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A Topic I am Interested in: Neuroplasticity in teenagers

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A Topic I am Interested in: Neuroplasticity in teenagers

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Consider these tips for understanding teen stress.

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Mental health is a topic that is not discussed enough in schools and is often joked about. But it is something we all struggle with. This is everything you need to know about mental health, how to improve yours, and my personal journey of trying to improve mine.

What is mental health?

Mental health is our ability to handle stress, control our behavior, and make choices. When someone has a mental health disorder or mental illness, these abilities can become compromised and affect your day-to-day life. Some mental illnesses are depression, anxiety, OCD, schizophrenia, eating disorders, and behavioral problems.

"Mental health includes our emotional, psychological, and social well-being. It affects how we think, feel, and act." Mentalhealth.gov

When mental illnesses are ignored and untreated, it can lead to decreased enjoyment in life, substance abuse, social problems, and self-harm. However, feeling down or tired does not mean you are depressed, someone can have poor mental health and not have a mental illness. If you feel that you might have poor mental health, ask yourself these questions:

Have I been feeling sad or down lately?

Have I been worrying excessively lately?

Have I been eating or sleeping too much or too little?

Has it been harder for me to perform everyday tasks recently?

Am I failing to cope with daily problems and stress?

Do I have any thoughts of suicide or self-harm?

More questions can be found at Mentalhealth.com.

If you find yourself answering yes to more than one of these questions, contact your primary care provider to discuss your mental health and how you should properly deal with it.

What causes depression?

Unfortunately, there is not a known cause for depression but life events, genetics, medications, and hormones can increase your risk of having depression. Major or personal events such as moving, losing a loved one, and divorce can contribute to the risk of developing clinical depression. You can also have a higher chance of having depression if members of your family also have depression. Even changes in the body's hormonal balance can trigger depression.

What is anxiety, and what causes it?

Anxiety can easily be classified as an intense and constant worry and fear of everyday situations.

Often, anxiety disorders involve repeated episodes of sudden feelings of intense anxiety and fear or terror that reach a peak within minutes (panic attacks). Mayoclinic.org

Anxiety is common and it is natural to experience it sometimes in your life. However, there are many anxiety disorders such as social anxiety, separation anxiety, agoraphobia, panic disorders, selective mutism, and substance-induced anxiety. These disorders need to be diagnosed by a doctor and, if severe enough, your doctor might recommend you to take treatment to help with it.

Some symptoms of anxiety are:

Feeling nervous

Feeling restless

Constantly feeling that you are in danger

Constant panic

Trembling and an increased heartbeat

Having trouble concentrating

Having trouble sleeping

You should see a doctor if you experience some of the above problems and fear that they might be causing you to have poor health, not perform day-to-day activities and if it is causing you to have suicidal thoughts or actions.

What is OCD (Obsessive Compulsive Disorder)?

OCD is a mental health disorder that happens when someone gets stuck in an ongoing cycle of obsessions and compulsions. These behaviors generally start as a way to reduce stress and worry. Many people will experience these thoughts and behaviors at some point in their life but it does not mean you have OCD. You must be diagnosed by a doctor to know for sure if you have OCD but you can ask yourself these questions to see if you should contact your doctor to discuss getting a diagnosis:

Do I doubt uncertainty?

Am I afraid of "the unknown"?

Do I go out of my way to make things orderly and symmetrical?

Do I have bad thoughts about losing control over certain aspects of my life?

Do I have unwanted thoughts?

Do I follow a strict routine every day?

Am I constantly demanding reassurance?

How to improve your mental health

There are many prescription drugs that a doctor can prescribe to you, such as antidepressants, anti-anxiety medications, and mood-stabilizing medications. However, there are many things that you can do every day to improve your mental health:

Talk to a mental health professional - Even if you feel that your mental health is in good shape, talking to a professional can help maintain your mental health and prevent any future mental health issues.

Engage in physical activity regularly - Exercise can reduce stress, anxiety, and depression and improve your self-esteem and cognitive function.

Get enough sleep - Sleeping more will make your mood better and strengthen your immune system.

Practice gratitude - Remember what/who you are thankful for. Also, start a gratitude journal and write three things that you are thankful for from that day.

Avoid alcohol, smoking, and drugs - Heavy drinking, smoking, and any digestion of drugs can affect the chemicals in your body and brain.

Take breaks - While working, many of us get stressed. Taking short breaks while working can give your brain a "factory reset" and give you a chance to distress and focus better.

My ongoing journey

For me, it is easy to hide my feelings and true emotions. I would rather not tell people how I feel deep down than have them know and feel like they have to help me. So, I don't say a lot about how I'm feeling. But recently my life has got a little more confusing and difficult to deal with. So I got thinking, what should I be doing to be happier? How can I improve my life and mental health? Around this time, my family started going to church again and my mom talked more about how I should get closer to God.

When I was younger, I would love the church and would try to go with my friends every Sunday, but I was never close to God. I never actually understood what was being taught during Sunday school. I went because I liked having friends and being part of something with them. So now, as I am fifteen years old, I am trying to learn and understand what the bible says and strengthen my relationship with God (if I've even ever had one).

I have always heard people talking about how they have felt God with them for their whole life and have never questioned it, but all I have ever done is question it. I have tried so hard to feel something so I can finally believe that God is real and he is always with me, but it never happens. So maybe I am struggling a bit with finding my identity and understanding the bible and God, but I am trying and that is enough.

I have also been trying to be less afraid of my emotions and ashamed of myself. I think that in today's world we have become really quick to be ashamed of who we are and what has happened to us, but we shouldn't be. We are not our past, our trauma, or others' assumptions. So, I have been trying to open up more to others and I recommend that others do too. Once you are your true self and not ashamed of it, life does become a little easier.

Some regards if you are reading this

If you just read my article completely, I hope that it is not because you're running off of your last hope for life, love, and happiness. I hope that you know you are not alone and people are going through the same things as you. Your life is so valuable and precious and although it feels like no one cares, someone out there does. Someone always does, they just don't always show it. Now I understand how backward it is for me to tell you to be happier and to work harder on yourself when I, myself, am not doing the best, but I am trying and I really advise you to try too, because I believe that things can get better if we just hold on for a little longer.

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Mental Health Talk: a Talk from a Teenager for Teenagers.

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Mental health is a topic that is not discussed enough in schools and is often joked about. But it is something we all struggle with. This is everything you need to know about mental health, how to improve yours, and my personal journey of trying to improve mine.

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Abstract

Adolescence is a time of many psychosocial and physiological changes. One such change is how an individual responds to stressors. Specifically, adolescence is marked by significant shifts in hypothalamic-pituitary-adrenal (HPA) axis reactivity, resulting in heightened stress-induced hormonal responses. It is presently unclear what mediates these changes in stress reactivity and what impacts they may have on an adolescent individual. However, stress-sensitive limbic and cortical brain areas that continue to mature during adolescence may be particularly vulnerable to these shifts in responsiveness. Consequently, perturbations of the maturing adolescent brain may contribute to the increase in stress-related psychological dysfunctions, such as anxiety, depression, and drug abuse, often observed during this stage of development. The purpose of this review is to describe the changes that occur in HPA function during adolescence, as well as briefly discuss the possible ramifications of these changes on the developing brain and psychological health.

Keywords: Adolescence, Hypothalamic-Pituitary-Adrenal Axis, Puberty, Stress

Stress happens. It's a fact of life. However, the type of stressors we experience and how we respond to them change throughout our life. Adolescence represents a stage in development when both of these aspects of stress are in flux. Though most of us appreciate that the nature of stressors change during adolescence, less appreciated are the unique ways in which adolescent individuals respond to stress. This review will focus on the substantial shifts in stress reactivity exhibited during adolescence, particularly in the context of hormonal responsiveness. It will also discuss the potential impact of these hormonal changes on the developing adolescent brain. The research described in this review will largely highlight the work conducted on basic animal models, as it is from these models that most of our mechanistic understanding of age-dependent changes in stress reactivity and neurobiological function are derived.

The Stress Response

When an individual experiences a stressor, be it physical or psychological, two hormonal systems are activated to help the individual cope with the situation. The first is mediated by the rapid actions of the sympathetic nervous system, leading to the release of epinephrine and norepinephrine into the blood stream. It is this immediate response that mediates the transient so called "fight-or-flight" reaction to stress. The second is a slower, more protracted hormonal response mediated by the hypothalamic-pituitary-adrenal (HPA) axis. This response is initiated by a group of neurons in the paraventricular nucleus of the hypothalamus (PVN), which secrete corticotropin-releasing hormone (CRH) to signal the pituitary to release adrenocorticotropic hormone (ACTH). ACTH, in turn, stimulates the adrenal glands to synthesize and secrete the glucocorticoids (i.e., cortisol in humans and corticosterone in many rodent species). Once the stressor has ended, the glucocorticoids act though negative feedback on the pituitary gland and a variety of forebrain regions, namely the hypothalamus, hippocampus, and prefrontal cortex, ultimately terminating the response by reducing the further production and release of CRH and ACTH ( Herman et al., 2003; ). Thus, in the context of the HPA reaction to stress, the brain is both the initiator and a major target of the glucocorticoid response.

The glucocorticoids are responsible for many of the adaptive physiological and behavioral responses to stressors, such as mobilizing energy stores, enhancing immune reactions, and increasing learning and memory abilities. However, chronic or more prolonged exposure to these hormones can result in numerous maladaptive outcomes, including metabolic disorders and impaired immune and cognitive functions. Thus, factors that regulate HPA reactivity and the dynamics of the hormonal stress response can have important short- and long-term consequences on an individual's physiology and behavior ( McEwen, 1998).

Adolescent Development of the Hormonal Stress Response

Although adolescence is marked by many neuroendocrine changes, the shifts in HPA function are more subtle than the relatively conspicuous increases in gonadal hormones associated with puberty. That is, though basal ACTH and glucocorticoid levels remain fairly stable throughout adolescence, it is the amount and duration of these hormones released in times of stress that show notable changes. Numerous studies in both male and female rats, for instance, indicate that animals on the cusp of adolescence (i.e., ~30 days of age) show significantly protracted ACTH and corticosterone responses compared to adults (i.e., > 65 days of age) following a brief exposures to a variety of stressors (e.g., foot shock, hypoxia, restraint; Goldman, Winget, Hollingshead, & Levine, 1973; Romeo, Lee, Chhua, McPherson, & McEwen, 2004; Romeo, Lee, & McEwen, 2004; Vazquez & Akil, 1993). Specifically, these hormonal stress responses can last 45-60 min longer in animals prior to adolescent maturation ( Romeo, 2010a, 2010b; ). These extended hormonal responses in per-adolescent animals are different than those of neonatal pre-weanling rats (i.e., prior to 21 days of age), which usually demonstrate hypo-responsiveness to stressors ( Sapolsky & Meaney, 1986). Interestingly, these prolonged ACTH and corticosterone responses following stress do not just gradually assume their adult-like patterns as puberty and adolescence progress, but instead show relatively more abrupt shifts, with stress-induced ACTH responses maturing later (i.e., between 50-60 days of age) than corticosterone responses (i.e., between 30-40 days of age; Foilb, Lui, & Romeo, 2011; ). These data indicate that each node along the HPA axis may have its own developmental trajectory during adolescence. It is important to note that recent studies in human adolescents have also reported changes in hormonal responsiveness, though not exactly paralleling the rodent studies. More specifically, boys and girls in later stages of adolescence (15-17 years old) displaying greater stress-induced cortisol levels compared to individuals in late childhood or earlier stages of adolescence (9-13 years old; Gunnar, Wewerka, Frenn, Long, & Griggs, 2009; Stroud et al., 2009).

