reduced the amount of forgetting. Because the time retention interval was identical for the sleep and awake conditions, the authors concluded that "... results of our study as a whole indicate that forgetting is not so much a matter of the decay of old impressions and associations as it is a matter of interference, inhibition, or obliteration of the old by the new" (p. 612 in Ref. 603). Because sleep represents a time in which new encoding of external and, perhaps, also internal information is strongly reduced, the reduction of interference by sleep appears to be crucial. However, the findings by Jenkins and Dallenbach also pose a challenge to the interference theory, because learning of highly similar material did not occur during the waking periods in these studies. Interference is considered to depend on the similarity between learning and interference materials with stronger interference for highly similar tasks (see Ref. 632 for a review). Regardless of this issue, the findings were interpreted as evidence that any waking mental activity increases forgetting by a kind of nonspecific interference ( 1332).

A time dependency of the effects of sleep on memory formation is indicated by studies showing stronger effects for sleep occurring shortly after learning than for sleep at a later time ( 80, 343, 431, 899, 1172). For example, sleep occurring within 3 h after learning vocabulary was more beneficial than sleep delayed by more than 10 h ( 431). Furthermore, recall of word pairs after 24 h was better when sleep occurred immediately after learning than after a day of wakefulness ( 899). Importantly, because the time between learning and retrieval as well as the time spent sleeping was identical for the immediate versus delayed sleep conditions of these studies, the findings cannot be explained by interference reduction per se, but stress the importance of the timing of reduced interference with reference to the learning period. That sleep after learning actually benefits the consolidation of memories and strengthens memory traces against future interference was compellingly demonstrated by Ellenbogen and co-workers ( 346, 347). In two studies, they revealed that the enhancing effect on word recall of sleep compared with wakefulness was strongly enhanced when the subjects had learned an interference list shortly before final recall testing. Further studies confirmed that a 90-min sleep period as well as 60-min naps, both containing mainly SWS, likewise protect memory against future interference ( 18, 290, 1069).

In fact, recent versions of the interference account on sleep-associated memory consolidation have integrated this issue, assuming that sleep provides a time of reduced interference on consolidation processes, which per se are considered to be time dependent ( 809, 1332). Thus any treatment that reduces interfering influences on consolidation should be more effective the shorter it is applied after learning. Still, these interference accounts assume a passive "opportunistic" role of sleep in memory consolidation occurring regardless of whether the brain is asleep or awake ( 809). Yet, with the assumption that sleep generally reduces interference from encoding of external events, this theorizing is challenged by a great body of studies indicating a dependence of consolidation on the composition of sleep, with differential outcomes for sleep rich of REM sleep or SWS ( 63, 343, 408, 930, 931, 1048, 1340). Thus explaining the improving effect of sleep on memory retention solely on the basis of reduced interference appears to be untenable unless sleep stages are thought to differ in their degree of interference, e.g., owing to associated dreaming ( 408).

C. Sleep and the Erasure of Information: Accounts of Emotional Memory

The idea that sleep might be involved in the erasure or filtering of information has been put forward by several authors (e.g., Refs. 210, 236, 362, 369, 854). In particular in 1983, Crick and Mitchison ( 236) proposed, based on a neurocomputational model of associative learning, that dreaming during REM sleep helps to forget "parasitic modes" of activity, thus ensuring an efficient mode of operation of the brain during waking. Such parasitic modes of activity particularly occurred after stimulation overload and included "fantasy" (i.e., the net produces far-fetched and bizarre associations), "obsession" (i.e., iterates the same response, irrespective of input) and "hallucination"-like responses (i.e., responds to inappropriate input signals). As a solution to this problem, the authors proposed a "reverse learning" mechanism during REM sleep-dreaming that dampens synaptic weights to reduce the probability of these parasitic activity modes and thereby also enhances the efficacy and storage capacity of the network. Thus, according to this account, dreaming reduces unwanted and bizarre forms of representations in memory, which enhances new learning the next day as well as retrieval of memories acquired before sleep ( 237). In simulation studies, repeated unlearning procedures indeed improved the learning capability of the network and retrieval of recently learned patterns, but concurrently weakened more remote memories ( 564, 1237).

Although computational scientists agree in that a mechanism is necessary that limits the strength of synaptic weights in artificial neural networks, empirical evidence for the proposed function of REM sleep, specifically with regard to the removal of "unwanted modes" of activation, is so far lacking. Several authors have reported an influence of REM sleep on emotional reactivity or mood ( 490, 491, 1243), but a specific influence on "obsessive" or "hallucination"-like behaviors has not yet been tested. In contrast, after awakening from REM sleep, the brain appears to remain in a "hyperassociative" mode, in which weak semantic primes produced distinctly stronger priming effects than during consolidated wakefulness or after awakenings from non-REM sleep ( 1154). Similarly, REM sleep awakenings also resulted in a 32% increase in a complex anagram solving task ( 1288), and conversely, the need for creative thinking increased subsequent REM sleep ( 730). Furthermore, priming before naps filled with REM sleep had a much stronger impact on later creative answers compared with naps without REM or quiet resting, indicating that REM sleep improves creative problem solving instead of reducing creativity ( 163). In volunteers asked to voluntarily suppress "unwanted memories," sleep and particularly REM sleep appeared to counteract this suppression as reflected by an improved retrieval for previously suppressed items, rather than to enhance forgetting of these unwanted memories ( 381). Finally, repetitive nightmares, which are highly prevalent in patients suffering from posttraumatic stress disorders (PTSD), do not lead to forgetting of the traumatic event, but are rather associated with increased severity of the disorder and considered a risk factor in the development of PTSD ( 75, 1240, 1331). Overall, these findings speak against the view posed by Crick and Mitchison ( 236).

Of note, in other computational models the mechanisms limiting the strength of synaptic weights in the neural network have been linked to non-REM rather than REM sleep ( 210). A recent version of this idea is the "synaptic homeostasis hypothesis" ( 1203, 1204) which will be discussed in section IV B and assumes that a global downscaling in the strength of synaptic connections takes place during SWS to prevent saturation and to reduce place and energy demands, thereby preparing the network for the encoding of new information during succeeding wakefulness ( 565, 566).

If the emotional tone of a memory is considered an "unwanted activation," then the "sleep to forget sleep to remember" (SFSR) hypothesis recently proposed by Walker and van der Helm ( 1282, 1284) bears some similarities with the ideas about REM sleep by Crick and Mitchison. The SFSR hypothesis assumes that REM sleep after an (aversive) emotional experience strengthens the content of the respective representations in memory, but simultaneously reduces the emotional tone associated with this memory, i.e., reduces the emotional response when the memory is retrieved. The process is not restricted to one night after encoding, but would continue during multiple nights. In depressed patients showing enhanced REM sleep, according to the SFSR hypothesis, this enhancement would bias strengthening of memories towards increased storage of negative contents, while suppression of REM sleep through antidepressants counteracts this bias. The impairment of mood associated with this REM-related process might indicate that the attenuation of emotional tone by REM sleep is not functional in these patients. Similarly, in traumatized patients, increased nightmare frequency would point to a failure to attenuate memory-associated emotions during REM sleep.

However, there are also contradicting findings. For example, two studies have shown that memory recall of negative pictures is less impaired by sleep deprivation after encoding compared with neutral pictures, suggesting a reduced dependency of negative memories on sleep-dependent consolidation processes ( 46, 1147). With respect to emotional reactivity, one study showed that REM sleep-rich sleep amplified subjectively experienced aversion to previously viewed emotional pictures ( 1273). Conversely, selective REM sleep deprivation after picture viewing reduced arousal ratings to negative pictures presented again on the next morning ( 704). Others found that emotional reactivity decreased across wakefulness, but was preserved during sleep, with the preserving effect on emotional reactivity being specifically linked to REM sleep ( 60, 481). In addition, amygdala responses to correctly recognized emotional objects (with reference to neutral objects) increased rather than decreased after sleep, compared with an assessment after a wake retention interval ( 896). The increased amygdala response was accompanied by a stronger connectivity among limbic regions after sleep in this study. Sleep after fear conditioning in humans increases the conditioned response and the associated amygdala activity, with this enhancement being positively associated with postlearning REM sleep (Menz, Rihm, Born, Kalisch, Pape, Marshall, and Büchel, unpublished observation). Sleep likewise facilitated the generalization of implicit fear responses ( 678). In animals, REM sleep has been consistently associated with a strengthening of conditioned fear memories (see sect. II B; for reviews, see, e.g., Refs. 538, 807, 1092, 1094). Furthermore, a recent study points towards an involvement of adrenergic activity during SWS instead of REM sleep for the consolidation of emotional information ( 482). In conclusion, it is still an open question whether the consolidation of emotional memories actually differs in quality from that of neutral declarative memories, or whether it is the same consolidation process that is simply enhanced or accelerated by the emotional arousal that is attached to the representation at encoding.

F. The Active System Consolidation Hypothesis

The hypothesis that sleep supports the formation of long-term memory in an active system consolidation process has been elaborated in several previous reviews ( 293, 345, 734, 828, 957, 958, 984, 988, 1284, 1305). The hypothesis integrates aspects of both the dual-process view and the sequential hypothesis. Central to the "active system consolidation" hypothesis is the assumption that memory consolidation during sleep originates from the repeated reactivation of newly encoded memory representations. These reactivations occur during SWS and mediate the redistribution of the temporarily stored representations to long-term storage sites where they become integrated into preexisting long-term memories (). The slow oscillations during SWS drive the repeated reactivation of hippocampal memory representations during sharp wave-ripples (SW-Rs; ) in the hippocampus together with thalamo-cortical spindles, which are involved in inducing enduring plastic changes in cortical areas . Thus reactivation and integration of temporarily stored memories into long-term stores accompany a qualitative reorganization (transformation) of the memory representation (system consolidation) that needs to be stabilized in a synaptic consolidation process assumed to take place during succeeding periods of REM sleep. In claiming that memory consolidation during sleep is an active process, this hypothesis contrasts with accounts that sleep only passively or opportunistically supports consolidation processes mainly by providing a time of reduced interference ( 809, 1332).

2. Selectivity of memory consolidation during sleep

As another key feature, the "active system consolidation" concept implies that memory consolidation during sleep is selective. It is rather unlikely that off-line consolidation strengthens recently acquired memory traces and their synaptic connections globally, because such global and unselective strengthening would inevitably produce a system overflow. In support of this notion, a growing body of experiments indicates that sleep does not equally benefit all memories, although the mechanisms determining whether or not a certain memory gains access to offline consolidation during sleep are currently not well understood.

Collectively these findings indicate that consolidation processes acting during sleep are driven by motivational factors and specifically strengthen those memories, which are relevant for our goals and future behavior. However, the mechanisms underlying this selection process are unclear. Prefrontal cortex executive functions mediate the processing of anticipatory aspects of behavior and, in collaboration with the hippocampus, these prefrontal regions also regulate the implementation of anticipated memory retrieval as well as the allocation of relevance and expectancies to a memory ( 219, 511, 820, 938). In rats, prefrontal cell assemblies that fired during learning when EEG theta coherence between the prefrontal cortex and hippocampus was increased showed a distinctly increased probability to be reactivated during subsequent SWS ( 73). Thus theta coherence in the prefrontal-hippocampal circuitry during the encoding of explicit memories might be a critical factor that tags these memories for later consolidation during sleep, with the prefrontal-hippocampal circuitry integrating also emotional and reward-predicting aspects of the encoded events ( 74, 423, 782). Whether theta coherence likewise mediates tagging that occurred after actual encoding of the memory, i.e., in experiments where subjects were instructed about the future relevance of the learned material after the learning phase ( 380, 1319) remains to be investigated. However, theta-related tagging during encoding might represent a mechanism likewise mediating the preferential consolidation of emotional contents and reward-associated behaviors during sleep, as the network activated by theta also spans brain regions implicated in the processing of emotional stimuli and reward, such as the amygdala and ventral tegmental area, in addition to the prefrontal-hippocampal axis ( 423, 728, 887).

3. A model of active system consolidation during sleep

The findings discussed above have been used to essentially refine the model of active system consolidation, mainly with respect to memories that are explicitly encoded, via activation of prefrontal-hippocampal circuitry, in the hippocampus-dependent declarative memory system. Basically, the model assumes that during wakefulness the various aspects of an experienced episode are encoded into cortical networks with the different parts of the new memory representation bound together by areas in the medial temporal lobe, especially the hippocampus. During sleep, reactivation of the episodic memory originating from hippocampal networks results in the activation of the different memory parts also at the cortical level, thereby successively strengthening cortico-cortical connections and transforming the temporary representations into long-term memories ( 158). Because resources for the strengthening of synaptic connections are less available during SWS, reactivations during SWS might only tag the involved cortical synapses for later strengthening during subsequent REM sleep, in accordance with the sequential hypothesis ( 989).

III. MEMORY REACTIVATIONS DURING SLEEP

The assumption that memories are reactivated during the consolidation phase is an integral part of standard consolidation theory as well as of the "active system consolidation" view of the memory function of sleep ( 418, 780, 800) (see sect. II F). Reactivations of memory representations are thought to transform new memories that are still labile and prone to decay into stable memories that are preserved for the long-term. In the standard two-stage memory model, comprised of a fast encoding temporary store (hippocampus) and a slow-learning long-term store (neocortex, see sect. I B3), reactivations are regarded as critical for distributing the newly encoded memories to long-term storage sites. These reactivations occur repeatedly and offline (during sleep) to enable the gradual integration of the gist of the new representations into preexisting long-term memory networks, without overwriting these older memories. There is now ample evidence that reactivations of memories occur during sleep.