Contributing Factors that Mediate the Adolescent Changes in Stress Reactivity

The mechanisms that mediate these adolescent-related changes in hormonal responsiveness remain unclear. However, it appears to involve both the activation and feedback phases of the HPA response. In the context of activation, experiments have shown that neural activity in the PVN, particularly in the CRH-containing cells, is higher in adolescent than adult animals following stress ( Romeo et al., 2006; Viau, Bingham, Davis, Lee, & Wong, 2005). These data suggest that the prolonged ACTH and corticosterone responses prior to puberty may in part be driven by greater stress-induced CRH production and release. Along with these differences in activation, studies on negative feedback have shown that pre-treatment with the synthetic glucocorticoid, dexamethasone is less effective at blunting a stress-induced corticosterone response in prepubertal compared to adult rats ( Goldman et al., 1973). Thus, these results would support the notion that periadolescent animals may show less glucocorticoid-dependent negative feedback on the HPA axis than adults. Future studies will need to address what cellular mechanisms mediate these putative age-dependent changes in sensitivity to negative feedback, such as differences in glucocorticoid receptor function in the brain and pituitary. To date, however, these avenues of research have been largely unexplored.

Another factor known to significantly modulate hormonal stress reactivity in adult human and non-human animals is gonadal hormones ( Viau, 2002). In males, testosterone tends to reduce hormonal stress responsiveness, while in females estradiol often enhances stress reactivity ( Viau, 2002). It is possible, therefore, that the substantial difference in gonadal hormones experienced by animals before and after puberty account for the changes in stress reactivity. However, non-human animal studies that have experimentally manipulated gonadal hormone levels through surgery and/or hormone replacement have shown that prepubertal animals continue to show greater stress-induced ACTH and corticosterone responses compared to adults ( Romeo, Lee, Chhua, et al., 2004; Romeo, Lee, & McEwen, 2004). These results suggest, therefore, that simple differences in gonadal hormone levels before and after puberty are not responsible for these adolescent-related changes in HPA stress responsiveness.

The Interaction of Adolescence and Stress History on Hormonal Responsiveness

Similar to age, previous experience with stressors can also shape one's hormonal stress responsiveness ( Grissom & Bhatnagar, 2009). For example, an adult animal repeatedly exposed to the same stressor (homotypic stress) displays a habituated hormonal response compared to an adult exposed to that stressor for the first time. On the other hand, if an animal experiences the same stressor over and over again and is then hit with a novel stressor (heterotypic stress), a sensitized hormonal response is exhibited above that evoked by the novel stressor alone. These experience-dependent changes in HPA reactivity are different before and after adolescent development. In particular, homotypic stress leads to habituation in adults, but not in pre-adolescent males ( Lui et al., in press), while heterotypic stress leads to a similar peak response at both ages, but a slower recovery in animals prior to adolescence ( Lui et al., in press; ). It is currently unknown at what time during adolescence development these responses to homotypic and heterotypic stressors assume their adult-like patterns.

The mechanisms responsible for this age- and experience-dependent plasticity in HPA reactivity are unclear. Though the contribution of negative feedback to these experience-dependent changes has not yet been explored, recent evidence suggests that differential activation of the PVN may be involved. That is, similar to the greater activation of PVN neurons in adolescent animals following acute stress ( Romeo et al., 2006), adolescent animals also demonstrate higher PVN activation after both homotypic and heterotypic stress compared to adults, suggesting greater stress-induced hypothalamic drive to the pituitary prior to adulthood ( Lui et al., in press). In addition to neurobiological substrates mediating these shifts in reactivity, peripheral factors may also play a role. For instance, it is possible that the adolescent pituitary and adrenal glands are more sensitive to CRH and ACTH, respectively, than they are in adulthood, thus in part potentially contributing to their greater responsiveness during adolescence. Regardless of the mechanisms that mediate these age-specific hormonal responses, these data suggest that following an acute or repeated stressor an adolescent individual experiences greater exposure to the glucocorticoids than an adult.

Stress and the Adolescent Brain: a Perfect Storm?

As alluded to above, the brain is a major target of the glucocorticoids and these hormones are known to be potent modulators of many neurobiological processes, including neuronal plasticity ( McEwen, 2007). In adults, chronic exposure to stress results in smaller and structurally less complex hippocampal and prefrontal cortical neurons. These morphological changes are also paralleled by decreases in spatial learning and attention shifting, cognitive abilities reliant upon an intact hippocampus and prefrontal cortex, respectively. Neurons in the amygdala, conversely, show stress-induced growth in adulthood, along with increased amygdala-dependent fear learning ( McEwen, 2007). Importantly, these effects of stress on the adult brain are reversible, such that if animals are allowed to recover from the stressors for at least 10 days, then these parameters revert to their pre-stress levels ( McEwen, 2007).

Though we know relatively little about how stressors experienced during adolescence may influence the immediate and long-term structure and function of the brain, many factors may converge during this stage of development that may make the adolescent brain particularly vulnerable to stressors. First, recent longitudinal structural neuroimaging studies have indicated that the areas known to be the most sensitive to stress in adulthood, namely the hippocampus, prefrontal cortex, and amygdala, all continue to mature during adolescence ( Giedd & Rapoport, 2010). Second, the adolescent brain may be more responsive to the glucocorticoids than the adult brain, as a previous animal study indicated that an equivalent dose of corticosterone increased gene expression to a greater degree in the adolescent compared to adult hippocampus ( Lee, Brandy, & Koenig, 2003). Finally, due to the increases in hormonal stress reactivity described above, it would appear that these maturing and exquisitely stress-sensitive brain regions in the adolescent would be exposed to greater and more prolonged levels of glucocorticoids. Thus, like a "perfect storm", the convergence of these factors may render the adolescent brain especially vulnerable to perturbations, and hence psychological morbidities ( Romeo & McEwen, 2006).

Unfortunately, there is a scarcity of studies that directly compare the effects of stress on the adolescent and adult brain, and fewer that track whether these effects are more enduring if the stressors occur during adolescence. Thus, support for the notion that the adolescence brain may be particularly sensitive to stress has yet to be thoroughly tested empirically. A growing body of research, however, has begun to report on the effects of acute and chronic stress exposure on the structure and function of the adolescent brain. Studies in young adult rats indicated that previous exposure to chronic stress during adolescence resulted in reduced structural plasticity in the hippocampus and prefrontal cortex, and increased plasticity in the amygdala ( Eiland, Ramroop, Hill, Manely, & McEwen, 2012; Isgor, Kabbaj, Akil, & Watson, 2004). Additional animal studies using models of social stress during adolescence (e.g., social instability, isolation) have also indicated decreases in markers of neural plasticity, such as neurogenesis and synaptic connectivity ( Leussis & Andersen, 2008; McCormick, Nixon, Thomas, Lowie, & Dyck, 2010). These stress-induced alterations in the adolescent brain are also associated with compromised emotional function and cognitive skills ( Eiland et al., 2012; Isgor et al., 2004; Leussis & Andersen, 2008). Although from these data it would seem that the impact of chronic stress on the adolescent and adult brain is similar, one important difference may be in the reversibility of these effects. Specifically, even a month after recovery from chronic adolescent stress, some of these structural and functional changes persist ( Isgor et al., 2004; Leussis & Andersen, 2008). It would therefore appear that the effects of stress on the adolescent brain may be longer lasting when compared to the adult. Future experiments will need to directly assess this possibility, as well as explore whether there are other unique effects of stress on the structure and function of the adolescent brain.

Conclusions

The data reviewed above clearly indicate that adolescence is time of dramatic changes in HPA function and stress responsiveness. Adolescence is also a significant period of continued neural maturation, specifically within stress-sensitive limbic and cortical regions. Thus it is possible that prolonged or repeated exposure to stress may result in a heightened sensitivity to these stressors, ultimately leading to maladaptive neurobehavioral development. Though the physiological and psychological implications of stress on the adolescent brain are far from clear, the increases in stress-related dysfunctions during adolescence, such as anxiety, depression, schizophrenia, and drug abuse highlight the importance of a better understanding of the interaction between changes in stress reactivity and adolescent brain development.

Acknowledgments
Funding
Preparation of this article was supported in part by grants from the National Institutes of Health (MH-090224) and the National Science Foundation (IOS-1022148).

Recommended Reading

McEwen, B. S. (2007). (See References). A thorough review on HPA physiology and the influence of stress on the structure and function of the brain.

Romeo, R. D. (2010b). (See References). This review provides greater detail of HPA changes during pubertal and adolescent maturation.

References

Lui P, Padow VA, Franco D, Hall BS, Park B, Klein ZA, Romeo RD. Divergent stress-induced neuroendocrine and behavioral responses prior to puberty. Physiology and Behavior (in press) [PMC free article]

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The Teenage Brain: The Stress Response and the Adolescent Brain

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Adolescence is a time of many psychosocial and physiological changes. One such change is how an individual responds to stressors. Specifically, adolescence is marked by significant shifts in hypothalamic-pituitary-adrenal (HPA) axis reactivity, resulting in heightened stress-induced hormonal responses. It is presently unclear what mediates these changes in stress reactivity and what impacts they may have on an adolescent individual.

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Why Teenage Brains Are So Hard to Understand

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It's not just you. Researchers are finding that teenage brains really are special.

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You don’t have permission to access this resource.

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Stress hormones have a profound effect on the body and brain.

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Study shows how the pandemic may have affected teens’ brains | CNN

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The social and emotional effects of the Covid-19 pandemic on teenagers may have resulted in accelerated brain aging in adolescents, according to a new study.

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INTRODUCTION

Completing the circle, there is increasing appreciation of the effects of stress on the mechanisms of neuroplasticity ( Shors et al, 1989; reviewed in McEwen, 1999). Clearly, then, there is an intimate relationship between the effects of stress, the mechanisms of neuroplasticity, and the pathophysiology of depression and mechanisms of antidepressant action.

We explore this relationship in this review, outlining the major molecular and cellular pathways related to neuroplasticity that are altered by stress and appear to contribute to behaviors related to depression. We then discuss the mechanisms of antidepressant response, their overlap with mechanisms of neuroplasticity, and how they oppose the effects of chronic stress in various behavioral models. Together, these studies support a model of disruption of neuroplasticity by stress that contributes importantly to the pathophysiology of depression, and that is blocked or reversed by antidepressant treatment.

IMPAIRMENTS OF LEARNING AND MEMORY IN MAJOR DEPRESSION

Cognitive impairment is a core endophenotype of major depression ( Hasler et al, 2004). One of the formal diagnostic criteria for the syndrome is a 'diminished ability to think or concentrate' ( American Psychiatric Association, 2000), and patients often complain of difficulty with cognitive function during everyday tasks.

Disruption of hippocampal function, including the capacity for neuroplasticity, could contribute to several aspects of major depression. In addition to its clear role in declarative memory, the hippocampus is a key regulator of prefrontal cortical function; hippocampus and DLPFC function cooperatively to regulate explicit memory. Disruption of hippocampal function in major depression could therefore contribute to the observed deficits in concentration, described above. Hippocampal afferents are also critical regulators of both the nucleus accumbens and the ventral tegmental area (VTA). It has been hypothesized that an indirect excitatory projection from hippocampus to VTA is critical for coordinating the firing of VTA cells in response to novelty ( Lisman and Grace, 2005); impairment of this hippocampal function could thus lead to reduced dopaminergic tone and contribute to anhedonia ( Warner-Schmidt and Duman, 2006). Finally, the hippocampus provides an important source of negative modulation of the hypothalamus-pituitary-adrenal stress hormone axis through its projections to the hypothalamus; hippocampal dysfunction therefore may contribute to the dysregulation of the stress response that is seen in major depression.