A. Animal Models

1. Reactivation of hippocampal place cells during sleep

Results from initial studies showing reactivation of assembly firing patterns during sleep were criticized because the tested animals were highly overtrained in the spatial tasks ( 538, 1204). Thus, when rats repeatedly perform stereotypical behaviors in a familiar environment, also the firing patterns during pretraining sleep periods become more similar to postsleep periods, and this similarity is reduced when the rat learns a new behavior ( 551). This discussion motivated several studies examining reactivations during sleep after rats had engaged in exploratory behavior involving the encoding of new information. These studies uniformly confirmed that signs of assembly reactivation occur in the hippocampus and several other regions of the brain also during sleep after exploration ( 870, 871, 985). Reactivations could last for more than 24 h, although in the earlier of these studies the data analysis was criticized on methodological grounds ( 1180). Neuron assemblies linked to place fields that were longer or more frequently explored during waking showed stronger reactivation during succeeding sleep ( 870, 871). Replay of hippocampal place cell assembly firing during sleep has been observed in many further studies, with the important findings summarized as follows (for detailed reviews, see Refs. 865, 1163): 1) during SWS, firing patterns observed during waking are replayed at a much faster (10-20 times) rate, suggesting a time-compressed form of memory reactivation ( 160, 551, 606, 715, 843, 1090); 2) replay activity is typically most prominent within the first 20-40 min of sleep or rest after learning and decays later ( 65, 673, 951, 1065, 1090), although in a few cases signs of hippocampal reactivation persisted for more than 24 h ( 985); and 3) in hippocampal neuron assemblies, reactivations are mostly observed in conjunction with SW-R ( 673, 849, 871), which are prominent oscillatory phenomena of the hippocampal EEG and occur in an irregular fashion mainly during SWS but also during quiet wakefulness (see sect. IV D).

2. Reactivation in nonhippocampal areas

4. Reactivation and behavioral relevance

IV. SLEEP-SPECIFIC ELECTRICAL OSCILLATIONS

Sleep and sleep stages are characterized by specific field potential rhythms of brain activity. Neocortical slow oscillations and SWA, thalamo-cortical spindles and hippocampal SW-R have been associated with processes of memory consolidation during SWS and might support the reactivation and redistribution of memory representations during this sleep stage. Theta rhythms and PGO waves have been proposed to support REM sleep-dependent processes of consolidation and might support enduring synaptic plastic changes during this sleep stage.

B. The Synaptic Homeostasis Hypothesis

1. The concept

The synaptic homeostasis hypothesis originated from Borbely's "two process" model of sleep ( 5, 8, 111, 112), assumes that, apart from a circadian process C, sleep and specifically SWS is regulated by a homeostatic process S, which rises during waking and declines during sleep. The most important marker of process S is SWA during non-REM sleep, which reliably increases as a function of time awake and shows an exponential decrease in the course of subsequent non-REM sleep. The synaptic homeostasis hypothesis basically links process S to processes of synaptic plasticity ( 1203, 1204). It relies on four key assumptions. First, it is assumed that wakefulness in general is a state of information intake and encoding that induces processes of LTP in cortical networks resulting in a net increase in synaptic weights. Second, it is assumed that SWA is a direct marker of the amount of synaptic potentiation during prior wakefulness such that "the higher the amount of synaptic potentiation in cortical circuits during wakefulness [is], the higher [is] the increase in slow wave activity during subsequent sleep" (p. 144 in Ref. 1203). Third, it is assumed that SWA is implicated in the downscaling of synaptic weights. As synapses are predominantly potentiated during wakefulness, such process would inevitably lead to increasing energy and space demands for permanently increased synaptic weights, ultimately saturating the network thus impairing further encoding of information. SWA and in particular the <1 Hz slow oscillations are assumed to proportionally downscale the potentiated synapses by a long-term depression-like mechanism, as neuronal firing at frequencies <1 Hz is known to preferentially induce long-term depression ( 630, 789). Moreover, down-states of neuronal silence following up-states of enhanced firing increase the probability that presynaptic input is not followed by any postsynaptic output, i.e., a mechanism leading to further depotentiation of the network. Also, the neuromodulatory milieu during SWS is characterized by low levels of acetylcholine, norepinephrine, and serotonin and therefore favors processes of depotentiation. The downscaling process, and in parallel the propensity for SWA, is self-limiting as synapses are gradually depotentiated, reaching a constant homeostatic level at the end of sleep. A computational model confirmed that a decrease in synaptic strength can fully account for the gradual decrease of SWA from the beginning to the end of the sleep period ( 360). Specifically, the model predicted a decrease in the incidence of high-amplitude slow waves, a decrease in slope, as well as an increase in the number of multipeak waves from early to late sleep, which was confirmed in related animal and human studies ( 994, 1269). Fourth, the synaptic homeostasis hypothesis assumes that memories are enhanced by sleep as a by-product of synaptic downscaling. During learning, correct (signal) as well as erroneous information (noise) is encoded, although the latter at a weaker strength. The proportional downscaling of synapses during SWS reduces the weights of weaker synapses below a threshold, making them completely ineffective, whereby the signal-to-noise ratio and the subsequent recall of the memory representation is enhanced.

The concept, and specifically the association of synaptic potentiation during wakefulness and subsequent SWA, was confirmed by several studies measuring markers of synaptic plasticity like plasticity-related genes [brain-derived neotrophic factor (BDNF), activity-regulated cytoskeleton-associated protein (arc), Homer, nerve-growth factor-induced gene A (NGFI-A)] ( 584). In rats, learning a reaching task increased the protein expression of two activity-dependent genes c- fos and arc in the motor cortex and increased subsequent SWA in the same brain region ( 510). Suppressing expression of LTP-related genes in rats by chronic lesion of the noradrenergic system produced a strong reduction in the homeostatic SWA response (see, e.g., Refs. 205 and 457, for similar results in flies). Levels of postsynaptic glutamatergic AMPA receptors containing the glutamate receptor (GluR1)-1 subunit reliably indicate synaptic plasticity and were revealed to be high during wakefulness and distinctly lower (by 40%) during sleep ( 1264). Correspondingly, results from a recent study suggest that discharge patterns of pyramidal neurons during SWS promote the removal of synaptic Ca ²⁺-permeable AMPA receptors in the somatosensory cortex of juvenile rats ( 701). Procedures assumed to induce local net increases in synaptic potentiation (e.g., the cortical application of BDNF and KCl) induced cortical spreading depression ( 81) and increased SWA during subsequent sleep, whereas BDNF receptor inhibition decreased SWA ( 366, 367). Importantly, in demonstrating that the encoding of information during waking enhances subsequent SWA in specific brain regions, these studies provide compelling evidence that SWA is regulated locally in addition to its global regulation by brain stem and diencephalic structures ( 672, 859, 975, 1267).

Supplementary evidence for sleep-associated synaptic downscaling was obtained in two recent studies measuring synaptic growth. Using staining techniques in fruit flies, Bushey et al. ( 156) showed that synapse size or number increased after a few hours of wakefulness and decreased only when flies were allowed to sleep. Increased synaptic growth due to an enriched wake experience (12 h spent together with 100 other flies) led to an increase in sleep with the time spent asleep after enriched experience being negatively correlated with spine density, suggesting that sleep renormalized synapses after potentiation during wakefulness. In juvenile mice in vivo, two-photon microscopy in the sensorimotor cortex revealed a net decrease in spine growth across periods of sleep, although there was also significant spine growth at the same time ( 772). In adult mice, no similar changes were observed.

Further support for a net increase in synaptic weights across the wake period and a decrease across sleep derives from measures of cortical excitability and actual firing rates which should be increased with net increases in synaptic strength. Indeed, in rats, slope and amplitude of the electrically evoked cortical potential as indicators of synaptic strength progressively increased during sustained wakefulness and decreased after sleep, and these changes were correlated with SWA ( 1264). In humans, cortical excitability as measured by a combined TMS/EEG study was increased after sustained wakefulness and decreased after sleep ( 71), although another study reported a decrease in TMS-induced cortical excitability after 40 h of sleep deprivation ( 445). Firing rates of cortical neurons were high after periods of sustained wakefulness and decreased during sleep, with the decrease correlating with SWA during sleep ( 1268). Miniature excitatory postsynaptic currents (mEPSC) are considered residual activity resulting from prior potentiating of synapses in the course of information encoding. Frequency and amplitude of mEPSCs were increased in the frontal cortex slices of mice and rats after prolonged wakefulness compared with slices obtained after sleep ( 740).

2. Critical issues

Although the synaptic homeostasis hypothesis integrates a wide variety of findings, especially on SWA, concerns have been raised about both the concept of downscaling in general, and specifically about how the theory explains sleep-dependent memory benefits. In light of clear evidence that learning during wakefulness relies both on LTP and LTD-like mechanisms (e.g., Refs. 222, 629) " ... it is thus most improbable that sleep need - to the extent this is determined by learning - is determined solely by Hebbian LTP (or any other single form of synaptic plasticity)" (p. 4 in Ref. 410). Also, molecular markers of synaptic potentiation like arc, BDNF or Calmodulin-dependent-kinase (CaMK) IV are involved in both the potentiation and depression of synaptic strength or other forms of non-Hebbian scaling ( 1026, 1067), questioning that the relative increase and decrease of these markers across sleep and wakefulness, respectively, is actually related to one specific form of synaptic plasticity. Furthermore, there is evidence that protein synthesis involved in LTP stabilization is enhanced during sleep, with the rate of synthesis linked particularly to SWS ( 848, 956, 1245) (see also effects of sleep on ocular dominance plasticity discussed in section VII A3). Recently, Chauvette and colleagues ( 187) showed in vivo that somatorsensory evoked potentials in cats were enhanced after a short period of SWS (about 5-10 min) compared with the previous wake period. Further experiments in vitro confirmed that the SWS-related enhancement in synaptic strength is a calcium-dependent postsynaptic mechanism which requires (i) the hyperpolarizing down-state of the slow oscillation and (ii) the coactivation of AMPA and NMDA receptors, suggesting that SWS is linked to synaptic potentiation rather than down-scaling ( 118). Related to that, although stimulation at the ∼1 Hz slow oscillation frequency typically induces LTD in vitro, in vivo such stimulation can remain ineffective or even induce LTP (e.g., Refs. 497, 919). In fact, the original concept of synaptic scaling as a self-tuning process of neuron networks assumes that periods of reduced synaptic activity, like sleep, produce net up-scaling rather than downscaling of synapses ( 409, 1219, 1220).

V. NEUROCHEMICAL SIGNALING AND MEMORY CONSOLIDATION DURING SLEEP

Sleep and sleep stages are characterized by a specific neurochemical milieu of neurotransmitters and hormones (see FIGURE 1 C), some of which contribute to memory consolidation by favoring processes of synaptic consolidation (i.e., synaptic LTP or synaptic LTD and depotentiation) or processes of system consolidation. Neurochemical studies of sleep-associated plasticity have taken two distinct approaches: 1) they have examined signals known to be essential for synaptic plasticity, such as glutamatergic synaptic transmission and the cascade of intracellular signaling mediating LTP, LTD, as well as changes in synaptic morphology thought to underlie long-term memory; or 2) they have examined signals known to be essentially involved in the regulation of sleep.

A. LTP/LTD During Sleep

Synaptic LTP and LTD are considered basic neurophysiological mechanisms underlying the formation of memory. LTP and LTD have been mainly studied in excitatory glutamatergic synapses but occur also in inhibitory GABAergic synapses. In glutamatergic synapses, LTP is induced via activation of postsynaptic NMDA receptors and subsequent calcium (Ca ²⁺) influx, which leads to activation of calcium-sensitive kinases like Ca ²⁺/calmodulin kinase II (CaMKII) and protein kinase C (PKC) that in turn activate transcription factors and immediate early genes that can eventually lead to an altered protein synthesis and resculpturing of synapses ( 4, 983). An early and late phase of LTP and LTD is discriminated with only late LTP (>3 h) requiring new protein synthesis. Maintenance of LTP, i.e., the development of late LTP from early LTP, is assumed to require a "tagging" of synapses due to associative heterosynaptic stimulation within a certain time window (∼30 min) following LTP induction ( 419). Heterosynaptic tagging can involve noradrenergic and dopaminergic transmission, but also the activation of mineralocorticoid receptors. The expression of BDNF and PKM-ζ are further important signals not only supporting induction of LTP but in particular for mediating the emergence of late LTP ( 746, 850, 1020).

It is likely that memory consolidation during sleep involves both synaptic and system consolidation processes ( 1305) (see sect. I B). Sleep might enhance memory by directly favoring late LTP and LTD in synaptic networks that were potentiated during the preceding wake phase. Alternatively, this form of synaptic consolidation may occur as part of a system consolidation process in which newly encoded memories are reactivated and redistributed to other networks during sleep where they subsequently undergo synaptic consolidation (see sect. II F). Considering that reactivation and redistribution of memory representations constitute a central mechanism of memory consolidation during sleep, then the basic question arises whether these reactivations during sleep can newly induce LTP and LTD or merely serve to support the maintenance of LTP and LTD induced during prior waking. These issues are presently far from being clear. Nevertheless, investigations of sleep-associated changes in the molecular signals that mediate the induction and maintenance of LTP and LTD have provided some important clues about possible contributions of sleep to persisting plastic synaptic changes. As discussed in section IV B, several studies show an increase in extracellular glutamate concentrations as well as molecular markers of LTP across wake periods and a decrease after sleep periods, particularly after SWS ( 204, 205, 207, 257, 457, 607, 940, 1264), suggesting that the induction of new LTP is more likely during wakefulness than sleep. While experimental induction of LTP and LTD is feasible during wakefulness and REM sleep, induction of long-lasting changes was less likely (although not impossible) during SWS ( 130). Sleep might, nonetheless, be critically involved in processes supporting the long-term maintenance of synaptic changes, particularly in those involving protein synthesis. More importantly, most of these studies assessed expression of the relevant signals on a global scale in large regions of the brain and cortex, and the extent of encoding of information, i.e., learning during wakefulness before sleep, was not systematically varied ( 989). Hence, this approach leaves open the basic question of how sleep specifically affects newly formed memory traces and underlying synaptic plasticity in discrete neuronal circuits.

1. Glutamate and intracellular PKA signaling

Blocking of ionotropic glutamate receptors during postlearning sleep was used as a pharmacological tool to study whether sleep-dependent memory consolidation involves the reactivation of glutamatergic synapses. Consistent with this hypothesis, in humans, blocking of NMDA or AMPA receptors by infusion of ketamine or caroverine during post-learning retention sleep completely abolished overnight gains on a visual texture discrimination task ( 435), presumably mediated by local synaptic plastic changes in the visual cortex ( 1049, 1051). Surprisingly, ketamine or caroverine administration during retention sleep did not impair consolidation of hippocampus-dependent declarative memories (word pairs) (unpublished observation). However, in these studies consolidation of word pair memories during sleep distinctly benefited from administration of d-cycloserine, a partial agonist of the NMDA receptor that acts at the glycine binding site to enhance Ca ²⁺ influx. These data suggest that the consolidation of hippocampus-dependent memory involves the reactivation of glutamatergic synapses, although the exact mechanisms of glutamatergic reactivation might differ between memories with primary hippocampal and primary neocortical representations.