STRESS EFFECTS ON NEUROPLASTICITY: A PATHOPHYSIOLOGICAL CONTRIBUTOR TO MAJOR DEPRESSION?

Chronic stress has many effects on the central nervous system, including effects on neuroplasticity in brain structures that are functionally abnormal in major depression. Given the clear clinical relationship between stress and major depression, these effects represent candidate pathophysiological links between stress, the mechanisms of neuroplasticity, and the development of major depressive disorder (MDD).

Hippocampus: Effects of Prolonged Stress on Hippocampus-Dependent Memory, Plasticity, Cell Survival, and Neurogenesis

Transient mild stress can enhance learning and memory ( Luine et al, 1996). However, chronic or severe stress is decidedly disruptive of hippocampus-dependent memory in experimental animals ( Conrad et al, 1996; de Quervain et al, 1998; Diamond et al, 1999; reviewed in Sapolsky, 2003). Extended or high-dose treatment with glucocorticoids has a similar effect ( Bodnoff et al, 1995; de Quervain et al, 1998). Specific impairments of hippocampus-dependent explicit memory are also seen after treatment of human subjects with glucocorticoids ( Newcomer et al, 1999; de Quervain et al, 2000) and after stress (reviewed in Shors, 2005).

Hippocampal synaptic plasticity, as modeled by long-term potentiation (LTP), is widely believed to represent an important component mechanism of hippocampus-dependent memory formation ( Malenka and Bear, 2004; see Figure 1). It is therefore striking that a sufficiently severe stress can impair LTP in the rodent hippocampus ( Foy et al, 1987; Shors et al, 1989; reviewed in Kim and Diamond, 2002). Conversely, similar stress paradigms in rodents enhance long-term depression (LTD) in the hippocampus ( Xu et al, 1997); the two effects are likely to have overlapping mechanisms, as both are prevented by N-methy-D-aspartate (NMDA) blockade during the behavioral stress ( Kim et al, 1996). The effect of serum glucocorticoids mirrors that of stress: low levels of glucocorticoids amplify LTP (perhaps through preferential activation of hippocampal mineralocorticoid receptors), while higher levels attenuate it (perhaps because they saturate the mineralocorticoid receptors and lead to robust activation of glucocorticoid receptors; reviewed in De Kloet, 2004).

Hippocampal anatomy and sites of well-characterized forms of neuroplasticity. Neuroplasticity has been particularly intensively studied in the hippocampus. (a) Anatomy of the rodent hippocampus in coronal section is shown. Major synaptic projections include the perforant path from entorhinal cortex to dentate gyrus, the mossy fiber pathway from dentate gyrus to area CA3, and the Schaffer collateral pathway from area CA3 to area CA1. Other pathways exist but have been less intensively studied and are left out for clarity. Neurogenesis occurs in the subgranular cell zone of the dentate gyrus. (b) Synaptic plasticity has been characterized in all major synaptic pathways, but has been particularly intensively studied in the Schaffer collateral pathway; typical placement of stimulating and recording electrodes in an in vitro LTP experiment is shown.

PowerPoint slide

Sustained levels of stress or glucocorticoids also damage the hippocampus at the level of morphological neuroplasticity (reviewed in Sapolsky, 2000) ( Figure 2). Excess glucocorticoids ( Woolley et al, 1990) or behavioral stress ( Watanabe et al, 1992; Magarinos et al, 1996) lead to atrophy and retraction of the apical dendrites of hippocampal pyramidal cells; this effect leads to a reduction in the amount of neuropil without frank cell loss, reminiscent of what has been documented in the post-mortem hippocampus of patients with major depression ( Stockmeier et al, 2004). Prolonged high-dose corticosterone-at higher levels than are typically achieved in vivo-can even result in death of hippocampal pyramidal cells ( Sapolsky et al, 1985).

Stress alters neuroplasticity at multiple structural levels. (a) Chronic stress can reduce the number of dendritic spines. In this example, 8 weeks of postweaning social isolation produced a significant reduction in dendritic spines in mPFC in stress rat (lower panel) compared to controls (upper panel), as visualized by Golgi-Cox staining. From Silva-Gomez et al, 2003, with permission; scale bar=5 μm. (b) Chronic stress can reduce the length and complexity of coritcal dendrites. In this example, repeated restraint stress (3 h a day for 3 weeks) produced shorter and less complex apical dendrites (indicated by arrows) in stressed rats (on the right) as compared to controls (on the left), as visualized in mPFC pyramidal neurons by computer-assisted resconstructions from Golgi-stained material. From Cook and Wellman, 2004, with permission; scale bar=50 μm. (c) Chronic stress can impair neurogenesis. In this example, 3 weeks of daily unpredictable stressors reduced the generation of new neurons in the rat dentate gyrus (lower panel) compared to unstressed controls (upper panel). Neurogenesis is visualized by labeling with bromo-deoxyuridine (BrdU), which labels recently divided cells, and doublecortin (DCX), a marker of immature neurons. Ja-Wook Kim and RSD; scale bar=20 μm.

PowerPoint slide

Prefrontal Cortex: Effects of Prolonged Stress on Morphology and Function

It is tempting to speculate that such stress-induced atrophy of prefrontal dendrites and a reduction in glial number contribute to the 'hypofrontality' observed in patients with major depression (see above). Some data support an effect of chronic stress on prefrontal physiology and information processing. For example, acute stress can perturb synaptic plasticity at the projection from amygdala to PFC ( Maroun and Richter-Levin, 2003). At the reverse projection, from PFC to amygdala, stress shifts the balance from one that favors LTD to one that favors LTP ( Maroun, 2006).

While the precise contribution of such perturbations to the network changes in brain function that characterize the depressed state is difficult to infer, these findings support the notion that sufficient levels of stress alter the mechanisms of neuroplasticity in a group of interconnected structures, which are functionally abnormal in major depression. Furthermore, even though only a few studies have examined synaptic plasticity in these structures after stress, the directions of the documented changes are concordant with the abnormalities seen in major depression. PFC is hypoactive in major depression; and potentiation of a major excitatory pathway leading to it is attenuated by stress. Conversely, the amygdala is hypertophic and hyperactive in major depression, and potentiation of a major input to it-from the ventro mPFC -is enhanced.

Amygdala: Stress-Induced Hypertrophy

The contrast between the effects of stress on the amygdala and those on the hippocampus and PFC is striking. Whereas acute and chronic stress impair hippocampal function, reduce the length and complexity of CA3 dendrites, and impair neurogenesis, very similar treatments lead to enhanced amygdala-dependent fear learning, increased length and complexity of amygdalar dendrites, and increased amygdala size. This contrast makes it clear that the well-documented effects of stress on hippocampal morphology and function are not manifestations of a universal effect of stress hormones or other aspects of stress on neuronal integrity. Rather, the effects of stress on brain morphology and function are region and circuit dependent. Both acute and chronic stress can have very different effects of different brain regions and functions, a fact with profound implications for our understanding of the pathophysiology of major depression.

Ventral Striatum: Stress-Associated Changes in Neuroplasticity and the Mechanisms of Reward

MOLECULAR AND CELLULAR MECHANISMS OF NEUROPLASTICITY

The mechanisms of synaptic and morphological plasticity have been extensively studied in the context of their contribution to learning and memory ( Malenka and Bear, 2004; Citri and Malenka, this volume). It is here that some of the most striking parallels between the mechanisms of neuroplasticity and those underlying MDD emerge, especially in the overlap between the cellular mechanisms of synaptic plasticity and the molecular and cellular changes that attend antidepressant treatment. A dizzying array of molecular components has been implicated in synaptic plasticity in various systems ( Sanes and Lichtman, 1999); it is not our intention to comprehensively review this vast literature. Rather, we emphasize some of the common themes in studies of synaptic and structural plasticity, and some of the specific molecular players most cogent to a subsequent discussion of the mechanisms of antidepressant response.

Inducers and Local Mechanisms of Synaptic Plasticity

Mechanistically distinct forms of experimentally induced synaptic plasticity have been described in a number of different systems ( Malenka and Bear, 2004). A common theme is that many forms of synaptic potentiation are triggered by increases in synaptic calcium influx and in the local concentration of the second messenger molecule cyclic AMP (cAMP). These pathways are particularly well suited to the requirements of a plasticity-inducing mechanism. Local calcium influx, for example, commonly derives from the NMDA receptor, which is a highly evolved coincidence detector-it is activated only when presynaptic and postsynaptic cells are depolarized simultaneously. Such coincidence detection is precisely what is required for many forms of homosynaptic plasticity ( Hebb, 1949). cAMP is regulated by many modulatory neurotransmitters, including serotonin, dopamine, and norepinephrine, as well as by calcium; it is therefore optimally suited for the integration of synaptic events with the modulatory influences of global variables such as arousal and attention.

Local elevations in calcium and cAMP induce events required for short-term synaptic plasticity. For example, the calcium-calmodulin-dependent kinase II (CaMKII), which is activated by local increases in calcium, is critical for early LTP. CaMKII has unique properties that make it well suited to a role in the induction of synaptic plasticity. Upon induction by a sufficient rise in the local concentration of calcium, it can phosphorylate itself. Autophosphorylated CaMKII is persistently active, even after calcium levels fall. This mechanism allows an inducing pulse of calcium to lead to more persistent activation of CaMKII, and thereby to activation of downstream processes that result in synaptic change ( Lisman and Goldring, 1988).

Several other calcium-calmodulin kinases exist in neurons. CaMKIV, in particular, is prominent in the neuronal nucleus, where it is an important activator of regulated transcription factor such as CREB ( Bito et al, 1996). Inhibition of CaMKIV impairs both long-lasting forms of LTP and long-lasting hippocampus-dependent learning ( Kang et al, 2001). Calcium calmodulin-dependent kinases can thus contribute to both short-term and long-lasting neuroplasticity.

Both CaMKII and other kinases can phosphorylate the GluR1 subunit of the AMPA glutamate receptor and associated proteins. This phosphorylation both increases the number of AMPA receptors in the postsynaptic membrane (by triggering insertion of new AMPA receptors) and enhances the function of those receptors already inserted. Both mechanisms contribute to an enhancement of synaptic strength.

At the structural level, insertion of AMPA receptors can result in the activation of 'silent synapses' ( Malenka and Nicoll, 1997). A silent synapse is a synaptic connection at which the postsynaptic membrane contains only NMDA receptors ( Figure 3). Because of the NMDA receptor's coincidence detection properties, such a synapse is not activated by simple depolarization of the presynaptic cell. Upon the induction of LTP, AMPA receptors are inserted into the postsynaptic membrane at such a synapse, rendering it active upon subsequent single presynaptic impulses (hence no longer 'silent'). This unsilencing of silent synapses contributes to synaptic strengthening and appears to be a major mechanism of LTP.

Major molecular pathways involved in neuroplasticity and affected by stress, depression, and antidepressant treatment. Some major molecular pathways involved in both short- and long-term neuroplastic changes are shown. Certain intermediates and other details are left out for clarity. Many of these pathways are influenced in opposite ways by stress and depression. For example, both chronic stress in animals and depression in humans have been associated with reductions in the transcription factor CREB, and antidepressants enhance CREB activity in the hippocampus. See text for further details and references. Abbreviations: NMDA, N-methyl-D-aspartate glutamate receptor; AMPA, amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid glutamate receptor; VGCC, voltage-gated calcium channel; 5-HT, 5-hydroxytryptamine (serotonin); NE, norepinephrine; DA, dopamine; BDNF, brain-derived neurotrophic factor; Trk-B, BDNF receptor; AC, adenylyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; AMP, adenosine monophosphate; PDE, phosphodiesterase; CaMK, calcium-calmodulin-dependent kinase; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; Rsk, ribosomal S6 protein kinase; CREB, cAMP response element-binding protein.

PowerPoint slide

Transduction to the Nucleus

While short-term changes in synaptic strength can be mediated by local events at the synapse, such as AMPA receptor phosphorylation and insertion into the postsynaptic membrane, longer-term changes require a broader coordination of cellular mechanisms-in particular, induction of genes and production of new protein ( Nguyen et al, 1994). Upon sufficient local elevation of calcium and cAMP, therefore, signal transduction cascades are activated that transmit the inducing signal to the nucleus ( Kandel, 2001). (Specific signaling molecules, such as kinases and phosphatases, can participate both in local, early events and in signaling to the nucleus and the transition to more persistent forms of plasticity, as in the case of CaM kinases discussed above).

One signal transduction cascade that has been particularly clearly tied to the mechanisms of late-phase LTP (L-LTP) is the cAMP-dependent protein kinase, PKA ( Abel et al, 1997). PKA consists of a regulatory and a catalytic subunit; at rest, the regulatory subunit binds to the catalytic subunit, inactivating it. Upon sufficient accumulation of cAMP, the two subunits dissociate, freeing the catalytic subunit to phosphorylate a variety of substrates. Since cAMP is increased by β-adrenergic, 5-HT4, 6, 7, and dopamine D1 receptors, activation of PKA represents a mechanism by which modulatory neurotransmitters can influence the mechanisms of long-lasting synaptic plasticity.

Effector Genes-Neurotrophins and Structural Change

BDNF acts by multiple mechanisms and influences both early and late phases of synaptic plasticity, in both the presynaptic and the postsynaptic cells. It acts, at least in part, via the MAPK signaling cascade, suggesting that this pathway plays multiple roles in the regulation of plasticity. Other growth factors have also been demonstrated to influence LTP, including vascular endothelial growth factor (VEGF; Cao et al, 2004). Like BDNF, VEGF activates the MAPK cascade and has been implicated in the actions of stress and antidepressant treatments, as will be further discussed below.

Positive and Negative Regulators of Neuroplasticity

Neurogenesis

Behavioral studies in animals in which neurogenesis has been experimentally perturbed lend support to the idea that the new cells play a critical causal role in some forms of hippocampus-dependent learning. Administration of a chemotherapeutic agent that kills dividing cells impairs step-down avoidance, which depends on the function of the hippocampus (along with other structures; Shors et al, 2001). Saxe et al (2006) found that ablation of new neurons impaired dentate gyrus LTP (as measured in vitro) and hippocampus-dependent contextual fear conditioning, but did not affect cued fear conditioning (which does not require the hippocampus). Data on the role of the new neurons in spatial learning are conflicting: Saxe et al (2006) found ablation of the new neurons to spare spatial learning in the Morris water maze, while others have found interference with neurogenesis to compromise spatial learning ( Snyder et al, 2005). Further studies will be needed to clarify the role that new hippocampal neurons play in learning and memory.

This outline of molecular pathways contributing to neuroplasticity is necessarily selective and incomplete. More thorough treatments are given elsewhere ( Malenka and Bear, 2004; Citri and Malenka, this volume), although this literature is so vast that it has become virtually impossible to review comprehensively. It does, however, lay the groundwork for an examination of how behavioral stress and pharmacological treatment with glucocorticoids alter signaling pathways associated with neuroplasticity.

IMPACT OF STRESS ON THE MOLECULAR PATHWAYS OF NEUROPLASTICITY

We have reviewed above some of the evidence that stress can lead to alterations in morphological plasticity: regression of dendrites, reduction in spine density, and a shrinkage of the neuropil in hippocampus and PFC. We now turn to effects of stress on some of the molecular mechanisms underlying neuroplasticity.

As noted above, acute and chronic stress can have quite different effects on learning: while acute stress can potentiate learning (and LTP; Shors, 2001), chronic stress leads to deficits in hippocampus-dependent memory reminiscent of those seen in major depression. It is therefore to be expected that the downstream molecular changes resulting from stress or manipulations of stress hormones may depend sensitively on the intensity and duration of the stressor glucocorticoid excess. This issue has not yet been explored in sufficient experimental detail for firm conclusions to be drawn. In the brief review presented here, we merely point out evidence that stress and glucocorticoids, either acute or chronic, can influence mechanisms implicated in neuroplasticity, without attempting to draw firm conclusions about the specific functional consequences of specific alterations in plasticity mechanisms or about mechanistic distinctions that may exist between the effects of acute and chronic stress on these systems.

Contributions of Glutamate to Neuronal Atrophy after Stress

The effects of chronic stress on glutamatergic neurotransmission can be seen in alterations in the expression of glutamate receptor genes. For example, glucocorticoids can enhance AMPA-mediated excitatory synaptic transmission ( Karst and Joëls, 2005). This contrasts with the finding that maternal separation stress has been shown to lead to lasting reduction in the expression of the NMDA receptor subunit NR2B and of the AMPA receptor subunits GluR1 and GluR2 ( Pickering et al, 2006); differences in the level and chronicity of stress or glucocorticoid exposure may explain these contrasting results, which merit further study.

Stress-Induced Alterations Plasticity-Associated Signaling Pathways

Stress Regulation of Growth Factors

Other Downstream Target Genes

ANTIDEPRESSANTS INDUCE NEUROPLASTICITY

If the effects of stress on the mechanisms of neuroplasticity contribute to the pathophysiology of depression, then antidepressant treatments might be expected to affect the same mechanisms. Substantial evidence suggests that this is in fact the case. In the simplest scenario, where chronic stress impairs the mechanisms of neuroplasticity, antidepressants would be predicted to have the opposite effect and enhance them. There are multiple situations in which this is in fact the case. Other instances are likely to be more complicated, as stress and antidepressant treatment impact the complicated and interacting mechanisms of neuroplasticity in contrasting but not directly opposite ways. A deepened appreciation of these interactions will inform our evolving understanding of the pathophysiology of depression and the mechanisms of antidepressant action, and is likely to guide the search for novel antidepressant strategies in the future.

Enhanced Neuroplasticity and Cognitive Function with Treatment in Depressed Patients

If depression entails a deficit in neuroplasticity, then antidepressant treatments may enhance neuroplasticity and even reverse deficits produced during the symptomatic period. Few studies to date have examined the effect of antidepressant therapies on cognition in normal human subjects, in part simply because of the ethical difficulties that would attend administration of chronic antidepressant therapy to patients who are not ill. One recent double-blind study suggested improvement in memory and a variety of other cognitive domains with chronic fluoxetine treatment in elderly patients with mild cognitive impairment ( Mowla et al, 2007). Given the mounting evidence that antidepressant treatment can promote neuroplasticity, further studies of this sort, using antidepressants with a primary goal of enhancing impaired cognitive function, may be warranted.

A small literature does address the improvement of cognitive deficits, and even of structural damage, in patients treated with a variety of antidepressant therapies. Electroconvulsive therapy (ECT) is perhaps the most efficacious antidepressant therapy (and, incidentally, the one with the most profound effects on the mechanisms of neuroplasticity). Examination of cognitive improvement in patients receiving ECT is complicated by the fact that memory difficulties, especially retrograde amnesia, are a clear side effect of the treatment ( Sackeim, 2000). However, many patients show clear cognitive improvement, even shortly after treatment ( Sackeim et al, 1992).

Antidepressants Enhance Learning and Memory in Animal Models

Investigations of the effect of antidepressants on LTP have produced mixed results, with some studies reporting increases in LTP with antidepressant treatment, some decreases, and some with no effects. However, closer examination, comparing effects in subfields of hippocampus (ie dentate gyrus vs CA1 pyramidal cell layer) and/or types of antidepressants (tricyclic vs nontricyclic SSRIs), reveals more consistency.

In the dentate gyrus, where high-frequency stimulation of the perforant pathway projection to granule cells is used to stimulate LTP, both chronic ECS and chemical antidepressant treatment increase LTP ( Stewart and Reid, 2000; Levkovitz et al, 2001). One of these studies ( Stewart and Reid, 2000) found that chronic ECS or SSRI (fluoxetine) administration increases baseline field potentials in the dentate gyrus. In vitro LTP was reduced; this was interpreted as representing a ceiling effect, resulting from prior induction of plasticity by ECS or fluoxetine. The other study reports that either desipramine or mianserin administration results in increased LTP of dentate gyrus ( Levkovitz et al, 2001). It is interesting to speculate that this increased potential for plasticity in the dentate could result from an increased number of newborn granule cells, which are known to have greater potential for neuroplasticity ( Toni et al, 2007; Tashiro et al, 2007).

Much less is known about the influence of antidepressant treatments on behavioral models of learning and memory. Chronic administration of fluoxetine or venlafaxine, a mixed action reuptake inhibitor, is reported to improve performance in the Morris water maze, a spatial learning and memory model ( Nowakowska et al, 2000, 2003, 2006), although another study found that fluoxetine did not influence performance in this task ( Stewart and Reid, 2000). Chronic imipramine or tianeptine were not effective in the Morris water maze ( Nowakowska et al, 2000, 2003), although another study found that chronic amitriptyline prevents age-induced impairments in learning and memory ( Yau et al, 2002). This latter study also found a decrease in circulating corticosterone levels in antidepressant-treated rats that could contribute to the observed improvement in learning and memory. Tianeptine, but not fluoxetine, has been reported to improve discrimination performance in a radial maze task ( Jaffard et al, 1991). Finally, chronic imipramine, but not paroxetine, has recently been reported to impair spatial working memory in a radial arm maze task ( Naudon et al, 2007). Clearly, additional studies are needed to further test the influence of different classes of antidepressants in a standardized manner on behavioral models of learning and memory to fully characterize the influence of these agents.

Antidepressant Treatment Enhances Structural Plasticity and Neurogenesis

Increasing evidence suggests that, in addition to enhancing functional neuroplasticity, antidepressants produce structural plasticity. This is observed at several different levels, including numbers of synapses, spines, dendrites, and even numbers of cells.

At the smallest scale, antidepressant treatment has been reported to increase the number of synapses, determined by electron microscopy ( Hajszan et al, 2005). This study examined the influence of fluoxetine administration of different durations in ovariectomized rats. As few as 5 days of fluoxetine treatment increases the number of synapses in the CA1 pyramidal cell layer, while longer treatment (14 days) also produced a similar increase in the CA3 pyramidal cell layer. Another study found that chronic administration of a tricyclic antidepressant (amitriptyline) blocked the decrease in spine density in dentate gyrus, CA3 and CA1 cell layers that results from olfactory bulbectomy, a widely used model of depression-like behaviors ( Norrholm and Ouimet, 2001; in this study, amitriptyptyline alone did not produce an increase in spine density). Although still preliminary, these labor-intensive studies provide evidence for altered structural plasticity at the levels of both synapse and spine density.