In animals, sleep-dependent plastic changes were also revealed to critically depend on glutamatergic and LTP-related mechanisms ( 411, 1066). In the developing cortex of cats, ocular dominance plasticity induced by monocular deprivation of one eye requires sleep ( 77, 412, 413). These sleep-dependent changes are prevented by blocking NMDA receptors or cAMP-dependent protein kinase (PKA) during sleep after monocular experience ( 48) (see sect. VII A3). Blockade of NMDA and PKA signaling was associated with reduced activation of the kinases CaMKII and ERK as well as phosporylation of GluR1 at Ser831, i.e., processes that are critical to the insertion of AMPA receptors into the postsynaptic membrane and the strengthening and maintenance of LTP. In mice, treatment with the selective phosphodiesterases (PDE) 4 inhibitor rolipram immediately and 2.5 h after single-trial contextual fear conditioning prevented the impairing effect of sleep deprivation on retention of the freezing response to the conditioned context ( 1246). These observations corroborate the concept that impaired memory retention following sleep deprivation results from the disruption of the cAMP-PKA-CREB pathway that supports the formation of late LTP. Impaired signaling in this pathway originates from increases in PDE activity during sleep deprivation, with rolipram counteracting this process ( 477, 498- 500, 546, 1246). Based on this research, Abel and colleagues ( 546) suggested that cAMP-PKA dependent consolidation in the hippocampus occurs as a "sort of molecular replay" of the same molecular events recruited during prior encoding of information during wakefulness. This notion fits well to a model proposed earlier by Ribeiro and Nicolelis ( 988), suggesting that memory encoding during waking involves calcium-dependent genetic processes which trigger plasticity-related gene regulation during subsequent sleep. Similar ideas have been formulated by Benington and Frank ( 77) as well Datta and colleagues ( 261). The molecular replay may mainly occur during REM sleep enabled through coactivation of muscarinic receptors in the presence of high global cholinergic and low serotonergic activity, although it may similarly occur in local circuitry during non-REM sleep ( 475, 546).

Also, cAMP-PKA-dependent memory formation for contextual fear conditioning is selectively sensitive to the inhibition of PKA and protein synthesis when this inhibition occurs within specific time windows after training, i.e., immediately or 4 h after training ( 128). Correspondingly, specific time windows of increased REM sleep and sensitivity to REM sleep deprivation have been observed after learning of hippocampus-dependent tasks (Morris water maze with hidden platform, radial maze) ( 1115), and blockade of NMDA receptors shortly after these REM sleep windows disrupted sleep-dependent consolidation of these tasks ( 1094, 1099) (see sect. II B).

2. GABA

GABAergic inhibition via interneurons is embedded in almost all central nervous networks and contributes essentially to both the induction of sleep via brain stem and hypothalamic mechanisms, and the local control of LTP and LTD at glutamatergic synapses. GABAergic agonists, like benzodiazepines that are also used clinically to improve sleep, were consistently revealed to impair LTP as well as LTP-related plasticity in glutamatergic synapses via activation of the ionotropic GABA A receptor (e.g., Refs. 225, 277, 549, 575, 633, 1008, 1270). In addition, GABAergic synapses themselves undergo plastic changes that predominate during early development, but some of which can be observed in the mature brain as well ( 683). Yet, it is presently unclear how these processes contribute to hippocampal memory formation.

In humans and rats, systemic administration of agonistic modulators of the GABA A receptor, including barbiturates, benzodiazepines, and zolipedem, reduces sleep latency and consistently increases both sleep in non-REM stage 2 and sleep spindles, but typically simultaneously reduces SWS and SWA ( 684). This pattern diverges from the concordant increase in both spindles and SWA typically associated with memory processing during sleep following intense learning. Interestingly, nonspecifically enhancing availability of GABA in the synaptic cleft by administration of the GABA reuptake inhibitor tiagabin induced profound increases in SWS and SWA paralleled by marked declines in light sleep and REM sleep in both rats and humans, leaving spindle activity unaffected ( 686, 793, 1299, 1301). Selective GABA A or GABA B receptor agonists like gaboxadol, muscimol, or γ-hydroxybutyrate produced similarly robust increases in SWS and SWA, while effects on spindle activity differed between drugs ( 304, 684, 685, 702, 1228, 1297, 1298, 1300). At the network level, GABA A agonistic drugs like diazepam in slice preparations suppressed the generation of SW-Rs that are known to accompany the neuronal reactivation of newly encoded memory representations during SWS. The effect was dose-dependent and not observed following the GABA A-receptor modulator zolpidem ( 655). Conversely, the GABA A agonist muscimol and also zolpidem impaired sleep-dependent plastic changes in the visual cortex in a developmental model of synaptic plasticity in cats [i.e., ocular dominance plasticity (ODP); see sect. VII A3 for details] ( 48, 411, 1059), suggesting that GABA plays a critical role for plastic processes occurring during sleep.

GABAergic effects on sleep-dependent consolidation of memory in humans have not been thoroughly investigated thus far, which is surprising given that GABA-agonistic substances like benzodiazepines are widely used for the treatment of sleep disorders. Interestingly, there is rather consistent evidence that benzodiazepines administered after the encoding of information can enhance memory for this information in waking subjects, possibly by preventing the encoding of new interfering information after learning ( 247, 888, 1313, 1332). However, the few studies concentrating on memory consolidation during sleep point towards opposite effects. Early experiments in healthy volunteers suggested an impairing influence of the benzodiazepine trialzolam and the non-benzodiazepine zopiclone administered after learning before sleep on the retention of words ( 1040, 1082), whereas one study did not find an impairing effect of the hypnotics zolpidem and triazolam on sleep-dependent memory consolidation of words and nonwords ( 813). Administration of the GABA B agonists sodium oxybate or baclofen before a nap increased SWS, without affecting sleep-dependent declarative memory consolidation of word pairs and face-location associations ( 1255). In rats, administration of the GABA A agonists eszopiclone and zolipem after learning before sleep impaired contextual memory tested 24 h later ( 577). Two more recent studies in humans showed similarly impairing effects of triazolam and zolpidem on sleep-dependent consolidation of finger sequence tapping skills ( 835, 836). This is remarkable, as the impairment in motor skill consolidation was paralleled by robust increases in the amount of non-REM sleep stage 2 and spindle activity as well as REM sleep in these studies. Sleep-dependent consolidation of motor skill memories was also impaired following administration of the GABA reuptake inhibitor tiagabin, and this impairment was paralleled by a substantial increase in SWS and SWA ( 370). No effects on declarative memory consolidation (word pairs) were found in this study. The negative findings after benzodiazepine or tiagabin administration during postlearning sleep suggest that EEG phenomena-like spindles and SWA do not represent mechanisms that per se are sufficient to support sleep-dependent memory consolidation. Yet it is not clear whether pharmacologically induced spindles and SWA are functionally equivalent to their endogenous counterparts.

B. Neurotransmitters Involved in Sleep Regulation

Most neurotransmitters and neuromodulators involved in sleep regulation are also involved in processes of memory and plasticity, speaking in favor of a high degree of overlap and functional interaction between these processes. The regulation of sleep and wakefulness is based on a balanced interaction between wake-promoting networks centered in the upper brain stem and lateral hypothalamus and sleep-promoting networks in the anterior hypothalamus, which mutually inhibit each other to enable transitions into the respective brain states depending on a switchlike mechanism ( 146, 262, 1032). The wake-promoting network includes mainly cholinergic neurons of peduncolopontine and laterodorsal tegemental nuclei (PPT, LDT), the noradrenergic locus coeruleus (LC), and the serotonergic dorsal and median raphe nucleus, as well as histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN), which have widespread projections to the lateral hypothalamus, basal forebrain, and cerebral cortex. Activity in this network is reinforced by orexin A and B (hypocretin 1 and 2) producing neurons in the posterior lateral hypothalamus (adjacent to the TMN). The sleep-promoting network includes mainly the ventrolateral (VLPO) and median (MnPO) preoptic nuclei of the hypothalamus, which contain neurons releasing GABA and galanin to inhibit the wake-promoting network at all levels.

The sleep-promoting network is stimulated by neurons sensing astrocytic adenosine that accumulates extracellularly as a rundown product of cellular metabolism at least in some parts of the brain ( 78, 506, 942, 1160). Signaling of adenosine via A1 receptors, which are diffusely distributed in the brain, may directly inhibit neurons of the wake-promoting arousal system (e.g., Refs. 741, 867, 884). A2a receptors located close to the VLPO mediate a direct sleep-inducing effect that is counteracted by A2a-receptor blockers like caffeine ( 578, 1035).

Transitions between non-REM and REM sleep are mediated by a balanced interaction in brainstem pontine networks between GABAergic neurons in the sublaterodorsal region (precoeruleus) that fire during REM sleep (REM-on) and GABAergic neurons in the periaqueductal gray matter and the adjacent lateral pontine tegmentum (vlPAG, LPT) that fire during Non-REM sleep to inhibit the REM-on neurons. This core REM switch is in turn modulated by noradrenergic LC neurons and serotonergic neurons of the dorsal raphe nucleus that act on both sides of the switch to inhibit REM sleep and cholinergic neurons of the PPT and LDT promoting REM sleep. Via the same core REM switch, hypothalamic orexin neurons inhibit, whereas VLPO neurons promote REM sleep ( 1032).

As a result of this regulation of non-REM and REM sleep, widespread changes in activity occur also for the wake promoting neuromodulators, mainly activity of acetylcholine, norepinephrine, and serotonin. Cholinergic activity reaches a minimum during SWS, whereas during REM sleep it reaches levels well comparable or even higher compared with cholinergic activity during wakefulness. Noradrenergic and serotonergic activity reaches a minimum during REM sleep, and is at an intermediate level during SWS. At the neurohormonal level, early periods of SWS are associated with a strong activation of somatotropic activity, whereas late periods of REM sleep are characterized by an increased release of corticosteroids from the adrenals.

2. Neuromodulation associated with sleep and SWS, and memory processing

The neuromodulatory changes characterizing SWS are indeed the same that accompany the induction of sleep. Studies specifically targeting the role of neurochemical conditions during SWS for memory processing have so far concentrated on astrocytic adenosine signaling, the minimum levels of cholinergic activity and intermediate-level, pulsatile activity of noradrenergic systems during SWS, as well as on SWS-related changes in hormonal systems.

Suppression of cholinergic activity during SWS alleviates tonic inhibition of hippocampal CA3 and CA1 feedback neurons, thereby it enables spontaneous reactivations of the hippocampal networks and of the memory information encoded in these networks, as well as the transfer of the reactivated information to neocortical networks (; Refs. 520, 522, 782). Consistent with this concept of low acetylcholine enabling systems consolidation of declarative memories, increasing cholinergic tone during a period of SWS-rich sleep by administration of the cholinesterase inhibitor physostigmine completely blocked the sleep-associated consolidation of word pair memories (; Refs. 429, 963). Some subjects showed slight decreases in SWA after physostigmine, but these were unrelated to the impairment in declarative memory consolidation, suggesting that cholinesterase inhibition primarily affected memory processing in hippocampal rather than thalamo-cortical circuitry. Conversely, blocking cholinergic receptors in waking subjects by simultaneous administration of nicotinic and muscarinic receptor antagonists improved the consolidation of declarative memories during wakefulness, but concomitantly decreased the ability to encode new information ( 963). These results strongly support the notion that high acetylcholine levels are critical for successful encoding, whereas low acetylcholine levels facilitate consolidation of memories, suggesting that acetylcholine might function as a switch between brain modes of encoding and consolidation as established during waking and SWS, respectively ( 522). Manipulating solely nicotinic or muscarinic receptor activity remained ineffective in these studies ( 864, 963). Since the cholinergic neurons mediating the recurrent inhibition in hippocampus receive strong inhibitory GABAergic inputs, strengthening this GABAergic activity should enhance hippocampal memory reactivation. This mechanism could explain why postlearning administration of benzodiazepines improves memory consolidation in waking subjects but not during SWS when cholinergic activity is already minimal ( 454, 813).

Noradrenergic activity during SWS, arising from the LC as the brain's main source of norepinephrine, seems to be particularly related to the depolarizing up-state of the slow oscillations as LC firing has been found to be entrained to these up-states ( 353). Moreover, a specific sleep-related window of increased LC burst activity ∼120 min after learning of odor-reward associations has been identified in rats ( 356). In humans, suppressing noradrenergic LC output by administration of the alpha2-autoreceptor agonist clonidine during a SWS-rich retention period reduced consolidation of odor memories, whereas the retention of these memories was enhanced when availability of epinephrine during sleep was increased ( 434). In a subsequent study, clonidine infused during a SWS-rich period of retention sleep appeared to impair specifically emotional memory processing ( 1031). Whereas temporal order of emotional stories was better remembered compared with neutral stories in the placebo condition, clonidine blocked this superiority of emotional memory consolidation during SWS-rich sleep. Together, these findings suggest that bursts of noradrenergic activity during SWS are particularly important for the consolidation of memories that involve both a strong amygdala-mediated emotional component as well as a hippocampus-mediated declarative component, as keeping temporal order in the events of an episode represents a key function of the hippocampal formation (e.g., Refs. 285, 722, 761). Phasic burst of noradrenergic LC activity can enforce plasticity-related immediate early gene activity ( 207, 208), and thereby contribute to LTP maintenance in circuitries that were potentiated during prior encoding. In the case of odor and emotional memories, these representations may partly reside in the basolateral amygdala as a main target of noradrenergic influences ( 804).

4. Neuro- and hormonal modulation associated with REM sleep, and memory

Cholinergic activity during REM sleep is high and comparable with that during waking, which might be particularly relevant for the consolidation of procedural memories during this sleep stage. Blocking muscarinic cholinergic receptors during "REM sleep windows" (i.e., time periods after learning in which REM sleep deprivation effectively impaired consolidation of respective materials, see sect. II B) by administration of scopolamine consistently impaired memory in a habit learning version of the radial arm maze ( 720, 721). Infusion of scopolamine into the dorsal striatum, a structure specifically involved in habit and skill learning, was particularly effective. In humans, the combined blockade of nicotinic and muscarinic receptors during REM-rich late sleep impaired off-line consolidation of a motor skill (finger sequence tapping) without affecting declarative memories ( 961). Conversely, increasing the availability of acetylcholine during post-training sleep by administration of an acetylcholinesterase inhibitor enhanced sleep-related benefits in a skill learning task ( 570). Anticholinergic treatment during wakefulness after learning remained ineffective ( 961). Taken together, these results identify high cholinergic tone as an important factor contributing to the off-line consolidation of procedural skills during REM sleep, in combination with other unknown processes. The effects are consistent with a role of acetylcholine in synaptic consolidation, e.g., by promoting activity of plasticity-related immediate early genes ( 475, 615, 1182) and maintenance of LTP in cortico-striatal networks ( 742).

It has been proposed that the inhibition of noradrenergic activity during REM sleep enhances procedural types of memory representations in cortico-striatal circuitry by enabling spontaneous reactivations in cortical networks that during wakefulness are under tonic inhibitory control by noradrenergic neurons ( 520). Similarly, it has been suggested that REM sleep allows for a replay of amygdala-dependent emotional memories that, in the absence of noradrenergic activation, decrease the emotional tone in these memories, whereas their information content is maintained ( 1294) (see sect. II C). Additionally, the decreasing effect on emotional tone could be further enhanced by glucocorticoids, the levels of which are distinctly increased during late-night REM sleep and which distinctly diminish emotional memory consolidation ( 1272). However, there is presently little empirical support for these theories. Thus, overall, the role of noradrenergic and serotonergic inhibition during REM sleep for memory processing remains enigmatic.

VI. GENETIC APPROACHES TO SLEEP-DEPENDENT MEMORY FORMATION

Sleep is genetically controlled. Although environmental factors clearly contribute, a large part of the interindividual differences in sleep architecture is likely due to genetic factors. The search for genes involved in sleep regulation has received a great boost in recent years with the discovery of quiescent states in simple organisms like the fruit fly and worms that fulfill the criteria for sleep: a reversible and repeatedly occurring period of reduced responsiveness and relative inactivity which is homeostatically regulated (i.e., deprivation of sleep leads to subsequent longer sleep periods) ( 209). In these organisms, molecular methodology can be applied much more efficiently and at low costs mainly due to the reduced number of genes and neurons and the high reproduction rate. However, there are also important caveats, as certain sleep stages (e.g., REM sleep) and oscillatory brain activity characterizing sleep in mammals and humans cannot be discriminated in these simple organisms. Also, although typically homologs of genes exist between species, they can be much more differentiated in complex animals. For example, one Shaker gene in the fly has 16 homologs in rodents ( 202). These limitations underscore the importance of genetic studies in rats and mice and optimally in humans.

A. Animal Models

Gene expression studies, mainly in flies and mice, show an upregulation of genes specifically during sleep, including genes involved in protein synthesis and synaptic depotentiation. In addition, several genes related to neural plasticity and synaptic potentiation are upregulated during sleep depending on prior learning and exposure to novel experiences. Also, genes have been identified that exhibit joint regulatory actions on sleep and memory. Intriguingly, short-sleeping genotypes often also show impairments in learning and memory.

1. Differential gene expression during sleep and wakefulness

Early studies suggesting that gene expression differs between sleep and wakefulness mainly examined overall changes in mRNA and protein synthesis. First experiments showed that an injected radioactive substance was incorporated into newly synthesized RNA at a faster rate during sleep than during wakefulness ( 462, 1257). Similarly, labeled proteins in rats increased after 90 min of sleep compared with 90 min of sleep deprivation ( 103). In rats and monkeys, the rate of protein synthesis correlated positively with the amount of non-REM sleep ( 848, 956). Analysis of several hundreds of proteins by mass spectrometry ( 309) revealed that protein levels in the mouse cerebral cortex were generally decreased after sleep deprivation compared with sleep. These studies indicate that sleep favors protein synthesis, thus pointing towards a differential expression of genes during sleep and wakefulness. Indeed, blocking protein synthesis during sleep impairs sleep-dependent consolidation of ocular dominance plasticity (ODP) in the visual cortex of cats ( 1060) (see sect. VII A3), indicating that the increased protein synthesis during sleep has functional consequences for plastic processes underlying memory formation.

Importantly, one category of gene transcripts upregulated during sleep is involved in synaptic plasticity. This includes mRNA expression levels of calmodulin-dependent protein kinase IV (CAMK4), a gene that is implicated in synaptic depression and long-term memory consolidation ( 617), and the expression of several other genes associated with depotentiation and depression of synaptic strength. In contrast, during wakefulness, expression of genes that are involved in LTP is upregulated, including genes coding for Arc, c-Fos, NGFI-A, and BDNF ( 206, 939, 940). Based essentially on these gene expression patterns, the synaptic homeostasis hypothesis has been proposed assuming that wakefulness is associated with prevailing synaptic potentiation in cortical networks, whereas processes of synaptic depotentiation and depression predominate during sleep to desaturate the network ( 1204) (see sect. IV B). Subsequent microarray studies in the mouse and fruit fly largely confirmed that expression of several genes is differentially regulated during sleep and waking and that these genes are related to synaptic plasticity, response to cellular stress, energy and lipid metabolism, and membrane trafficking ( 201, 610, 752, 753, 771, 1357). In particular, the expression of genes involved in macromolecular synthesis increased during sleep, supporting a role for sleep in the synthesis of proteins and lipids (e.g., fats, sterols, vitamins) ( 753). Conversely, sleep deprivation strongly attenuates the expression of genes related to protein synthesis and thus downregulated translation in the mouse hippocampus, mainly mediated by key regulators of protein synthesis like mammalian target of rapamycin (mTOR) ( 1247). In the developing visual cortex in cats, expression of LTP-promoting genes (e.g., Arc, BDNF) was likewise found to decrease across sleep in the visual cortex as in adult rodents ( 1060) (see sect. VII A3). Notably, however, translation of the corresponding proteins at the same time was increased particularly during early sleep, suggesting that the first hours of sleep might be a period of accelerated protein synthesis in these networks.

2. Experience-dependent local regulation of genes

Exposure to novel tactile stimuli as well as experimental induction of hippocampal LTP during wakefulness produced an upregulation of Arc and Egr-1 in neocortical and hippocampal regions during subsequent REM sleep ( 986, 987, 989). The reinduction of both immediate early genes during REM sleep after novelty exposure was only transient in hippocampal regions, and more pronounced and persistent in the neocortex, where it was particularly strong in the somatosensory areas most activated by the previous tactile novelty experience ( 986, 989). Cortical expression of Arc was correlated to EEG spindle activity during prior non-REM sleep, possibly favoring immediate early gene activity during REM via Ca ²⁺-dependent mechanisms ( 989). Spindles likely promote massive calcium influx into cortical pyramidal cells and through activation of CaMKII may set the stage for the expression of immediate early genes during ensuing REM sleep ( 283, 1061). Both Arc as well as Egr-1 are known to interact with CaMKII in synaptic remodeling during LTP. Ribeiro et al. ( 989) related the REM sleep-associated increase in immediate early gene expression occurring preferentially in cortical over hippocampal regions to waves of synaptic plasticity that hippocampus-dependent memories undergo during successive non-REM-REM sleep cycles (see FIGURE 7 , A AND B). Reactivation of hippocampal memory representations during non-REM sleep stimulate the redistribution of these memories to neocortical areas where they are synaptically consolidated during ensuing REM sleep ( 293). Across several waves of plasticity associated with the non-REM-REM sleep cycles, memories become stored mainly within neocortical networks while they fade out in the hippocampus, the latter coinciding with the fading of reinduction of immediate early gene activity during postencoding REM sleep in hippocampal areas .

3. Deletion and gene knockout studies

In flies, several genes that regulate the amount of sleep have been identified by mutagenesis screenings. Whereas wild-type flies sleep ∼8-10 h/day, flies with a loss-of-function mutation in the genes Shaker (Sh) or hyperkinetic (Hk) sleep only 2-4 h/day ( 154, 202, 203). Shaker codes for the alpha subunit of a specific K⁺ channel (alpha-subunit of a tetrameric potassium channel that mediates a voltage-activated fast inactivating IA current), and hyperkinetic codes for a regulatory beta-subunit of this channel that interacts with the alpha-subunits encoded by Shaker ( 202, 1052). Shaker-modulated K⁺ channels have homologs in vertebrates (Kv.1 and other Shaker-like channels, Kv.2, Kv.3, Kv.4, etc.). In both flies and mammals, they play a major role in membrane repolarization and likely also modulate EEG oscillatory phenomena like spindles ( 35, 155, 244, 320, 357, 358, 717, 934, 1266). Importantly, both Shaker and hyperkinetic mutants showed marked impairments in learning and memory, as well as a reduced life span. Similarly, reduced sleep and life span have been reported for flies with a loss of the gene Sleepless (SSS) which codes for glycosylphosphatidylinositol-anchored protein with unknown function, with the effects of this mutation possibly in part also mediated by Shaker channels ( 202, 272, 653, 1306, 1337). However, its influence on learning and memory has not been investigated so far.

There is strong evidence for an involvement of clock genes in sleep-dependent plasticity. Clock genes regulate the circadian rhythm and affect sleep ( 681). In mammals, genetic variations in both clock genes activating circadian rhythm, like Clock (Clk) and cycle (cyc), and clock genes with repressing functions on circadian rhythm, like period (per) and Cryptochrome (Cry), have been linked to variations in sleep ( 663, 703, 851, 1073, 1328, 1329), whereas in flies only the activators Clk and cyc affect sleep phenotypes ( 531). Per, which is regulated by CREB, plays a key role in long-term memory formation in Drosophila ( 1023). Recent studies in fruit flies by Shaw and colleagues revealed that per, together with other clock genes, also regulates sleep-dependent memory formation ( 314, 438). These studies first established that waking experience, i.e., a socially enriched environment where the flies were housed in groups of ∼40, compared with social isolation increased sleep time and sleep bout duration ( 315). Sleep need likewise increased after a learning task (conditioned suppression of courtship behavior), and this increase in sleep was critical for successful recall of the conditioned behavior 48 h later ( 314, 438). Remarkably, flies mutant in the clock gene per failed to show this experience-dependent increase in sleep need and in parallel showed no long-term memory after 48 h. Similar results were observed in flies with mutations in the rutabaga gene (involved in cAMP signaling) and blistered (involved in synaptic LTP and contextual habituation). Rescue of the genes in clock neurons of the flies reestablished the experience-dependent increase in sleep as well as long-term memory ( 314).

Several other genes and transcripts have been identified that not only strongly influence sleep quantity, but also are involved in major pathways regulating synaptic plasticity, like CREB ( 477, 532, 916), the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK), and the epidermal growth factor (EGF) (e.g., Ref. 401, for a review see Ref. 202). However, direct links between sleep and memory formation have not been demonstrated for most of these signals. An exception is the gene bunched, a regulator of the transmembrane receptor Notch which is involved in both sleep homeostasis and learning in flies ( 1062). Overexpression of the Notch ligand Delta as well as the introduction of a Notch gain-of-function allele reduced sleep rebound and prevented impairments in new learning (aversive phototaxic suppression) induced by prior sleep deprivation. Interestingly, the effects on sleep and memory of Notch signaling were mainly observed in glia cells, pointing to a critical role of neuron-glia interactions for regulating sleep-dependent learning benefits ( 1338). Similar effects of Notch signaling were observed in worms ( Caenorhabditis elegans) ( 1085).

Knockout procedures have also been used in numerous studies as a genetic tool to examine the impact of neurotransmitter systems on sleep regulation (reviewed in Ref. 202; see also sect. V B) and oscillatory EEG activity during sleep (reviewed in Ref. 37; see also sect. IV). For example, a genetic region on chromosome 13 (containing several genes) was identified by quantitative trait loci analysis (QTL) that explained almost 50% of the variance in the rebound in non-REM sleep EEG delta activity after sleep deprivation in rodents ( 414). However, for none of these genes have any links to sleep-dependent memory formation been examined in a more systematic manner.

3. Heat-induced sleep in transgenic animals

Using a similar approach, Donlea et al. ( 316) introduced a temperature-sensitive cation channel in neurons of Drosophila. Activating the channel by raising temperature above 31°C resulted in a sleeplike state. Inducing 4 h of sleep in this way after massed trials on a courtship conditioning procedure enhanced retention of the conditioned behavior at a retest 48 h later, compared with flies that did not sleep after training. The effect cannot be explained by an activation of the temperature-gated neurons per se, because sleep deprivation during periods of high temperature did not enhance long-term memory. Of note, temperature-induced sleep also benefited new learning on the next day, fitting the idea that memory consolidation during sleep is concurrently linked to processes preparing the brain for the future encoding of new information ( 828).

B. Human Studies

1. Stability and heritability of sleep

Human sleep and particularly oscillatory EEG activity during sleep is highly heritable and very stable within individuals ( 689). In addition, large interindividual differences in the sleep EEG exist, which are more than 10 times higher than those, observed within subjects across multiple nights of sleep. Already in 1937, Geyer ( 453) reported a higher similarity in sleep profiles for monozygotic compared with dizygotic twins. Systematic twin studies using large samples indicate that genetic differences account for 30-45% of the variance in subjective sleep quality and sleep disturbances ( 186, 526, 889) and for ∼50% in physiological measures of sleep stages ( 137, 737, 738). Highest heritability values are observed for REM density (h ² = 64-95%) as well as EEG spectral power particularly in the alpha (8-11 Hz) and spindle (11-15 Hz) frequency bands (h ² = 76-96%) ( 29, 266, 444, 736, 1227). Similar heritability estimates (h ² = 40-60%) have been reported for sleep amount and sleep organization in rodents ( 1165, 1166, 1226), with even higher estimates of genetic control for oscillatory electrical activity during sleep ( 37, 414, 416, 417).