Establishing the causal role of neurogenesis in the behavioral actions of antidepressants has been challenging, as it is technically difficult to functionally perturb the new neurons without simultaneously disrupting other aspects of behavior or hippocampal function. Evidence to date, however, suggests that the induction of neurogenesis is required for antidepressant action. A casual role for neurogenesis in behavioral change requires that a response to antidepressants be dependent on chronic treatment, because it takes several weeks for newborn neurons to differentiate and mature into functional neurons; such a delayed mechanism of action is consistent with the typical delayed therapeutic response to antidepressants. Two paradigms that are dependent on long-term antidepressant administration are novelty-suppressed feeding and chronic unpredictable stress. These models differ from other standard antidepressant screening paradigms, such as the forced swim and tail suspension tests that respond to acute or short-term antidepressant treatments. An initial study found that blockade of cell proliferation by irradiation blocked the actions of antidepressants in novelty-suppressed feeding and chronic unpredictable stress paradigms ( Santarelli et al, 2003). In addition, 5-HT1A mutant mice, in which SSRI induction of neurogenesis is blocked, show an attenuated antidepressant response ( Santarelli et al, 2003). Recent studies using another a genetic model to ablate cells that express GFAP, which includes neural precursors, have confirmed these effects (Rene Hen, personal communication).

Effects of Antidepressant Treatment on Glutamatergic Neurotransmission

Several lines of evidence suggest that established antidepressants can directly modulate glutamatergic neurotransmission. For example, tricyclic antidepressants directly block the NMDA receptor pore at micromolar concentrations ( Reynolds and Miller, 1988). Chronic antidepressant treatment alters the conformation of the NMDA receptor, suggesting some form of longer-term compensatory change (reviewed in Paul and Skolnick, 2003). Such actions of antidepressants on the NMDA receptor may represent a mechanism whereby they can influence the mechanisms of neuroplasticity at the synaptic level.

A striking recent finding that emphasizes the interaction between antidepressants and glutamatergic neurotransmission is the rapid antidepressant effect of the NMDA antagonist ketamine. This startling effect was first observed in a small study designed to test the psychotomimetic properties of ketamine in depressed patients ( Berman et al, 2000) and was more recently replicated in a larger study ( Zarate et al, 2006). As in the case of increased glutamate after chronic stress, this effect is initially counterintuitive: NMDA activation is trophic and enhances neuroplasticity, so NMDA blockade might be expected to worsen cellular damage. Two observations may make sense of this apparent conundrum. As noted above, synaptic and extrasynaptic NMDA receptors have contrasting effects on neuroplasticity and cellular survival. It is likely that subanesthetic doses of an NMDA antagonist have a preferential effect on extrasynaptic NMDA receptors, both because the higher-affinity NR2B-containing receptors may be more prevalent in the extrasynaptic space and because the ambient glutamate concentration with which the NMDA antagonist must compete is much lower. In addition, in vivo evidence from rats suggests that, again at subanesthetic concentrations, ketamine may preferentially block NMDA receptors on GABAergic interneurons and thereby paradoxically increase synaptic glutamate tone, at least in the frontal cortex ( Moghaddam et al, 1997). This possibility is supported by the observation that NMDA receptor antagonists increase the expression of BDNF, and activity-dependent gene expression ( Metsis et al, 1993), and increase adult hippocampal neurogenesis ( Gould and Cameron, 1997). Appropriately dosed ketamine may therefore simultaneously decrease activation of extrasynaptic NMDA receptors and enhance glutamate tone at synaptic NMDA receptors, producing a net pro-neuroplasticity effect (reviewed in Pittenger et al, 2007).

ANTIDEPRESSANTS INCREASE NEUROPLASTICITY-RELATED SIGNALING PATHWAYS

Overlap between the molecular actions of synaptic plasticity and those targeted by antidepressants provided some of the earliest and strongest evidence for mechanistic overlap between the two phenomena. These studies demonstrate that some of the key signaling components identified as critical regulators of LTP and synaptic plasticity are also regulated by antidepressants and are required for the cellular and behavioral actions of antidepressant treatments.

Antidepressants Upregulate the cAMP-PKA-CREB Cascade

Evidence from a number of different studies has demonstrated that antidepressant treatments upregulate the cAMP signal transduction pathway. This includes increased levels of Gαs coupling to adenylyl cyclase in the hippocampus and frontal cortex and resulting elevation of cAMP production in response to chronic administration of different classes of antidepressants (reviewed in Donati and Rasenick, 2003). Levels of PKA are also reported to be upregulated by chronic administration of different classes of antidepressants, including tricyclics, MAOIs, and ECS ( Nestler et al, 1989; Perez et al, 1989). Levels of PKA are increased in particulate fractions, and subcellular fractionation studies demonstrate increases in both the nuclear ( Nestler et al, 1989; Tiraboschi et al, 2004b) and microtubule fractions ( Perez et al, 2000). The increases in nuclear PKA levels are more consistent with SNRI than SSRI antidepressants, and vary somewhat depending on the brain region examined (PFC vs hippocampus) and type of enzyme activity (basal vs cAMP-stimulated) in different studies.

These studies provide convincing evidence that the cAMP-PKA-CREB cascade is regulated by antidepressant treatment, and that activation of this pathway can produce an antidepressant response in behavioral models. The evidence linking these effects to synaptic plasticity is less robust. As described above, the cAMP-PKA-CREB pathway has a central role in many forms of neuroplasticity, and antidepressants can enhance LTP and memory; but this argument for a role for CREB-mediated neuroplasticity is circumstantial. No studies to date have directly tested the role of this pathway in the actions of antidepressants, and future studies will be required to test this hypothesis.

Antidepressants Regulate CaMKII

A number of studies have investigated the regulation of CaMKII by antidepressants. Several studies have reported that chronic, but not acute, antidepressant treatment increases CaMKII enzymatic activity in neuronal cell bodies of the hippocampus, due to an increase in autophosphorylation of CaMKII at Thr ²⁸⁶ ( Popoli et al, 1995; Celano et al, 2003; Tiraboschi et al, 2004a). As described above, phosphorylation at this site leads to Ca ²⁺-independent activation of CaMKII and therefore extended enzymatic activity. Subsequent studies demonstrate that there is also an increase in CAMKII expression, enzymatic activity, and phosphorylation in synaptic vesicles of the hippocampus and PFC after antidepressant treatment ( Celano et al, 2003), but a decrease in phosphorylation of CaMKII in synaptic terminals and synaptic membranes ( Bonanno et al, 2005). This apparent contradiction has been resolved by a recent study from the same group, demonstrating that antidepressant treatments (with either an SSRI or an SNRI) cause a redistribution of CaMKII from synaptic membranes to vesicles and a corresponding decrease in membrane-associated synapsin I ( Barbiero et al, 2007). Since vesicles localized with the synaptic membranes are closely related to the readily releasable pool of glutamate, this redistribution suggests that antidepressant treatment reduces the potential for glutamate release. This is supported by a functional study demonstrating that depolarization-induced release of glutamate is decreased ( Bonanno et al, 2005).

If this interpretation is correct-that modulation of CaMKII by antidepressants leads to a net decrease in synaptic release of glutamate-antidepressant treatment would decrease the potential for synaptic plasticity, at least via this mechanism. While a reduction in membrane-associated synaptic vesicles could decrease the overall release of glutamate, the resulting effect could be to increase the signal-to-noise ratio such that only salient stimuli lead to synaptic plasticity-related changes in the hippocampus and PFC. An enhanced signal-to-noise ratio may be further enhanced by potentiation of other mechanisms contributing to plasticity through alterations in downstream postsynaptic mechanisms such as cAMP-mediated and MAPK signaling (as reviewed above and below, respectively). Alternatively, the reported upregulation of CAMKII in cell bodies, as opposed to presynaptic terminals, could lead to other types of synaptic plasticity and neuroprotection that also contribute to the actions of antidepressant treatments.

Antidepressants Upregulate the MAPK Cascade

Taken together these studies indicate that antidepressants upregulate the MAPK pathway, opposing the actions of suicide/depression, and that blockade of the MAPK cascade results in despair/helplessness and inhibition of the antidepressant actions in behavioral models. However, there are also conflicting reports on antidepressant regulation of phospho-ERK1/2, depending on the brain region, subcellular fraction, and antidepressant tested.

ANTIDEPRESSANTS UPREGULATE NEUROTROPHIC FACTOR EXPRESSION

Another line of evidence supporting the hypothesis that antidepressant treatment leads to altered neuroplasticity is the regulation of neurotrophic factors by antidepressants. As described above, certain neurotrophic factors, such as BDNF, are regulated by activity; BDNF has been shown to be necessary and sufficient for induction of LTP and performance in some models of learning and memory (reviewed in Pang and Lu, 2004). Furthermore, BDNF is critical to numerous forms of neuroplasticity, and is reduced by chronic stress, as reviewed above. We now review the evidence that antidepressant treatment increases BDNF and other trophic factors.

Antidepressant Treatment Increases the Expression of BDNF

Chronic antidepressant administration increases the expression of BDNF in the hippocampus and PFC ( Nibuya et al, 1995; reviewed in Duman and Monteggia, 2006); this effect contrasts with the inhibition of BDNF by chronic stress, as reviewed above. Increased expression of BDNF is observed with different classes of antidepressants, including SSRI, SNRI, MAOI, atypical agents, and ECS. The induction of BDNF is dependent on chronic treatment for 2-3 weeks and is pharmacologically specific: other types of psychotropic drugs do not increase BDNF in the hippocampus and PFC.

There have been a number of conflicting studies, reporting no change or even decreased BDNF expression. These discrepancies are most likely due to differences in the time course or dose of antidepressant tested, or the time after the last treatment (reviewed in Duman and Monteggia, 2006). Since BDNF expression is also decreased by stress and increased by neuronal activity, the individual experimental conditions (eg housing, treatment) are critical for the outcome of these studies.

Together, these studies provide strong support for the hypothesis that reduced BDNF expression contributes to depression-like behavior in animal models and may lead to similar effects in humans, and that antidepressant treatment increases or reverses this deficit. These findings are consistent with the hypothesis that BDNF-induced neuroplasticity contributes to the actions of antidepressants, although it is also possible that other BDNF actions (such as neuroprotection) also play a role.

Antidepressant Treatment Increases the Expression of VEGF

The results of these studies suggest that VEGF is necessary and sufficient for the behavioral and neurogenic actions of antidepressants. Moreover, the results demonstrate that VEGF contributes to the actions of antidepressants in both short- and long-term responses. It is possible that the rapid effects of VEGF and antidepressants are mediated by regulation of neuroplasticity and synaptic transmission, while the more long-term effects occur via regulation of neurogenesis. Further studies will be required to more completely delineate the cellular mechanisms underlying the actions and interactions of VEGF and antidepressants.

It is striking that multiple neurotrophins have now been implicated in antidepressant action. Indeed, the list may not end here-there is evidence that insulin-like growth factor-1 and fibroblast growth factor-2 are involved in stress, depression, and antidepressant responses ( Duman and Monteggia, 2006). There are several possible explanations for this apparent redundancy. First, multiple trophic factors may provide redundancy for neuroplasticity and neuroprotection-critical neuronal functions. However, complete redundancy of the different factors is not supported by data, suggesting that BDNF and VEGF are individually necessary, not just sufficient, for antidepressant responses. It is possible that the different trophic factors exert different, complementary actions, in addition to functions that have some overlap. Additional studies will be needed to fully characterize the interactions of these neurotrophic/growth factor systems.

LIMITATIONS OF THE NEUROPLASTICITY HYPOTHESIS

The neuroplasticity hypothesis suggests that impaired mechanisms of neuroplasticity are a core pathophysiological feature of MDD, that chronic stress is an important causal factor in the development of this impairment, and that antidepressant treatments act, at least in part, through mitigation of impaired mechanisms of plasticity. This hypothesis unifies much clinical and preclinical data, which we have sought to summarize above. However, the hypothesis also has important limitations.

Neuroplasticity in the amygdala may likewise work contrary to antidepressant effects, though here the argument is more circumstantial. Chronic stress and glucocorticoid treatment increase dendritic branching and synaptic connectivity in the amygdala, perhaps paralleling the increased size of the amygdala reported in some neuroimaging studies of depressed patients. It seems likely that these plastic events contribute to the development of a depressive state, rather than contributing to antidepressant response.