2. Genetics, sleep and cognitive function

Studies in healthy humans revealed clear associations between sleep and genes involved in regulating circadian rhythm, mainly the clock gene PER3 that can occur in a different number of repetitions, so-called "variable number of tandem repeats" (VNTR) polymorphisms. Homozygosis for the 5-repeat allele (PER3 5/5) has been repeatedly associated with morning preferences (morning types) compared with homozygotes for the 4-repeat allele (PER3 4/4) and heterozygotes (PER3 4/5) ( 41, 61, 349, 609, 874, 917), as well as with increased SWS percentage and SWA during non-REM sleep and increased theta power during REM sleep and wakefulness ( 1256). In addition, PER3 5/5 carriers were more vulnerable to sleep deprivation in the early morning hours (e.g., Refs. 1256 and 483, but see Ref. 467) and exhibited a stronger decrease in brain activity assessed by fMRI in prefrontal areas from morning to evening ( 1244). Altogether, these findings suggest that circadian genotypes contribute to differences in the allocation of cognitive resources, thus possibly also affecting memory processing during sleep.

With regard to noncircadian genes, Landolt and co-workers identified a genetic difference (G->A transition at codon 22) in the gene encoding the adenosine metabolizing enzyme (adenosine deaminase, ADA) that was significantly associated with SWS duration and SWA, in particular in the <2 Hz range (e.g., Refs. 54, 798, 982; but see Ref. 797). A-allele carriers who exhibited more SWS also showed poorer performance in focused attention (as indicated by the d2 test), but not in several other tests of short-term memory and executive functions (verbal, figural memory, digit span, Stroop test. etc.) (see Ref. 688 for a review).

Differences in the widely researched functional Val158Met polymorphism in the gene coding for the catechol- O-methlytransferase (COMT) were associated with more global alterations in alpha peak frequency as well as in spectral power in the 11-13 Hz band, occurring during REM, non-REM sleep, and also during wakefulness ( 104, 105). Investigation of the Val66Met polymorphism, i.e., a valine to methionine amino acid substitution at codon 66 of the BDNF gene, revealed that Met-allele carriers (compared with Val/Val homozygotes) exhibit less SWS and reduced delta and theta activity during non-REM sleep in baseline nights as well as in response to sleep deprivation ( 54). BDNF is particularly expressed in the prefrontal cortex and the hippocampus in humans ( 927), and the Val66Met BDNF polymorphism has been repeatedly associated with a range of cognitive functions including memory (e.g., see Ref. 614, for a meta-analysis). Unfortunately, none of these studies included direct tests of sleep-dependent memory formation.

3. Genetic studies on sleep-dependent memory consolidation

Studies mainly on flies indicated that similar genes are involved in sleep regulation and memory processing, and that memory and plasticity-related genes are expressed differentially during sleep and wakefulness. No such studies are available in humans. In addition, no genome-wide association study in humans with regard to sleep and memory parameters has been conducted thus far, although such studies would be highly informative. In fact, presently, direct evidence for a genetic contribution to the sleep-dependent formation of memory is entirely lacking.

There is a strong genetic influence on sleep parameters (discussed above) and also on memory formation. Twin studies have estimated that 50% of the variance in learning performance, typically measured after short retention periods of 5-30 min, is due to genetic factors ( 127, 885, 1164, 1262). Against this background, as both sleep and memory measures strongly differ among individuals, a putative genetic determination of sleep-dependent memory consolidation should basically express itself in significant correlations between the respective sleep and memory parameters on the interindividual level. Hence, the demonstration that sleep and memory processes share significant portions of their interindividual variance represents a first and most important step towards the demonstration of any genetic contribution to sleep-associated memory formation, although it does not prove such contribution because the associations can basically result from parallel, but independent, influences of the putative genetic factor on the sleep and memory processes of interest. Also, it cannot be concluded from interindividual sleep-memory associations whether a putative genetic factor primarily affects sleep to change memory processing or, conversely, affects memory processing to change sleep, although clues can be derived from temporal relationships. For example, Dionne et al. ( 310) showed in a longitudinal twin study that longer and more consolidated sleep at the age of 6 mo predicted better language development at 18 and 30 mo. As the type of sleep was highly heritable, the findings suggest a sleep-mediated genetic influence on later language proficiency.

Although the importance of SWA and slow oscillation for memory processing is well established (see sect. IV A), interindividual correlations between these EEG oscillations and learning capabilities and intelligence have been less frequently reported. This is remarkable given the great interindividual variance and intraindividual stability of these sleep EEG parameters (discussed above). Several studies reported correlations between SWS or SWA and the overnight retention of declarative memory ( 55, 58, 464, 1319) as well as procedural motor skills ( 581, 582). However, because in these studies the sleep EEG was assessed after the learning phase in highly homogenous subject samples, learning-induced changes in EEG activity could not be clearly dissociated from trait-dependent variance.

The studies discussed so far examined associations between sleep and memory in rather small samples (12-30 participants). Together with the testing of multiple sleep parameters (like amounts of SWS, REM sleep, spindle numbers, density, etc.) and with multiple measures of memory and learning capabilities, this can lead to an overestimation of the strength of associations due to multiple comparisons. To overcome such limitations, in recent study, we assessed sleep (at home by portable polysomnography) together with measures of pictorial and procedural motor learning and overnight memory retention in a large sample of 855 young healthy participants (Ackermann, Pappassotiropoulos, De Quervain, and Rasch, unpublished results). In accordance with previous studies, the number of fast spindles (13-15 Hz) showed a positive (but rather small) correlation with short-term recall (tested after 10 min) of pictures. However, this correlation was entirely explained by gender differences, as women remembered more pictures and exhibited also an increased number of spindles. Short-term recall of pictures was also correlated with the percentage of REM sleep ( r = 0.09), with this correlation surviving control for gender. Also, with regard to overnight retention of pictures, the only significant correlation was revealed for time in REM sleep: increased REM sleep was associated with diminished overnight retention of pictures ( r = −0.13), independently of whether these pictures were emotional or neutral. No such associations were observed for SWS-related measures, spindles, or sleep length. Overall, these data indicate a surprisingly weak association between interindividual differences in sleep and memory parameters. Specifically, they suggest that the genetic determination of sleep, particularly of SWS-related measures and spindles, does not substantially contribute to sleep-dependent memory formation processes, as these parameters do not appear to be associated with each other on the interindividual level. It is important to note, however, that the lack of association between sleep and memory parameters among subjects does not at all rule out a basic role of sleep in memory formation. For example, one individual can display higher SWA than others due to neuroanatomical and related genetic factors in the absence of any differences in memory among these individuals, yet increasing SWA in this same individual might still lead to a distinct improvement in memory consolidation during sleep.

VII. DEVELOPMENTAL ASPECTS OF SLEEP-RELATED BRAIN PLASTICITY

Only a handful of studies have been conducted to explore memory-consolidating functions of sleep during early postnatal periods, infancy, and adolescence in humans. The developmental approach might be particularly important for understanding the mechanisms underlying sleep-dependent memory consolidation, mainly for two reasons. First, compared with adults, infants and children sleep longer and deeper. In parallel, during early life the brain exhibits particularly strong plasticity shaping memory systems and underlying neuronal circuit formation. During limited periods early during development, the brain is particularly sensitive to certain experience that instructs neuronal circuits to represent respective information as very persistent memories determining performance throughout later life ( 650). However, the mechanisms underlying neuronal plasticity during such critical periods differ from that during adulthood. As a consequence of maturational processes, critical period plasticity is linked to a distinct biochemical milieu, a change in the subunit composition of NMDA receptors in forebrain synapses from a predominance of NR2B subunits at birth to a prevalence of synaptic NR2A subunits towards the end of the critical period, a specific adjustment of the balance between excitatory and inhibitory inputs to neuronal networks, and eventually also to different features of spike timing-dependent plasticity ( 332, 352, 545, 838, 1212). The specific characteristics of plasticity during critical periods prevent a straightforward generalization of the effects of sleep on plasticity in the adult brain. Nevertheless, it is striking that studies of the developing brain, including those targeting critical period plasticity, show an influence of sleep on the formation of memory that is even more profound than that observed in the adult brain.

A. Early Development: Animal Models

Filial imprinting in domestic chicks, song learning in zebra finches, and ocular dominance plasticity in the visual cortex of cats have been studied as models of developmental brain plasticity and memory formation in animals in conjunction with sleep. Recent research has indicated that the formation of these three types of memory indeed critically depends on sleep.

3. Ocular dominance plasticity

Ocular diminance plasticity (ODP) has been studied mainly in cats as a developmental model of synaptic plasticity that is induced by specific stimulus conditions, i.e., monocular deprivation ( 77, 411). In critical periods during development (in cats between about postnatal days 28 and 40), blocking vision in one eye causes a massive rewiring of cortical circuitry in favor of the open eye. ODP is sleep-dependent inasmuch as sleep following a period of monocular deprivation resulted in an almost twofold increase in synaptic remodeling in visual cortical areas, whereas after a similar waking interval in complete darkness, a tendency for erasure of the effects induced by the preceding monocular deprivation was observed ( 412). The beneficial effect of sleep on consolidation of ODP mainly leads to a strengthening of the cortical responses to stimulation of the nondeprived eye ( 48). Inactivating the sleeping visual cortex by administration of the Na⁺ channel blocker lidocaine or the GABA A agonist muscimol inhibited ODP, indicating that postsynaptic activity during sleep is required for consolidating the plastic changes induced by a monocular experience ( 411, 605). Sleep-dependent ODP is prevented by blocking glutamatergic NMDA receptors or cAMP-dependent protein kinase (PKA) during sleep after monocular deprivation ( 48). Blockade of NMDA and PKA signaling was associated with reduced activation of the kinases CaMKII and ERK as well as phosphorylation of GluR1 at Ser831, i.e., processes that are critical to the insertion of AMPA receptors into the postsynaptic membrane and the strengthening and maintenance of LTP. Most recently, Seibt et al. ( 1060) demonstrated the critical dependence of ODP on protein synthesis during sleep, as respective plastic changes in visual cortex could be prevented by inhibition of mTOR-mediated protein synthesis through rapamycin. Rapamycin had no effect on plasticity induced during wakefulness. Furthermore, phosphorylation of regulators of protein synthesis as well as translation of plasticity-related mRNAs (e.g., Arc and BDNF) was increased during sleep, overall speaking for the notion that sleep is a period of enhanced protein synthesis in these networks. ODP was paralleled by increased multiunit activity during both SWS and REM sleep, and was correlated to the time spent in non-REM sleep ( 412). Of the GABA A agonistic substances zaleplon, eszopiclone, zolpidem, and triazolam, only zolpidem impaired sleep-dependent ODP, although all substances distinctly reduced REM sleep and increased non-REM sleep ( 48, 1059). The differential efficacy of these substances in diminishing ODP may be related to differences in their pharmacodynamics and selectivity for binding specific GABA A receptor subtypes, but is independent of their profound changes in sleep architecture, as determined by standard EEG sleep recordings. ODP was impaired following application of the atypical hypnotic trazodone, probably acting via blocking 5-HT 2c receptors during sleep ( 48). Since serotonin activity is at a minimum during REM sleep and at intermediate levels during non-REM sleep, this finding suggests that processes during non-REM are more important for the expression of ODP. Interestingly, there is evidence that ODP critically depends on the T-type calcium channel function ( 1224), which also plays an essential role in the generation of spindles and slow oscillations during non-REM sleep ( 282, 283).

In sum, this research indicates that sleep plays an essential role for behaviors that are formed during critical or sensitive periods in early postnatal life. The mechanisms mediating synaptic plasticity during critical periods in essential aspects differ from those during later life ( 838) and differences in the regulation of synaptic plasticity may still exist between juveniles and adults ( 772). Yet, this does not necessarily imply that the manner in which sleep contributes to critical period plasticity also basically differs from the effect of sleep on memory formation in the adult brain. Sleep during the early postnatal period and in adults mainly differs in quantity of total sleep, time in SWS and REM sleep, intensity of SWS and SWA, etc., suggesting that the impact of sleep on memory formation during early development is overall stronger than during adulthood, rather than differing in quality. This view may account especially for developmental learning processes that are less clearly linked to an early postnatal critical period but extend towards adolescence, like song learning in birds or language learning in children. Indeed, the power of sleep in forming memory during early life and the fact that these memories are the first to be formed may suffice to explain the unique strength of these memories being difficult to overwrite or reverse.

B. Early Development: Human Studies

Investigations of the effects of sleep on memory formation during early development in humans focused on declarative and procedural memory processes similar to those examined in adults, rather than on behaviors linked to sensitive periods, like social imprinting and amblyopia as a consequence of monocular deprivation. Overall, these studies point towards the particular relevance of SWS for sleep-dependent memory consolidation in children. In adults, SWS has been revealed to play a causal role for the consolidation of hippocampus-dependent declarative memories ( 783, 957), but may play a similar role for explicitly acquired procedural memory (e.g., Ref. 691, see also sect. IV A).

Infants and children sleep longer than adults. However, compared with adults, the proportion of REM sleep in children increases only during the first 6 mo of life, whereas the proportion of SWS remains enhanced throughout development until adolescence ( 480, 866). The EEG during SWS also shows typical changes during development: the amplitude and slope of slow waves as well as SWA (i.e., spectral power in the 0.5-4 Hz band, including both <1 Hz slow oscillation and 1-4 Hz delta activity) increases until the beginning of puberty at the age of 10-12 years to levels distinctly higher than in adults, and thereafter starts to decrease ( 169, 604, 680). Several studies indicated that sleep disturbances and sleep loss impairs learning and school performance in children (for reviews, see Refs. 44, 246, 286, 662, 1178). Considering the importance of SWS specifically for the consolidation of hippocampus-dependent memory in adults, it was hypothesized that the effect of sleep on the consolidation of declarative memories is even greater during development ( 1321).

1. Consolidation of declarative memory

C. Sleep and Memory Formation in Aged Rats and Humans

Sleep undergoes characteristic changes in the course of aging. Older adults sleep less and awaken more frequently during the night. Beginning already around the age of 40, there is a distinct decrease in SWS ( 167, 866). Non-REM sleep in the elderly is characterized by decreases in SWA, especially over the prefrontal cortex, as well as decreases in spindle density ( 176, 177, 690, 786). The time in REM sleep, on the other hand, remains relatively unchanged in late life. However, there is a significant decrease in the density of phasic REMs in elderly persons ( 254).