This suggestion raises the concerning possibility that novel therapeutic strategies aimed at the enhancement of neuroplasticity may have unintended pro-depressant effects through their impact on the nucleus accumbens or other structures outside the hippocampal system that has informed most of our discussion. Early studies suggest that the predominant effect of activating neuroplasticity-associated signaling systems is an antidepressant response. Systemic administration of rolipram, which activates the cAMP-CREB cascade, produces an antidepressant effect in behavioral models ( O'Donnell and Zhang, 2004). Similarly, intraventricular infusions of BDNF produce an antidepressant response in the forced swim test ( Hoshaw et al, 2005). Despite these promising results, further studies in a variety of behavioral models are needed to fully characterize the global effects of activation of neuroplasticity-associated pathways.

RELEVANCE OF ENHANCEMENT IN NEUROPLASTICITY TO BEHAVIORAL MODELS OF DEPRESSION

Although enhanced neuroplasticity is considered a desirable adaptation, the relationship with the actions of antidepressants is not readily interpretable. Are the enhancements in neuroplasticity we have reviewed part of an important pathway that contributes to antidepressant effects? Are they a consequence of altered mood state or homeostasis of modulatory neurotransmitters or hormone systems? Or is the association of enhanced neuroplasticity with antidepressant effect an epiphenomenon-suggestive of shared underlying mechanisms, perhaps, but not necessarily indicative of a causal relationship between the two phenomena?

The nature of the behaviors in rodents that are widely used to model aspects of depression and have proven validity for predicting antidepressant response may shed some light on this question. Most of the behaviors used to assay antidepressant effect in rodents-learned helplessness, the forced swim test, and the tail suspension test, for example-are models of behavioral despair and coping. Animals are placed in an adverse circumstance from which it is difficult or impossible to escape, and they enter a behavioral state of passivity in which they no longer attempt to do so. It may be that enhancements in neuroplasticity, and the corresponding increased capacity to adapt and learn, lead to an enhanced potential repertoire of behaviors or capacity to explore new escape options in these adverse circumstances, and thus reduces the tendency to enter such a state of behavioral despair. This interpretation predicts that enhanced neuroplasticity is, indeed, causally important for reduced depression-like behaviors, at least in models of behavioral despair. It is to be hoped that as our understanding of the complex relationships between stress, depression, and neuroplasticity grows, the functional interrelationship of one to another will become more clear. Even at this early point, the extensive mechanistic parallels between these disparate phenomena suggest a deep causal connection.

SUMMARY AND CONCLUSIONS

The molecular mechanisms of antidepressant response overlap with those of neuroplasticity to a striking degree. We have described three levels of neuroplasticity in which this parallel can be seen. Synaptic plasticity (including morphological change in dendritic spines and other concomitants of synaptic connections) has been well characterized in many brain regions, most prominently the hippocampus. Many of the molecular mechanisms of synaptic plasticity are induced by antidepressants; again, the hippocampus presents the best-characterized example of this fact. Parallels are seen both with the mechanisms of short-term plasticity-such as the insertion of AMPA receptors into the membrane and the modulation of CaMKII-and with those of long-term plasticity-such as the activation of transcription factors such as CREB and the induction of plasticity-enhancing genes such as BDNF.

Parallels are also seen at the level of dendritic morphology. Increases in dendritic branching can be induced by enriched environments ( van Praag et al, 2000), growth factors, and other neuroplasticity-inducing manipulations. Similar increases in dendritic length and complexity can be induced by antidepressant treatment. Finally, neurogenesis represents a more recently appreciated but profound mechanism of neuroplasticity, permitting the insertion of new neurons into the dentate gyrus of the adult animal. Here, too, neurogenesis is stimulated both by plasticity-inducing stimuli (such as environmental enrichment, exercise, and electrical stimulation) and by antidepressant treatments.

While it is difficult to examine these mechanisms in tissue from depressed humans, evidence exists for impairment of neuroplasticity in major depression. Molecular concomitants of certain aspects of synaptic plasticity-such as expression and phosphorylation of the transcription factor CREB-are reduced in post-mortem tissue from depressed subjects. Depression leads to shortening and reduced complexity of dendritic trees, in the hippocampus and the PFC. It remains to be determined whether neurogenesis is reduced in patients with major depression (the one study published to date was negative; Reif et al, 2006); but neurogenesis has been shown to occur in the human hippocampus in adulthood ( Eriksson et al, 1998), and thorough examination of whether it is reduced in major depression is certainly warranted by the strength of the preclinical evidence.

Stress is well established to contribute to the development of major depression in susceptible individuals. It is likely that any comprehensive account of the pathophysiology of mood disorders will include an important causal role for psychological and physiological stress. It is therefore striking that chronic stress, too, opposes many forms of neuroplasticity. As reviewed above, chronic stress reduces synaptic plasticity and dendritic spines, reduces the length and complexity of dendrites, and impairs neurogenesis.

The convergence of these literatures-neuroplasticity, antidepressant response, and the consequences of chronic stress-on an overlapping set of molecular and cellular mechanisms is increasingly apparent and suggests a deep connection between these three phenomena. Further explorations and better understanding of these relationships is likely to point the way toward a deeper understanding of affective disorders and, it is to be hoped, toward novel treatments. This will include the development and use of novel strategies for imaging structural and molecular pathways in human subjects in vivo, as well as post-mortem and genetic studies to identify and define the exact alterations underlying the disruption of neuroplasticity in depressed subjects. The findings demonstrating altered neuroplasticity have already provided novel targets for drug development and future studies will continue to identify and refine the information for further development of more effective therapeutic interventions.

DISCLOSURE/CONFLICT OF INTEREST

RSD is a consultant for Taisho Pharmaceuticals and Psychogenics, has received funding for investigator initiated research from Lilly, Organon, Pfizer, Sepracor, and Roche, and has received speaker honorariums from Lilly, Pfizer, Sepracor, Roche, Bristol-Myers-Squibb and Wyeth-Ayerst. CP has no disclosures or conflicts to report.

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Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms - Neuropsychopharmacology

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Increasing evidence demonstrates that neuroplasticity, a fundamental mechanism of neuronal adaptation, is disrupted in mood disorders and in animal models of stress. Here we provide an overview of the evidence that chronic stress, which can precipitate or exacerbate depression, disrupts neuroplasticity, while antidepressant treatment produces opposing effects and can enhance neuroplasticity.

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Abstract

Adolescence represents a critical period for brain and behavioural health and characterised by the onset of mood, psychotic and anxiety disorders. In rodents, neurogenesis is very active during adolescence, when is particularly vulnerable to stress. Whether stress-related neurogenesis changes influence adolescence onset of psychiatric symptoms remains largely unknown. A systematic review was conducted on studies investigating changes in hippocampal neurogenesis and neuroplasticity, hippocampal-dependent cognitive functions, and behaviour, occurring after adolescence stress exposure in mice both acutely (at post-natal days 21-65) and in adulthood. A total of 37 studies were identified in the literature. Seven studies showed reduced hippocampal cell proliferation, and out of those two reported increased depressive-like behaviours, in adolescent rodents exposed to stress. Three studies reported a reduction in the number of new-born neurons, which however were not associated with changes in cognition or behaviour. Sixteen studies showed acutely reduced hippocampal neuroplasticity, including pre- and post-synaptic plasticity markers, dendritic spine length and density, and long-term potentiation after stress exposure. Cognitive impairments and depressive-like behaviours were reported by 11 of the 16 studies. Among studies who looked at adolescence stress exposure effects into adulthood, seven showed that the negative effects of stress observed during adolescence on either cell proliferation or hippocampal neuroplasticity, cognitive deficits and depressive-like behaviour, had variable impact in adulthood. Treating adolescent mice with antidepressants, glutamate receptor inhibitors, glucocorticoid antagonists, or healthy diet enriched in omega-3 fatty acids and vitamin A, prevented or reversed those detrimental changes. Future research should investigate the translational value of these preclinical findings. Developing novel tools for measuring hippocampal neurogenesis in live humans, would allow assessing neurogenic changes following stress exposure, investigating relationships with psychiatric symptom onset, and identifying effects of therapeutic interventions.

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Introduction

The adolescent hippocampus has more granule cells and a larger volume compared to the adult hippocampus in both rodents and humans [ 13, 14]. Hippocampal neurogenesis, defined as the generation of new neurons within the subgranular zone of the dentate gyrus (DG), and their integration into the granule cell layer [ 15], is four times higher in adolescence compared to adulthood in rodents [ 16] and humans [ 17]. Evidence generated from rodent studies suggests that neurogenesis is necessary for specific cognitive functions, including pattern separation, which is the ability to distinguish between similar but different contexts and to differentiate a threat from a neutral situation [ 18], as well as for antidepressant efficacy [ 19, 20, 21, 22], and resilience to stress [ 23]. Hippocampal neurogenesis has been shown to decrease after stress in mouse models involving exposure to an intruder, intermittent feeding, social isolation, communication deprivation, and others, which can result in impaired memory, learning, and emotional regulation [ 24, 25].

It is well known that adolescence is a critical period for the onset of psychiatric disorders; with a peak/median age at onset of 14.5/20 years for obsessive compulsive disorders, 15.5/30 for stress disorders, 20.5/31 for mood disorders and 20.5/25 for schizophrenia [ 40], and is characterised by the presence of cognitive and emotional symptoms which persists into adulthood [ 41]. Changes in neurogenesis during adolescence may affect the preservation and integration of emotional memories, and the selection of memories that are maintained versus those that are filed away [ 42, 43, 44], which may contribute to personality development and adult mental health. As such, understanding how hippocampal neurogenesis is affected during adolescence is important, not only from a mechanistic perspective, but also for the development of novel therapeutic strategies (or for the repurposing of existing ones) targeting neurogenic mechanisms during this critical period in people suffering environmental stress exposure.

This systematic review aims to investigate acute and long-term (during adulthood) changes in hippocampal neurogenesis, neuroplasticity, and hippocampal-dependent cognitive and behavioural outcomes, in rodents exposed to stress during adolescence. In addition, this review discusses findings from studies employing pharmacological and non-pharmacological interventions as therapeutic strategies to reverse or prevent post-exposure deficits in hippocampal neurogenesis, neuroplasticity, cognition, and behaviour.

Methods

This systematic review complies with the PRISMA (Preferred Reporting Items for Systematic Reviews) guidelines. It comprises of papers published so far until July 2023, identified across the following databases: PubMed, Embase, PsycInfo and Web of Science, which assessed hippocampal neurogenesis and neuroplasticity in adolescent rodents exposed to stress paradigms, and cognitive and depressive-like behaviour outcomes both immediately after the stress exposure as well as during adulthood. Adolescent stress models were biological, such as cortisol or cytokine injections, and behavioural paradigms, including social defeat, isolation and chronic mild stress in either rats or mice from PND21 to PND65, which corresponds to adolescence in humans [ 16]. Hippocampal neurogenesis was assessed by quantifying cells at different stages of maturation. In particular, cell proliferation was quantified by counting cells expressing Ki67, a marker expressed in each mitotic phase except G0, and Bromodeoxyuridine (BrdU), a marker injected either weeks and/or briefly before sacrifice. BrdU is also used to measure new-born neuron differentiation when in co-labelling with the marker NeuN, and survival. Immature neurons were quantified in those studies using the marker doublecortin (DCX) [ 45]. Hippocampal neuroplasticity was quantified measuring pre- and post-synaptic density proteins, long-term potentiation, as well as neurotrophic factors, which are necessary for newly generated neurons maturation and integration in existing circuits.