1. Hippocampus-dependent declarative memory

Considering that the major age-related changes in sleep architecture concern SWS and associated SWA, prominent impairments in the consolidation, especially of hippocampus-dependent declarative memory, may be expected ( 512). Consistent with this notion, aging rats at rest after spatial memory encoding showed weaker reactivations of temporal firing patterns in hippocampal neuron ensembles, and this was associated with diminished spatial memory performance in the Morris Water maze at the final testing day (e.g., Ref. 448, see sect. III A4). The weakening of temporally sequenced reactivation patterns in aged rates did not appear to be a consequence of age-related decreases in SWS. Interestingly, simple reactivation patterns in CA1 cell ensembles, not taking into account the relative temporal order of cell-pair firing, was comparable between aged and young rats ( 449).

VIII. SLEEP-DEPENDENT MEMORY CONSOLIDATION IN THE IMMUNE SYSTEM

A. Memory Formation in the Immune System

The immune system forms long-lasting memories for an antigen in a multistep process. The mounting of a so-called adaptive immune response is at the core of this process. Once antigens invade the organism at certain barriers, they are taken up and processed by antigen presenting cells (APC). APC carry the antigenic information to secondary lymphoid organs where they present fragments of the processed antigen to naive T cells, which become only activated if they express the specific cognate receptor that can recognize this particular antigenic epitope. The T cell recognizing its antigen, together with the APC, form the so-called immunological synapse. Activation of the T cell is linked to the release of different proinflammatory cytokines by APC, among which interleukin-12 (IL-12) is central for the subsequent differentiation of the activated T cell into T-helper 1 (Th1) cells. T-cell growth, proliferation, and differentiation is additionally supported by the release of IL-2, whereas the release of IL-10 in this context plays an antagonistic role favoring differentiation of Th2 cells and the recruitment of immediate but preformed humoral immune responses. Th1 cells also support the differentiation of B cells and their production of antigen-specific antibodies. Whereas most effector cells differentiated during acute infection do not survive for a long time after the infection, there is a subset of differentiated T and B cells that maintains the antigenic memory for the long-term. These memory cells mediate a speedy and more effective immune response upon reencounter of the antigen ( 13, 1258).

There are apparent differences between memory formation in the immune system and in the central nervous system. Most obvious, in the immune system cells migrate to act in different tissues and body compartments and, unlike neurons, they often show strong proliferation in response to (antigenic) stimulation. These conditions may partly explain why memory formation in the immune system takes much longer (several days to weeks) than in the central nervous system. Nevertheless, immunological memory, like neurobehavioral memory, is formed as part of an adaptive organismic response to an environmental stressor, and shares the basic subprocesses of encoding, consolidation, and retrieval ( 641, 695). Also, consolidation includes a cell-cell interaction in which the antigenic information is transferred from a temporary to a long-term store, with both stores represented by different cellular networks. Specifically, in this conceptual approach (see ), encoding in the immune system would denote the uptake of antigenic information by APC. Consolidation would refer to processes at the immunological synapse that is subsequently formed between APC and T cells ( 338, 473) and comprise the transfer of the antigenic information from the APC, only serving as temporary store, to the T cells serving as long-term store. Recall would refer to the faster and facilitated immune response when the antigen is re-encountered.

B. Effects of Sleep on the Formation of an Adaptive Immune Response

1. Experimental vaccination

Vaccination as an experimental model of infection has been used as a straightforward approach to comprehensively assess effects of sleep on the formation of immunological memory mainly in humans where this approach quite consistently revealed an enhancing effect of sleep on the adaptive immune response and measures of antigenic memory. Human volunteers who slept normally in the first night after a single vaccination against hepatitis A, 4 weeks after the vaccination displayed a twofold increase in antigen-specific antibody titers, compared with participants who stayed awake on the first night after vaccination ( 697). Similar effects were found in recent experiments using repeated and combined inoculations with hepatitis A and B antigens (, Ref. 694). In this study, nocturnal sleep after the inoculations doubled blood counts of antigen-specific Th cells, as marker of antigenic memory. During antigen reencounter, these Th cells stimulate the production of antibodies specifically directed against hepatitis A and B. Moreover, sleep profoundly increased the proportion of T cells producing proinflammatory and Th1-cytokines like IL-2, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). The effects persisted over 1 year. In a further study, short sleep duration after hepatitis B vaccination predicted a decreased antibody response to the immunization ( 946). Together, these studies provide a compelling demonstration that nocturnal sleep after vaccination suffices to strengthen the evolvement of an adaptive, i.e., memory-forming immune response to a clinically relevant extent. A strengthening role of sleep for immunological memory formation is also supported by observations of reduced total IgG under conditions of sleep restriction (to 4 h/night) for several days after vaccination against influenza ( 1130).

The strengthening effects of sleep on the human primary immune response to infection were revealed with sleep occurring within the first 36 h after inoculation. This time window suggests that sleep affects the cascade of responses to the viral challenge at a rather early stage. Indeed, research has identified two main targets that are affected by sleep in this process, i.e., 1) the interactions between APC and T cells at the immunological synapse and 2) the migration of these cells to secondary lymphoid tissues.

4. Contribution of SWS to memory formation in the immune system

Although effects of the experimental manipulation of specific sleep stages on the adaptive immune response have not, thus far, been systematically assessed, there is converging though indirect evidence that the strengthening effects of sleep on the formation of long-term antigenic memory originates from processes during SWS. The sleep-induced increase in antigen-specific Th cells after hepatitis A vaccination was strongly correlated with the amount SWS and EEG SWA on the night after vaccination ( 693). The increase in percentage of hepatitis A virus specific antigen-specific Th cells measured 18-20 wk after vaccination was correlated with r = 0.72, and that measured 1 year later with a coefficient of r = 0.94 with SWA. Other measures, including REM sleep-related parameters, were not predictive of this increase. Corresponding findings were obtained in rabbits, where the amount of SWS predicted the survival rate after a pathogen challenge ( 1205). Moreover, in humans, early nocturnal SWS-rich sleep is associated with a shift towards Th1 cytokine activity predominating over Th2 activity which is replaced by a shift towards the predominance of Th2 cytokine production during late sleep when SWS is fading and REM sleep becomes prevalent ( 308). In fact, peaks in Th1 cytokine activity and, more generally, in proinflammatory cytokine activity during the rest period were mainly detected during the early SWS-dominated portion of sleep, in humans as well as in animals in different tissues including the brain ( 487, 671) and lymph nodes ( 359), but also in blood and circulating leukocytes ( 109, 120, 172, 306, 308, 487, 696, 749, 1158). Interestingly, some of these cytokines were found, conversely, to promote SWS, pointing towards a positive-feedback loop between the central nervous and immune systems ( 693).

IX. CONCLUDING REMARKS

For more than a century it has been known that memory benefits from sleep, and research in this field has put forward different explanations for this phenomenon. Here we aimed to establish a review covering the progress of research in this field of sleep and memory in its entireness, simultaneously taking into account the vastly differing approaches that have been adopted to clarify the mechanism mediating the memory benefit from sleep. Whereas initially it was commonly assumed that sleep improves memory in a passive manner, by protecting it from being overwritten by interfering external stimulus inputs, the current theorizing assumes an active consolidation of memories that is specifically established during sleep, and basically originates from the reactivation of newly encoded memory representations. In parallel, the perspective on the researched memory has changed. Whereas initial research largely concentrated on the stability of memory, demonstrating how sleep contributes to the persistence of a memory in all of its qualities, recent research has begun to concentrate on the dynamics of memory formation, systematically examining the changes a memory representation undergoes during sleep-dependent consolidation. The active system consolidation process assumed to take place during sleep leads to a transformation and a qualitative reorganization of the memory representation, whereby the "gist" is extracted from the newly encoded memory information and integrated into the long-term knowledge networks.

Most recently, the focus of research in the field has broadened, indicating that sleep benefits memory not only in the neurobehavioral domain, but also in the formation of immunological long-term memories, stimulating the idea that forming long-term memories represents a general function of sleep. There are first cues that sleep-dependent memory formation in the immune and central nervous system share common mechanisms, that in both domains appear to be linked to SWS. Also in the immune system, sleep appears to support the intercellular reorganization of memory representations such that during the APC-T cell interaction the epitopic information is extracted from the antigen to be stored by T cells. Certain features of active system consolidation, like cell assembly reactivation of neurobehavioral representations, can occur also during wakefulness, but with different consequences. The effective reorganization of the representation requires a specific milieu of neurotransmitter and endocrine activity as it is established only during sleep, specifically during SWS. Subsequent REM sleep may then be involved in strengthening the reactivated and reorganized representations on a molecular and synaptic level. Thus sleep and wakefulness appear to be associated with different and mutually exclusive modes of memory processing, with sleep favoring processes of memory consolidation that are incompatible with the efficient encoding and retrieval of stimuli, as required while coping with environmental demands in the wake phase.

GRANTS

This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 654 Plasticity and Sleep and Swiss National Foundation Grant PP00P1_133685.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

ACKNOWLEDGMENTS

We thank Maren Cordi, Anja Otterbein, Ursula Rasch, Julia Rihm, Thomas Schreiner, Sarah Schoch, and Manuela Steinauer for assistance in preparing the manuscript and Sandra Ackermann-Wohlgemuth, Luciana Besedovsky, Susanne Diekelmann, and Ines Wilhelm for helpful comments on earlier versions of the manuscript. In particular, we thank Drs. Ted Abel, Igor Timofeev, and Paul Shaw for very constructive comments and corrections.

Addresses for reprint requests and other correspondence: J. Born, Institute of Medical Psychology and Behavioral Neurobiology, Univ. of Tuebingen, Gartenstraße 29, 72074 Tuebingen, Germany (e-mail: ed.negnibeut-inu@nrob.naj); or B. Rasch, Institute of Psychology, Div. of Biopsychology, Univ. of Zurich, Binzmühlestrasse 14, Box 5, CH-8050 Zurich Switzerland (e-mail: hc.hzu@hcsar.nreojb).

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Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of "sleep and memory" research by providing a historical perspective on ...

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It is no secret that a good night's sleep makes you feel better. Not only does sleep give your body time to rest and recharge, it may also be crucial to your brain's ability to learn and remember.

During sleep, while your body rests, your brain is busy processing information from the day and forming memories. If you are sleep deprived, you are at risk of developing a number of serious health problems, such as hypertension, obesity, and diabetes, and your ability to learn and retain new information may be impaired.

This may not be news to anyone who has pulled an all-nighter cramming for a test only to find the facts and figures they knew at 2 a.m. could not be recalled the next day. Without adequate sleep, your brain becomes foggy, your judgment poor, and your fine motor skills hindered.

Imaging and behavioral studies continue to show the critical role sleep plays in learning and memory. Researchers believe that sleep affects learning and memory in two ways:

Lack of sleep impairs a person's ability to focus and learn efficiently.

Sleep is necessary to consolidate a memory (make it stick) so that it can be recalled in the future.

There are different types of memories. Some are fact-based, such as remembering the name of state capitals. Some are episodic -- based on events in your life, such as your first kiss. And some memories are procedural or instructional, such as how to ride a bike or play the piano.

For something to become a memory, three functions must occur, including:

Acquisition -- learning or experiencing something new

Consolidation -- the memory becomes stable in the brain

Recall -- having the ability to access the memory in the future

Both acquisition and recall are functions that take place when you are awake. However, researchers believe sleep is required for consolidation of a memory, no matter the memory type. Without adequate sleep, your brain has a harder time absorbing and recalling new information.

Sleep does more than help sharpen the mind. Studies show that sleep affects physical reflexes, fine motor skills, and judgment, too. One study showed that participants who were sleep deprived were more likely to think they were right when they were, in fact, wrong.

Studies involving memory tests show that after a single night of sleep, or even a nap, people perform better, whether on a test, in the office, on the athletic field, or in a concert hall.

Scientists don't know exactly how sleep enhances memory, but it appears to involve the brain's hippocampus and neocortex -- the part of the brain where long-term memories are stored. It is thought that during sleep, the hippocampus replays the events of the day for the neocortex, where it reviews and processes memories, helping them to last for the long term.

Researchers continue to investigate the stages of sleep involved in making certain types of memories. Some studies have shown that certain kinds of memories become stable during rapid eye movement (REM) sleep -- the time when you dream. Other studies have found that some types of memories are most often secured during slow-wave, deep sleep. Scientists are getting closer to understanding what sleep does to our brain, but there are still many questions to be answered.

What's certain is that sleep is a biological necessity -- we need it to survive. Unfortunately, in this day and age, few of us are able to get the sleep we need to function our best. Experts recommend adults get seven to nine hours of sleep each night. Although this may not be attainable every night, it should be the goal.

Here are some tips to help you get more sleep:

Go to sleep and wake up at the same time each day.

Get regular exercise, but do not exercise close to bedtime. Experts recommend allowing at least three hours between exercise and bed.

Avoid caffeine, alcohol, and nicotine before going to sleep.

Take time to unwind before going to sleep. Take a warm bath, read a book, drink some caffeine-free tea, and avoid any activities that can cause tension.

Finish eating two to three hours before going to bed.

Create a pleasant sleeping environment: make the room dark, cool, and comfortable.

Use a sound machine, or other type of white noise device, to block out unwanted sounds.

Wearable sensors such as Fit Bit, Apple watch, Garmin, and Whoop, can collect biometric data such as heart rate, heart rate variability and hours of sleep.

Technologies such as Apollo wearable can also deliver light vibrations to the skin at different frequencies and intensities, which may help to positively alter the nervous system to help focus, reduce stress, and improve sleep.

Do not watch TV or use the computer in bed. Use your bedroom for sleep and sex only.

Maintaining a healthy lifestyle, including getting regular and quality sleep, can be a challenge, especially when you are stressed with a work deadline or test. But, remember (and you need sleep to do this!), sleep is your friend. So, when it comes to learning and memory, sleep on it.

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How does sleep affect your memory? WebMD explores the effects of sleep deprivation on memory retention and loss.