The complete inclusion and exclusion criteria, and the search algorithm, can be found in the Supplementary Materials, along with the PRISMA flowchart. Additionally, the studies were assessed for risk of bias, including failing to describe rodents' baseline characteristics, random housing or blinding, following the SYRCLE guidelines for rodent studies [ 46] (Supplementary Table 1). The results of these studies are summarised in Table 1.

Table 1 Summary of studies investigating acute and long-term changes in hippocampal neurogenesis, neuroplasticity, and hippocampal-dependent cognitive and behavioural outcomes, in rodents exposed to stress during adolescence.

Results

In total, 905 studies were extracted and 37 of these met our inclusion criteria (Supplementary Fig. 1). Inclusion criteria for the studies were: using rodents who underwent stress exposure biological or behavioural paradigms during adolescence, and assessed hippocampal neurogenesis and neuroplasticity, together with behavioural and cognitive outcomes immediately after stress exposure and later during adulthood. Specifics about timings and type of adolescent stress paradigms, hippocampal neurogenesis measures, neuroplasticity markers, and cognitive and behavioural assessments, are reported in Table 1.

Acute cellular and behavioural outcomes of adolescence stress exposure

Hippocampal neurogenesis and hippocampal-dependent cognitive and behavioural functions

Three studies [ 40, 41, 53] quantified Ki67+ cells, which are in any phase of mitosis except G0 and showed that early on Ki67+ cells are found increased at PND33 [ 54] and decreased at PND35 [ 50], and there was no longer any change at PND46 [ 54] or PND49 [ 49]. Types of stress were social defeat or social instability, and the timing of stress exposure was earlier (PND24-34) in the study that found decreased Ki67+ cells [ 50], and later (PND30-45) in the study reporting a Ki67+ cell increase [ 49, 54]. No relationship with memory (spatial and object recognition) or depressive-like behaviour (forced swim and sucrose preference test) was found in the study reporting decreased proliferation after social defeat at PND24-34 [ 50] and social instability stress at PND30-45 [ 49, 54].

Five studies measured the effects of adolescent stress exposure on number of cells expressing doublecortin (DCX+) [ 47, 54, 55, 56, 57], which has been largely used to assess numbers of neuroblasts or immature neurons in rodents, human, and non-human primates [ 58], although recent studies have questioned its specificity as neurogenesis marker [ 16, 59].

After exposure to social defeat fewer DCX+ cells were reported in rats at PND42, and the adolescent defeated rats more frequently initiated play behaviour but adopting submissive postures, while once they became adults, they coped behaviourally and physiologically better with a similar exposure to an aggressive male rat than unstressed controls [ 47].

Fewer DCX+ cells and reduced neurite branching on hippocampal neurons were also observed at PND63 after treatment with interleukin (IL)-1beta (IL1β), without an effect on performance in pattern separation, novel object recognition or spontaneous alternation in the Y maze [ 57].

An increase in DCX+ cells was reported at PND46 after social instability [ 54], and at PND65 after chronic mild stress (CMS) [ 55], while there was no change in DCX+ cells after CMS at PND42 [ 55] or restraint stress at PND56 [ 56]. No change in pattern separation, memory (object recognition, spatial recognition), or depressive-like behaviour (forced swim and sucrose preference test) was found when increased or unchanged DCX+ cell number were reported after stress [ 54, 56, 57].

New-born neurons quantified by counting cells co-localising for BrdU and the neuronal marker NeuN (BrdU/NeuN+), after BrdU injections three and four weeks before sacrifice [ 50, 51, 53] were fewer after chronic social defeat exposure during PND24-34 [ 50] and social isolation at PND21-49 [ 53]. These effects were reversed by mifepristone, a glucocorticoid receptor (GR) antagonist [ 50], and the antidepressant fluoxetine [ 53]. A study did not show any difference in new-born neuron number in rodents exposed to chronic cortisol treatment at PND28-48 [ 51].

The study showing fewer BrdU/NeuN+ new-born neurons after social isolation at PND21-49, found altered spatial memory and emotion-related behaviours in juvenile mice [ 53]. While two studies showing fewer BrdU/NeuN+ new-born neurons after social defeat at PND24-34 [ 50] or no difference in BrdU/NeuN+ neurons after cortisol treatment at PND28-48 [ 51], did not find an effect of these exposures on depressive-like behaviour measured with the sucrose preference test [ 50, 51].

Neuroplasticity and hippocampal-dependent cognitive and behavioural outcomes

Additionally, proteins expressed in the presence of neuroplastic activity, such as polysialylated-neural cell adhesion molecule (PSA-NCAM) and neural cell adhesion molecule L1 (NCAM-L1), were increased in a study upon exposure to auditory fear conditioning soon after the stressful experience and during adulthood, suggesting alteration of the normal maturational decrease in L1 expression and therefore delayed maturation of the limbic system [ 65]. Another study exposed juvenile rats to variable stress, delivering a different stressor every day for 3 days, forced swim, elevated platform, and foot shock or restraint stressors (at PND27-29) [ 66] and found missing development-related decrease in PSA-NCAM to NCAM expression ratio in the basolateral amygdala, in the CA1 and dentate gyrus regions of the hippocampus, and in the entorhinal cortex, with an increase in the polysialylation of NCAM soon after exposure and in adulthood. A third study of exposure to chronic peripubertal stress protocol consisting of two different fear-inducing stressors: exposure to a synthetic fox odour, and elevated platform at PND28-42 found that peripubertal stress led to changes in emotional and glucocorticoid reactivity to novelty exposure, as well as in the expression levels of the plasticity molecule PSA-NCAM in the hippocampus. [ 67]. Similarly, other neuroplastic proteins, such as the immediate early gene Arc, involved in the consolidation of memories, were increased in two studies upon exposure to restraint and social defeat stress at PND21 and PND45-46, respectively [ 68, 69], whereas Erg1, involved in learning and memory, was decreased after social defeat only in male rodents [ 69].

Two studies found a decrease in LTP after acute restraint stress during PND28-30 [ 72], and PND30 [ 71], but no cognitive or behavioural changes were measured.

Six studies reported that dendritic formation, density and morphology were disrupted after adolescent stress [ 61, 73, 76, 77, 78, 79]. A marker of dendrite formation, spinophilin, was increased in males after social isolation, but decreased in females upon exposure to social isolation at PND30-35, and was associated with a decrease in latency to immobility during forced swim test, considered a measure of behavioural despair or learned helplessness, in both males and females [ 76]. Four studies reported that exposure to social defeat (PND35-44) and chronic restraint stress (PND20-41, PND21-35, PND21-28) reduced dendritic spine density and detrimentally affected their morphology (length and size) [ 61, 73, 77, 78]. Dendritic spine density and morphology changes were accompanied by memory deficits, measured using the Morris water maze test, and depressive-like behaviours, measured with the forced swim test and the sucrose preference test [ 73, 77]. Chronic physical stress decreased mossy fibres, axons of DG granule cells that project within the hilus and stratum lucidum, and innervate hilar cells and CA3 pyramidal cells and increased hippocampus Cornu Ammonis (CA)1 volume in both wild type (exposed at PND28-55) and in variable physical stress sensitive rats (exposed at PND28-41) [ 79, 80]. The rats were classified on the basis of their locomotor reactivity to novel objects, which has been associated with sensitivity to stress [ 80]. These changes were accompanied by spatial memory deficits, measured using the Morris water maze test, and increased depressive-like behaviour, measured with the forced swim test [ 79, 80]. Overall, deficits in dendrite formation and changes in their density and morphology were associated with memory dysfunctions and depressive-like behaviour.

Delayed cellular and behavioural outcomes of adolescence stress exposure

Hippocampal neurogenesis, cognitive functions, and behavioural outcomes

Studies reporting fewer DCX+ cells at PND42 after social defeat [ 47] showed more submissive behaviour in adolescence, although rats were able to cope once they got to adulthood.

Neuroplasticity and hippocampal-dependent cognitive and behavioural outcomes

Another study exposed juvenile rats to variable stress, delivering a different stressor every day for 3 days, forced swim, elevated platform, and foot shock or restraint stressors (at PND27-29) [ 66] and found reduced novel-setting exploration and impaired two-way shuttle avoidance learning in adulthood.

Interestingly, only cognitive but not behavioural changes occurring during adulthood were prevented by the dietary supplements (omega-3 fatty acids and vitamin A), that ameliorated cognitive function and in depressive-like behaviours during adolescence, even if tehre were continuously administered since adolescence (PND30-75) [ 85]. However, only cognitive but not behavioural changes occurring during adulthood were prevented by the dietary supplements, administered since adolescence (PND30-75). Together, these studies found that detrimental effects on neuroplasticity, cognitive functions and behaviour can either persist or develop in adulthood as a consequence of stress exposure during adolescence, and demonstrate the beneficial role of nutritional interventions in preventing these effects.

Discussion

We provided the first systematic review of the available literature investigating acute and long-term changes in hippocampal neurogenesis, neuroplasticity and hippocampal-dependent cognitive and behavioural outcomes occurring in rodents exposed to stress during adolescence. Overall, studies found a reduction in hippocampal cell proliferation (BrdU+ cells only) associated with increased depressive-like behaviours in rodents exposed to stress challenges, however a reduction in the number of new-born neurons was not accompanied by changes in cognition and behaviour. In addition, studies observed alterations in neuroplasticity, including a decrease in pre- and post-synaptic markers, dendritic spine length and density, and in synaptic potential. Changes in neuroplasticity were accompanied by cognitive impairments, such as a decrease in learning and memory, and by an increase in depressive-like behaviours. The detrimental effects of stress on cell proliferation, cognition and depressive-like behaviour that were observed during adolescence had variable impact in adulthood. Interestingly, treatment with antidepressants, glutamate receptor inhibitors or GR antagonists (during adolescence), or omega-3 fatty acids and vitamin A supplements administered (during both adolescence and adulthood), prevented or reversed those detrimental changes.

Changes (increase or decrease) in the aforementioned outcomes are indicated with arrows. Legend: increase (↑) or decrease (↓).

An opposite trend was observed when using chronic social stress [ 54, 55], where the animals might have had time to adapt to the social stress and develop coping strategies. We reported that resilient individuals, with early life adversity exposure before age 16 and no psychopathology lifetime, have more granule cells and a larger DG than suicide decedents with and without early life adversity exposure, and non-exposed controls [ 87]. This is in line with the possibility that resilient mice within the same strain might have more neurogenesis and more granule neurons, supporting their effective coping strategies.

Novel object recognition, sucrose preference, and forced swim test did not show any deficit associated with changes in DCX+ and BrdU/NeuN+ cell numbers, irrespective of the stress challenge used (restrain stress, social instability, cortisol or IL1β injection) [ 50, 51, 54, 56, 57].

Decreased PSD95 and synaptophysin were accompanied by depressive-like behaviours, measured using the sucrose preference test [ 60, 62] (Fig. 1), independently of the type of stress challenge used, either biological (cortisol) [ 62] or psychological (CUMS) [ 60] that were applied chronically (PND29-49, PND28-61) [ 60, 62]. Therefore, future studies should test the differential effects of acute and chronic stress exposure on different types of neuroplasticity as well cognitive and behavioural functions, during adolescence and later in life.

Changes (increase or decrease) in the aforementioned outcomes are indicated with arrows. Legend: increase (↑) or decrease (↓).

In addition to pharmacological treatments, nutritional intervention with omega-3 fatty acids and vitamin A since adolescence (PND30-45), reversed the decrease in BDNF level and object discrimination performance, previously observed during adolescence (at PND50), but also prevented their persistence during adulthood (at PND70) (Fig. 2) [ 85]. The omega-3 fatty acids and Vitamin A dietary supplements could prevent the decrease in sucrose preference shortly after the intervention in adolescence (PND45), however this preventative effect did not persist during adulthood (PND70) [ 85]. Since the sucrose-preference test was the only measurement of depressive-like behaviour, additional tests, such as the forced swim test and the tail suspension test could be conducted to validate these results, as done by other aforementioned studies [ 50, 51, 56, 77]. Accordingly, previous studies have shown that consumption of diets rich in omega-3, vitamin A or vitamin E are able to induce an increase in the levels of hippocampal neurogenesis and hippocampal volume, and reduce depressive symptoms, respectively in adult rodents [ 94, 95] and humans [ 96, 97, 98]. However, at present, studies investigating the effect of these interventions, especially non-pharmacological, on neurogenesis during adolescence are relatively limited. Further investigations will be of fundamental importance to understand the exact neurogenic mechanisms through which these treatments work in adolescent rodents and, as a consequence, how they can be best used as therapeutic strategies in adolescent humans where putatively similar mechanisms are compromised.

Although this review has limitations due to the relatively small number of studies, there were a variety of models used, and numerous molecular as well as cognitive and behavioural tests were performed in the studies. This is the first attempt at conducting a systematic review summarising changes in hippocampal neurogenesis, hippocampal neuroplasticity, and hippocampal-dependent cognitive function and behavioural outcomes in adolescent rodents exposed to stress models of depression, and also investigating long-term changes in the same outcomes during adulthood. Such a comprehensive insight into the possible holistic effects of neurogenesis is necessary to uncover and translate its potential as a therapeutic target for patients experiencing adolescent depression. While more rodent research is needed to determine whether there is a causal relationship between reduced neurogenesis (induced by a stress challenge) and onset of depressive-like behaviours, it is important to note that out of the 15 studies investigating both neurogenic changes and depressive-like behaviour, 10 studies reported both a decline in neurogenesis or neuroplasticity and concomitant depressive behaviours [ 48, 51, 60, 61, 62, 76, 77, 80, 84, 85]. Of note, while depressive behaviours in rodents are not fully comparable with human depressive symptoms, they still reliably recapitulate some of the aspects of the depressive phenotype often observed in depressed individuals.

Conclusion and future directions

In conclusion, this is the first systematic review reporting detrimental changes in hippocampal neuronal survival, hippocampal neuroplasticity, and in hippocampal-dependent cognitive function and behavioural outcomes in adolescent rodent models of depression. Much of what is known about the functional role of hippocampal neurogenesis has been studied in adult animals. Given the limited number of studies performed in adolescent animals, more work is needed to elucidate the behavioural effects of changes in hippocampal neurogenesis in adolescence, both in terms of immediate and long-term effects. Moreover, the effect of antidepressants and dietary interventions in adolescence remains to be fully understood. There is the need for novel neuroimaging tools to measure hippocampal neurogenesis in living humans, ultimately bridging the translational gap between animal and clinical findings and contributing to the development of novel and effective treatment approaches targeting hippocampal neurogenesis for adolescents with depression.

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Funding

This work was funded by a Wellcome Trust Mental Health 'Active Ingredients' commission awarded to Dr Alessandra Borsini at King's College London.

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Author notes

These authors contributed equally: Alessandra Borsini, Juliette Giacobbe.

Authors and Affiliations

1. Stress, Psychiatry and Immunology Laboratory, Institute of Psychiatry, Psychology and Neuroscience, Department of Psychological Medicine, King's College London, London, UK

Alessandra Borsini, Juliette Giacobbe & Gargi Mandal

2. Department of Psychiatry, Columbia University, Molecular Imaging and Neuropathology Division, New York State Psychiatric Institute, New York, NY, USA

Maura Boldrini

Contributions

AB, JG and GM have conducted the literature search. AB drafted the manuscript. MB, JG and GM provided feedback on the draft and approved the final manuscript.

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Correspondence to Alessandra Borsini.

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Borsini, A., Giacobbe, J., Mandal, G. et al. Acute and long-term effects of adolescence stress exposure on rodent adult hippocampal neurogenesis, cognition, and behaviour. Mol Psychiatry 28, 4124-4137 (2023). https://doi.org/10.1038/s41380-023-02229-2
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Acute and long-term effects of adolescence stress exposure on rodent adult hippocampal neurogenesis, cognition, and behaviour - Molecular Psychiatry

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Adolescence represents a critical period for brain and behavioural health and characterised by the onset of mood, psychotic and anxiety disorders. In rodents, neurogenesis is very active during adolescence, when is particularly vulnerable to stress. Whether stress-related neurogenesis changes influence adolescence onset of psychiatric symptoms remains largely unknown.

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Brain Development During Adolescence: Neuroscientific Insights Into This Developmental Period

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Adolescence is the phase of life between late childhood and adulthood. Typically, adolescents seek diversion, new experiences, and strong emotions, sometimes putting their health at serious risk. In Germany, for example, 62% of all deaths among…

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Originally published in the Harvard Mental Health Letter, July 2005

In every generation, it seems, the same lament goes forth from the parents of adolescents: "What's the matter with kids today?" Why are they so often confused, annoying, demanding, moody, defiant, reckless? Accidental deaths, homicides, and binge drinking spike in the teenage years. It's the time of life when psychosis, eating disorders, and addictions are most likely to take hold. Surveys show that everyday unhappiness also reaches its peak in late adolescence.

Plenty of explanations for teenage turmoil are available. Adolescents need to assert their independence and explore their limits, taking risks, breaking rules, and rebelling against their parents while still relying on them for support and protection. ("What's the matter with the older generation?") They have to cope with disconcerting new sexual impulses and romantic feelings. Cultural change heightens incompatibility between the generations. Now scientific research is suggesting a new reason for the clashes between teenagers and their environment. Unsettled moods and unsettling behavior may be rooted in uneven brain development.

It's not a question of intellectual maturity. Most studies show that abstract reasoning, memory, and the formal capacity for planning are fully developed by age 15 or 16. If teenagers are asked hypothetical questions about risk and reward, they usually give the same answers as adults. But the emotional state in which they answer questionnaires is not necessarily the one in which they make important choices. In real life, adolescents, compared to adults, find it more difficult to interrupt an action under way (stop speeding); to think before acting (learn how deep the water is before you dive); and even to choose between safer and riskier alternatives. It is easy for them to say that they would not get into a car with a drunk driver, but more difficult to turn down the invitation in practice. Adolescents' judgment can be overwhelmed by the urge for new experiences, thrill-seeking, and sexual and aggressive impulses. They sometimes seem driven to seek experiences that produce strong feelings and sensations.

Resisting social pressure is also more difficult for teenagers. Much of their troubling behavior, from gang violence to reckless driving and drinking, occurs in groups and because of group pressure. In a psychological experiment, adolescents and adults took a driving simulation test that allowed them to win a reward by running a yellow light and stopping before they hit a wall. Adolescents, but not adults, were more likely to take extra chances when friends were watching.

Another revealing psychological experiment is the Iowa gambling task. Subjects can choose from one of two decks of cards in the hope of picking a card that provides a reward. The "good" deck contains many cards that provide some reward; the "bad" one, many cards that provide nothing and insufficient compensation in the form of a few that hold a jackpot. The choices of adults correspond fairly well to their tested reasoning capacity. In adolescence, the correlation is much weaker.

Evidence is appearing that these differences have a definite basis in brain structure and functioning. Recent research has shown that human brain circuitry is not mature until the early 20s (some would add, "if ever"). Among the last connections to be fully established are the links between the prefrontal cortex, seat of judgment and problem-solving, and the emotional centers in the limbic system, especially the amygdala. These links are critical for emotional learning and high-level self-regulation.

Beginning at puberty, the brain is reshaped. Neurons (gray matter) and synapses (junctions between neurons) proliferate in the cerebral cortex and are then gradually pruned throughout adolescence. Eventually, more than 40% of all synapses are eliminated, largely in the frontal lobes. Meanwhile, the white insulating coat of myelin on the axons that carry signals between nerve cells continues to accumulate, gradually improving the precision and efficiency of neuronal communication - a process not completed until the early 20s. The corpus callosum, which connects the right and left hemispheres of the brain, consists mostly of this white matter.

Another circuit still under construction in adolescence links the prefrontal cortex to the midbrain reward system, where addictive drugs and romantic love exert their powers. Most addictions get their start in adolescence, and there is evidence that adolescent and adult brains respond differently to drugs. In both human beings and laboratory rats, studies have found that adolescents become addicted to nicotine faster and at lower doses. Functional brain scans also suggest that teenagers and adults process reward stimuli differently; the adolescents are hypersensitive to the value of novel experiences.

Hormonal changes are at work, too. The adolescent brain pours out adrenal stress hormones, sex hormones, and growth hormone, which in turn influence brain development. The production of testosterone increases 10 times in adolescent boys. Sex hormones act in the limbic system and in the raphe nucleus, source of the neurotransmitter serotonin, which is important for the regulation of arousal and mood. The hormonally regulated 24-hour clocks change their settings during adolescence, keeping high school and college students awake far into the night and making it difficult to rise for morning classes.

As long as the brain is still in formation, things can go wrong in many ways, and some of them involve the onset of psychiatric disorders. Stress can retard the growth of the hippocampus, which consolidates memories. According to some theories, the pruning of gray matter or the thickening of the myelin coat in late adolescence allows the early symptoms of schizophrenia to emerge.

At least one important social policy conclusion may have been drawn in part from the neuroscience research on the adolescent brain. In 2005, the Supreme Court, affirming a Missouri high court decision, declared by a vote of 5-4 that the execution of 16- and 17-year-olds is unconstitutionally cruel and unusual punishment. The minimum age for capital punishment is now the same as the minimum age for voting and serving on juries. In writing their decision, the justices referred to evolving standards of decency, practices in other countries, the immaturity of adolescents, and their greater potential for change. They did not specifically mention brain research, but they had the opportunity to read friend-of-the-court briefs citing this research that were submitted by the American Bar Association, American Academy of Child and Adolescent Psychiatry, and American Psychiatric Association, among others.

Some critics, even if they welcome the Supreme Court decision for other reasons, have complained that this research stereotypes adolescents and provides a biological rationalization for irresponsible behavior. Animal experiments have limited value because laboratory animals do not undergo a lengthy human childhood. And human brain development does not unfold automatically and uniformly. There is much individual variation that reflects experience as well as genetic programming. The problems of teenagers are not all in their brains but have many causes, social and individual, genetic and environmental. At present and probably for a long time, researchers will be getting better information on the mental and emotional development of adolescents from interviews, observations, and behavioral tests than from brain scans.

But neuroscience research is becoming more sophisticated. There are already long-term studies in which people undergo frequent periodic brain scans over the course of their lives. The results are being used to investigate the effects of behavioral and cognitive therapies on attention deficit disorder and reading deficiencies in adolescents. Scientists are also looking at typical adolescent brain development to provide clues to the ways in which things go wrong. Some day, this research may provide results that will influence treatments for psychiatric disorders and other problems in adolescence.

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The adolescent brain: Beyond raging hormones - Harvard Health

# data[].attributes.attachment_link.description
Originally published in the Harvard Mental Health Letter, July 2005In every generation, it seems, the same lament goes forth from the parents of adolescents: "What's the matter with kids today?" Why are they so often confused, annoying, demanding, moody, defiant, reckless? Accidental deaths, homicides, and binge drinking spike in the ...