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(QuickHoney for The Washington Post)

Sleep-deprived adolescents - forced for generations to wake for school before the chimes of their circadian clocks - have had an unexpected break amid the anxiety and losses of the pandemic. Remote learning has allowed many of them to stay in bed an extra hour or more, providing a "natural experiment" that sleep experts hope will inform the long and stubborn debate over school starting times.

FAQ: What to know about the omicron variant of the coronavirus

So far, many results are anecdotal. Some kids are sleeping longer and more soundly, starting classes ready and refreshed. Others are tossing and turning, beset by anxiety or staying up later staring at screens. The varying experiences offer families and schools a glimpse of the effects of later schedules - and the possibility that the past year will yield enough evidence to persuade schools to follow scientists' guidance to begin the school day no earlier than 8:30 a.m.

Finally, some were able to get the eight to 10 hours of sleep that experts have long recommended for their age group, but which they've missed for having to catch buses and report to their classrooms as early as 7:30 a.m.

"From a health standpoint, it's overwhelmingly positive to have this reset and see what a little more sleep feels like," said Rebecca Robbins, an instructor in medicine at Harvard Medical School who studies sleep and circadian health.

Jack Poppleton, an eighth-grader at the Manhasset Secondary School in Long Island, can speak to the benefits of this small silver lining. Early in the pandemic, his school switched to remote learning on alternate days. On the in-person days, Poppleton must report to class by 8:10 a.m., the pre-coronavirus schedule. But on remote days, his first class begins at 9:04, letting him snooze an extra hour.

"I do better work on the days I start later," he said. "When I'm kind of sleepy, I feel detached. It's harder to think. And why go to school if you can't think?"

Sid Rundle, the principal of Cresthill Middle School, in the Denver suburb of Highlands Ranch, said he has heard many similar stories despite the upheaval of the past year.

"There's no question that some students are thriving with this newer model," he said.

Rundle's school is a test case in itself.

When his district switched to fully remote learning last November, he delayed the start of the day's first class by an hour, to 8:30 a.m., a change he had wanted to make for years.

"We were all in a survival mode," he said. "So I didn't have any bureaucracy around to tell me I couldn't go ahead."

He said the later schedule proved to be "an absolute game-changer" for teachers and students. "The kids were definitely more awake, excited and engaged," Rundle added, with "fewer zombies and more active learners."

Melissa Rapp said she has seen the change in her daughter Emma, 12, a student at Rundle's school. Before the pandemic, Rapp said she had to drag Emma out of bed each weekday morning. Even after Emma set two alarms, Rapp said she had to come in at least three times, flipping on lights and playing loud music by the indie pop group Walk Off the Earth and other bands her daughter dislikes.

The switch to the later schedule was "super-amazing," Rapp said. For nearly three months, until Cresthill switched back to in-person learning in February, Emma was waking by herself, rested and ready to learn. Since then, however, her daughter's morning mood has soured, Rapp said.

Trendy as it may be to complain about " blursday," the pandemic's conflation of weekdays and weekends may be also helping the sleep-deprived by eliminating the " social jet lag " that comes from waking early Monday after sleeping in on Sunday.

Other kids have found no advantage in the past year's changing schedule, however, for reasons that await further research.

"I'm hearing about some improved sleep, but more of my clients are having serious sleep issues," said Sarah Gumlak, a psychiatrist working with young people in Maine. "I've never given out so many sleep hygiene resources." (See "Pandemic sleep advice.")

The students who are struggling to adapt are challenged by changes in routines, less physical activity, more anxiety about school, increased screen time because of remote learning, and a lot of cabin fever at home, Gumlak said.

"There's also a need for alone time once everyone else has gone to bed, as well as testing rules around sleep," she said. "Kids will always feel the need to test something, and they don't have as many outside world rules to test right now."

Hope and Elle Drahos, 14-year-old twins attending school in Williamstown, N.J., have both had worse sleep since the switch to remote learning, even though it gives them an extra hour in the morning.

Elle said she wakes up once or twice every night, worrying about her friends. "I can't see them. I can just text them, so I can't really catch up with them," she said.

Hope said she stays asleep all night but that it takes her about 20 minutes longer to fall asleep, mainly because of school-related worries, such as trying to recall if she had turned in an assignment.

"Before, we'd always remember because we'd be right there in class," she said. "Remote learning gives us more responsibility."

She misses her in-person classes, but said that on the mornings after a poor night's sleep, she is extra grateful for the later start.

For several years, doctors and sleep researchers have been urging schools to follow abundant scientific evidence and push back the start of the class day.

Scientists argue that adolescents - an age group some contend should extend until 24 - are suffering severe sleep-deprivation. That contributes to a startling list of problems, surfacing sooner or later, including but not limited to: obesity, diabetes, heart disease, substance abuse, mood disorders and vehicle crashes, experts say. Getting adequate sleep improves overall health, even bolstering immune systems, possibly improving the effectiveness of some vaccines.

The Academy of Pediatrics recommends that middle and high schools start their days no earlier than 8:30 a.m. Even so, at last count, 93 percent of U.S. high schools and 83 percent of middle schools were not following that guidance.

In October 2019, California became the first state to pass legislation, set to take effect in 2022, mandating that high schools start no earlier than 8:30 a.m. and middle schools no earlier than 8 a.m.

In early February, Cresthill Middle returned to in-person learning and resumed its previous schedule, leaving Rundle to wonder whether the pandemic's "natural experiment" would someday help convince school officials to switch permanently to later starting times.

"I do hope we can have a conversation about what we learned from all this," he said. "I don't know of one colleague of mine who doesn't believe that later start times are the right way to go."

For now, the signals from school leaders' groups aren't encouraging. James Minichello, speaking for the School Superintendents Association, said his organization wasn't tracking the issue of school start times. Bob Farrace, spokesperson for the National Association of Secondary School Principals, said in an email: "It's just not a trend that we've been attending to as our members have not identified it as top of mind."

Teenage sleep can be harmed by early school time

Sometimes a better pillow can help improve a teenager's sleep

Later school times helped these teens

With many schools returning to in-person learning - and earlier schedules - even as the pandemic continues, how can parents help their adolescents sleep more soundly?

"As I often phrase it, multilevel interventions are needed," says Wendy Troxel, a senior scientist and sleep expert at the Rand Corp. By that, she says she means that families, schools, and state and local governments should contribute to finding solutions.

Families, Troxel says, can do a lot to support teen sleep by removing technology from their bedrooms. Have a central place - not a bedroom - for the entire family to disconnect from their phones and charge them overnight. Research suggests parents can be influential role models: children often copy their mother and dad's technology habits.

Rebecca Robbins, an instructor in medicine at Harvard Medical School, says another evidence-based way  for teenagers to get sleep during the pandemic and beyond is to get plenty of exposure to natural light, ideally in the morning.

"Light is the strongest physiological cue to the brain, providing vital information to kick-start the alert phase of our circadian rhythm," she says.

If natural light isn't abundant, try one of the sunlight lamps designed for people who suffer mood changes in the winter.

Robbins and other sleep experts say now is the time to double down on basic sleep hygiene. Persuade your adolescent to stick to a regular routine; avoid caffeine, alcohol and aerobic exercise within four hours of sleep time; and make sure the bedroom is dark and quiet.

Facts and recommendations

The American Academy of Sleep Medicine recommends that children ages 6 to 12 should sleep from nine to 12 hours per day and teenagers 13 to 18 should sleep eight to 10 hours.

The American Academy of Pediatrics and the Centers for Disease Control and Prevention recommend that middle and high schools start no earlier than 8:30 a.m.

A 2013 CDC study found that 68 percent of U.S. high school students reported getting less than eight hours of sleep on school nights.

Some schools in Australia and New Zealand that have experimented with start times of 10 a.m. or later report that this has helped students' focus in class.

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Sleep-deprived kids have gotten a break with remote learning's later start times. Some hope it's a wake-up call for schools.

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Sleep-deprived adolescents - forced for generations to wake for school before the chimes of their circadian clocks - have had an unexpected break amid the anxiety and losses of the pandemic. Remote learning has allowed many of them to stay in bed an extra hour or more, providing a "natural experiment" that sleep experts hope will inform the long and stubborn debate over school starting times.

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Evidence is mounting that teenagers should start school a little later. So why aren't they?

he medical community doesn't fully understand why, but there's something about puberty that throws kids' systems out of whack. It's as if teenage bodies switch over to daylight savings time, a condition sometimes known in the medical community as a "phase delay." They begin to have trouble falling asleep early and then, of course, want to sleep in the morning for as long as possible. While teenagers may not need as much sleep as they did when they were children, their growing bodies still get pretty fatigued; they just don't feel it until about two hours later.

"Why this happens nobody has a clue-hormone changes are a good bet," says Dr. David Gozal, a pediatric sleep expert at the University of Chicago. "Paradoxically, this period of puberty is associated with an increased need for more and longer sleep. So now they're in conflict with the sleep schedules of our society."

That's why advocacy groups, administrators and recently the American Academy of Pediatrics (AAP) have started to push for high schools to delay their start times so that students get more shuteye. In an August 2014 policy statement, the AAP said it supports middle and high schools adopting delayed start times (that is, no earlier than 8:30 a.m.) to allow teens to get the recommended hours of sleep a night (eight to 10), to improve their physical and mental health, safety, academic performance and quality of life. "[The] research indicates that the average teenager in today's society has difficulty falling asleep before 11:00 p.m. and is best suited to wake at 8:00 a.m. or later," the statement reads.

Data from a National Sleep Foundation poll shows 59% of kids in grades six through eight and a full 87% of high schoolers in the U.S. say they are getting less than the recommended amount of sleep. More than one in five of these students says he or she falls asleep while doing homework at least once a week.

With evidence suggesting that delaying the start of the school day can lead to more sleep, less reported fatigue and even improved academics, the switch seems like a no-brainer.The AAP recommends that schools should start at 8:30 a.m. or later, yet the most recent data from the U.S. Department of Education shows more than 80% of public schools in the U.S. start earlier than that. (And almost 10% start earlier than 7:30am).

"The evidence is clearly mounting in terms of understanding the repercussions that chronic sleep loss has on the health, safety, and performance of adolescents," Dr. Judith Owens, director of sleep medicine at Boston Children's Hospital and author of the AAP statement told TIME writer Alice Park in the book, The Science of Sleep. Some data suggests that anything under 8.5 to 9 hours of sleep on school days can contribute to health problems like obesity, mood changes and diabetes. Other data has linked poor sleep to a higher reliance on substances like caffeine, tobacco and alcohol. Not getting enough sleep can also take a toll on academic performance.

"There's also really compelling data supporting the fact that delaying school start times is a very important intervention that can mitigate some of the impact of sleep loss," Owens tells TIME, suggesting if schools make the switch now, there's time to prevent some of those negative outcomes. Even a half-hour delay, some studies showed, can have dramatic effects on improving children's health and academic performance.

The research has caught the eye of some very influential educators. "It's completely a local decision, but I'd like to see more school districts at least consider delaying start times," says U.S. Secretary of Education Arne Duncan. "A later start to the school day could help boost students' academic performance and reduce tardiness and absenteeism. Our commonsense tell us that sleepy students don't do well in school, but the research also exists to back it up. Studies show that when students are rested, they are more alert and ready to learn."

Intuitively, it makes sense. If teenagers are supposed to get up to 10 hours of sleep a night and get up for school at 6 a.m., that means many will have to be in bed by 8 p.m. or 9 p.m. Anyone who knows a teenager, or remembers what it was like to be one, knows that an 8:00 p.m. bedtime for a 16-year-old is laughably unrealistic. Not to mention that as entrance to highly regarded colleges gets more competitive, today's teens keep incredibly busy schedules and trying to balance time for extracurriculars and homework can make it hard for them to fall asleep on time, and for their schools get everyone from parents to coaches on board to push back the start time.

Take Perrin Jones, a junior at Saratoga Springs High School in Saratoga Springs, New York. He wakes up every day at 5:30 a.m. to finish his homework and hops on the bus at 6:50 a.m. to make it to school for a 7:49 a.m. start time. Jones takes almost entirely all AP courses (he wants to get into a college like Carnegie Mellon or University of Michigan to major in physics and computer science), and he volunteers with the school's IT department during the day. To keep up the schedule, he dropped lunch. After school he has at least one club meeting-he's in the NASA club and the physics club-and at 6:30 p.m. he goes to the local theater where he's on the sound crew. He gets home around 11 p.m., and then starts three hours of homework. He says he gets four hours of sleep on average, sometimes six on a good day.

"I don't know how I keep going with such little sleep, but I do. I feel like I must learn how to survive without sleep to survive high school," says Jones. "It sure would be nice if school started a little later, I'd definitely appreciate the extra sleep, even if it was half an hour."

Trevor Weinrich, a senior at Rockhurst High School in Kansas City, Missouri keeps a similar schedule. From 5 a.m. to 7 a.m. he's at swim practice. School starts at 8 a.m. and goes until 3 p.m., and he also skips lunch frequently for voice lessons. From 3:30 p.m. to 6 p.m. he has more swim practice followed by choir rehearsal. In the spring he was in three musical productions at once, and had rehearsals until 9:30 at night.

"My homework load averages about two to 2.5 hours a night. Many nights I eat dinner around nine or 10, and don't get to bed until about 1 a.m or 2 a.m.," he says.

While Weinrich and Jones are both ambitious students, the crowdedness of their schedules is not all that rare. It's an issue many schools face-teens are overextended and too tired. So why have so few schools made the switch? Because it's not as simple as it seems to persuade a whole community to change its schedule.

The Promise

ive years ago, Sharon High School in Sharon, Massachusetts decided to delay its start time after nearly eight months of deliberation. A task force of representatives from the school committee, the athletic department, teachers, parents, and students decided the school should move its start time back 40 minutes from 7:25 a.m. to 8:05 a.m.

"If [the change] was going to help them live a better life in some respects then it was the right decision to follow and that's ultimately what we decided," says Sharon High School Principal Jose Libano. "We will never go back. There is not a kid in this building who would say I prefer to be here at 7:15 in the morning. Not one."

A year after the shift, the school polled its students, teachers and parents and found that parents and students largely felt the change was positive, while teachers were more split. The teachers felt they functioned better early in the morning, and they ran into commuting problems with the new start time. Still, there was a notable decline in tardiness, and teachers did say that since the change, students seem to be more alert and less lethargic during first period.

"They tend to be more active and willing to participate in discussion, volunteer to go to the board, or engage in group work, because they have gotten more sleep at night," says Sharon High School Latin teacher Jen Orthman. "I think that despite some initial resistance to the change, most teachers appreciate having additional time in the morning to meet with students, collaborate with peers, partake in meetings, and set up classrooms for the day."

Of course there was an adjustment period, as there tends to be with most schools that agree to push back their start times. Since community life can revolve around public school schedules, lots of factors-from sports games to when parks are open-need to be taken into account. Not to mention there's often pushback from parents who are concerned about what impact the later time will have on their child's after school schedule.

But other schools that have adopted similar changes have also noticed positive benefits. A three-year University of Minnesota study released in 2014 showed that high schools that started at 8:30 a.m. or later allowed 60% of their students to get at least eight hours of sleep each night. The teens who got less than that reported higher levels of depression symptoms, greater use of caffeine, and were at higher risk for making poor choices regarding substance use. Schools that started at 8:35 a.m. or later had better attendance and tardiness rates and better academic performance in core subject areas and in national achievement tests. The report also showed that the number of car crashes involving teen drivers was reduced by 70% when a school shifted start times from 7:35 a.m. to 8:55 a.m..

In Wake County, North Carolina, a study showed that delaying the start of school by one hour could lead to a two to three percentile point increase in math and reading test scores. The effect was greatest among students who were struggling.

When Glens Falls High School in New York first suggested pushing back its start time for the 2012-2013 school year, it met with a lot of opposition. Student athletes and their parents argued that their practices and games would end later, and therefore they would go to bed later too. The Board of Education was divided on the issue. The vote to implement the time change passed by a 5-4 margin in May 2011 and a motion to rescind the change failed by a margin of 4-5 in December 2011.

The school says it has seen improvements among its students since it required them to be at school later. The percentage of late students dropped around 3% from the 2011-2012 school year to the 2013-2014 school year. The number of students failing classes dropped 2.2% and the absentee rate dropped 1.5%.

It's hard to draw a definitive line between later start times and better scores, mental health and safety, but many who are watching the experiments agree that the numbers showing teens get more sleep with a later start time are promising, given that more shuteye is the ultimate objective.

"Starting school later is in the best interest of your students," says Libano, who is quite the evangelist for a later-starting day. "When there is a will there has got to be a way. It's the right thing to do."

The Challenge

hile the evidence in support of letting students sleep in is intriguing, it's an often-difficult feat to pull off.

"There were a lot of obstacles. It was divisive," says Libano about the year the school pushed the new start time through. "It's a topic that generates a lot of emotions because it's a significant change."

Significant may even be an understatement. Sharon High School was lucky; local buses were able to shift their pick-up and drop-off times without the school incurring additional costs. But the middle and grade schools had to change their start times too to accommodate the high school. Officials from Sharon had to go to the other schools in the district they compete against in extracurriculars and sports and ask them to plan competitions accordingly. Sharon also started regulating how long students could be held at practice after school. Ultimately the community was willing to adapt.

"It is very complicated to change a school or district schedule because community life revolves around school hours,"says Terra Ziporyn Snider, the co-founder and executive director of Start School Later, a non-profit working to persuade public schools to change their schedules. "It's true even if you don't have kids. Imposing a schedule change on an unwilling community is politically unpopular."

The time schools start affects traffic flow, day care hours, small businesses that employ high school students, and when parks are open. While all that adjusting can cause some seriously ruffled feathers, Snider says if the change is done the right way, the whole community is involved in the implementation, and it comes off without a hitch.

Most of the time, according to Snider, people just don't want to change the status quo. "The fear of the impact is incredibly powerful politically," she says. "It's fear of change and failure of imagination. It doesn't mean that because you change the time you suddenly can't have sports practice because school gets out an hour later. But people do think that and it stops change in its tracks."

A common concern among critics of later school times is whether pushing back school will just mean that students get to sleep even later and will still be late for school. However, there's evidence to suggest that's not usually the case. A 2002 study of Minneapolis high school students showed that after the city's school districts switched from a 7:15 a.m. start time to 8:40 a.m., kids in schools that switched had similar bedtimes to students whose schools didn't change, resulting in one additional hour of sleep for the students. A 2010 study of a school that delayed its start time by 30 minutes showed average bedtimes actually shifted 18 minutes earlier, and average reported sleep duration increased 45 minutes. If teens are biologically programmed to go to sleep at a certain hour, pushing back a start time means they have more time in the morning when their bodies want to sleep in. And if their circadian clock is keeping them up at night, it's not as big of deal.

"There's zero evidence that the current hours are doing anyone any good and a lot of evidence that they are doing a lot of harm," says Snider. "We are not talking about letting kids sleep in until 1pm every day, we are taking about letting them sleep until seven or eight in the morning. It's not a very radical proposition."

The Way Forward

or communities that want to take on the fight for a later start time, Snider recommends building an argument about sleep as the third pillar of health, after eating and exercise, an argument public health experts are increasingly promoting. Start School Later has 43 local chapters around the country that are available as a resource. Bringing in outside sources and advisors, say, from schools that have already taken on the challenge- can make the process much smoother, says Snider.

It's hard to tell just how many schools have made a switch to a later start time, since some do so individually and others as a district, but interest is mounting. Libano fields many calls from schools inquiring about the change, and the U.S. Department of Education tells TIME that districts from Portland, Maine, to Ann Arbor, Michigan, to Durham, North Carolina, are looking at changing start times.

"While the decision of when to start school is up to the nation's 15,000 school districts, the Department is interested in how innovative local efforts impact student achievement," says Duncan. "School systems cannot carry on this work alone - parental involvement is critical to ensuring success for all students."

In 2011, Fairfax County, Virginia, surveyed some of its 8 th-, 10 th- and 12 th-graders to see how much sleep they were getting at night. The results showed that less than a quarter of high school seniors were sleeping seven or more hours. The data prompted the district to partner with the Children's National Medical Center's Division of Sleep Medicine to further study their students' bedtime routines. Last year, the school board voted for a later school start. Come fall, students at the over 20 high schools in Fairfax County, who used to have to be at school at 7:20 a.m., can roll over and rest. High schools are now starting between 8:00 and 8:10 a.m., which is not exactly up to the AAP's recommendation of 8:30, but it's a start.

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Evidence is mounting that teenagers should start school a little later. So why aren't they? he medical community doesn't fully understand why, but there's something about puberty that throws kids' systems out of whack. It's as if teenage bodies switch over to daylight savings time, a condition sometimes known in the medical community as a "phase delay."

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The movement to start the school day later is gaining traction, and for good reason.

Research shows that puberty shifts the circadian rhythm of children, contributing to later bedtimes and wake times.

It also shows that teenagers need eight-and-a-half to nine-and-a-half hours of sleep a night, but only one in three are getting at least eight.

It's why nearly 200 education and health leaders are meeting at the first-ever National Conference on Adolescent Sleep, Health and School Start Times Thursday and Friday in Washington, D.C.

Their goal: Encourage school districts to start the class day no earlier than 8:30 a.m. for middle and high school students in order to accommodate their changing body clocks and improve their chances for quality sleep.

"This is an opportunity to network, share ideas, to have a dialog about what's going on in our communities," said Judith Owens, director of Sleep Medicine at Boston Children's Hospital and a faculty member at Harvard Medical School.

The RAND Corporation, Yale School of Medicine, Robert Wood Johnson Foundation and Start School Later Inc. are sponsoring the conference.

Phyllis Payne, a spokeswoman for Start Schools Later, told CBN News that hundreds of districts have delayed their start times in recent years but that the majority still start before 8:30 a.m.

Payne says logistical challenges remain the biggest obstacle.

"People have a status quo bias," she said. "There's a natural fear of change."

The conference will help educators create strategies to implement earlier start times and explain the science behind it.

Most major medical organizations, including the American Medical Association, the American Academy of Pediatrics and the Centers for Disease Control, have joined the American Academy of Sleep Medicine in recommending that secondary schools start no earlier than 8:30 a.m.

They cite research which shows that sleep deprivation has become a public health epidemic among American adolescents. A loss of sleep leads to problems with health, academic performance, behavior and overall well-being.

The American Academy of Pediatrics reports that lack of sleep is associated with an increase in injuries, high blood pressure, obesity and depression. Getting enough sleep leads to improved attention, learning, emotional and physical health.

RAND social scientist Dr. Wendy Troxel says teens who don't get enough sleep are more likely to abuse drugs and alcohol. They're also more likely to be involved in a car crash.

"Sleep loss is directly linked to decision making and mood," she said.

Troxel says school start times are about more than just mornings. Early start times also mean early end times and data shows most violent crimes commited by teens happen between 3 and 6 p.m.

"We need to encourage educators, community members and policy makers to heed the science and support later start times for the health, well-being and functioning of our teens, as well as for our collective public safety," said Troxel.

Dr. Charles Czeisler studies sleep at Harvard Medical School.

He spoke about his research at the conference and pointed to his high school daughter's schedule as a common example. In order for her to get to school by 7:15 a.m., she has to wake up at 5:45 a.m. Her day doesn't end until 8 p.m. when lacrosse practice lets out and she usually gets home around 8:30 p.m. Most nights she has at least a couple hours worth of homework, which means it's impossible for her to get to bed at a decent hour. Like most teens, she doesn't get enough sleep.

In addition to pushing back school start times, Czeisler recommends allowing at least 11-hours between the end of the last scheduled school sponsored activity and the start of the next school day.

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Why Are Teens so Tired? Sleep Debate Could Change How America Does School

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The movement to start the school day later is gaining traction, and for good reason. Research shows that puberty shifts the circadian rhythm of children, contributing to later bedtimes and wake times. It also shows that teenagers need eight-and-a-half to nine-and-a-half hours of sleep a night, but only one in three are getting at least eight.

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Centers for Disease Control and Prevention

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Learn how later school start times may help adolescents get sleep.

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Memory: It isn't just something, it's everything. And although scientists have pursued and puzzled over it for centuries, a definitive explanation of the actual memory process still eludes us--partly because our brain is so incredibly complex (it is made up of approximately 90 billion cells after all!).

Let's take a look at the basic neuroanatomy elements, which makes memory possible. Brain cells, called neurons are the core component of the nervous system and have the remarkable ability to communicate with each other and transfer information. They are able to accomplish through a process called synaptic transmission. Neurons release specialized proteins called neurotransmitters that travel through the space connecting each other together called synapses, and bind to specific proteins called receptors. In regards to memory, the more often neurons communicate with each other, the stronger the connection between them becomes. This process, called long-term potentiation, is thought to be the foundation of memory storage.

In order for new memory formation to occur, information needs to undergo certain processes. The first is called encoding, a process used to change information into a usable form. Second, memory is stored for later use and finally the retrieval process allows stored memories to be brought back into our awareness.

Memory can go through several different stages before it stored long-term. The first stage is called sensory memory, the shortest element of memory (up to ½ a second). Due to the vast amount of sensory information (sight, hearing, smell, taste and touch) our brain is constantly flooded with, we attend to only certain aspects of this sensory memory, filtering out most of the information. Therefore, only select information is passed into the next stage - short-term memory. This is the information we are currently thinking about and is stored for approximately 10 to 30 seconds.

Want to test your short-term memory? Take a fun memory test here!

While many of our short-term memories are quickly forgotten, making a conscious effort to retain this information allows it to continue on the next stage-- long-term memory. Other helpful techniques include repetition, patterns and imagery, using mnemonic devices and chunking. Information stored in long-term memory is largely outside of our awareness, but can be called back into working memory when needed. It can also be further divided by type including: declarative & procedural; episodic & semantic; and retrospective and prospective.

What parts of the brain are involved in these different types of memories? Find out here.

While memory fascinates our culture, the loss of it causes even greater fascination (and anxiety), in part, because we ALL experience it. For example, how many times have you been late for something because you can't remember where you left your keys? Or how many times has someone's name suddenly eluded you? Because memory loss can be very concerning-it's important to understand the underlying factors causing or contributing to it, especially if it becomes severe. Read more about additional causes of memory loss (besides those mentioned in the lesson), including: Alzheimer's Disease, Stroke and certain types of Medication.

The good news is that no matter what your age, it's never too late to take steps to prevent memory loss. A healthy lifestyle and good habits can reduce can only help to preserve and improve your memory. Find out some additional ways to give your brain a work out (for example, learning a new language) to help keep your memory sharp.

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How memories form and how we lose them - Catharine Young

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Think back to a really vivid memory. Got it? Now try to remember what you had for lunch three weeks ago. That second memory probably isn't as strong-but why not? Why do we remember some things, and not others? And why do memories eventually fade? Catharine Young gives the basics on memory and memory loss.

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Listening Comprehension Questions

What was one of Malala Yousafzai's first experiences with the dangers of religious extremism?

After miraculously surviving her attack, what has Malala focused her work on?

What is the message that Malala is trying to send to those in power?

What does Malala want to do in the future?

What are the goals of Malala's mission to support girls?

Discussion Themes

What is your opinion on Malala's message about the power of education?

Why do you think that ISIS might want to silence people like Malala?

Socrative users can import these questions using the following code: SOC-1234

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Listenwise: Boosting People's Memory While They Sleep

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Listening Comprehension Questions What was one of Malala Yousafzai's first experiences with the dangers of religious extremism? After miraculously surviving her attack, what has Malala focused her work on? What is the message that Malala is trying to send to those in power? What does Malala want to do in the future?

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Wendy Suzuki: The brain-changing benefits of exercise | TED

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Stress and memory are most notably faced in a classroom setting. This journal article discusses the implications of all the deadlines, assignments, and evaluations in a classroom setting on memory.

You can find more information on the relationship between stress and memory here and here.

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The surprising link between stress and memory - Elizabeth Cox

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You spend weeks studying for an important test. On the big day, you wait nervously as your teacher hands it out. You're working your way through, when you're asked to define "ataraxia." You know you've seen the word before, but your mind goes blank. What just happened?

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Newsela | Media multitasking disrupts memory, even in young adults, scientists say

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Simultaneous TV, texting, Instagram and other forms of screen-based media lead to memory-sapping attention lapses.