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What is the brain?

The brain is a complex organ that controls thought, memory, emotion, touch, motor skills, vision, breathing, temperature, hunger and every process that regulates our body. Together, the brain and spinal cord that extends from it make up the central nervous system, or CNS.

What is the brain made of?

Weighing about 3 pounds in the average adult, the brain is about 60% fat. The remaining 40% is a combination of water, protein, carbohydrates and salts. The brain itself is a not a muscle. It contains blood vessels and nerves, including neurons and glial cells.

What is the gray matter and white matter?

Gray and white matter are two different regions of the central nervous system. In the brain, gray matter refers to the darker, outer portion, while white matter describes the lighter, inner section underneath. In the spinal cord, this order is reversed: The white matter is on the outside, and the gray matter sits within.

Gray matter is primarily composed of neuron somas (the round central cell bodies), and white matter is mostly made of axons (the long stems that connects neurons together) wrapped in myelin (a protective coating). The different composition of neuron parts is why the two appear as separate shades on certain scans.

Each region serves a different role. Gray matter is primarily responsible for processing and interpreting information, while white matter transmits that information to other parts of the nervous system.

How does the brain work?

The brain sends and receives chemical and electrical signals throughout the body. Different signals control different processes, and your brain interprets each. Some make you feel tired, for example, while others make you feel pain.

Some messages are kept within the brain, while others are relayed through the spine and across the body's vast network of nerves to distant extremities. To do this, the central nervous system relies on billions of neurons (nerve cells).

Main Parts of the Brain and Their Functions

At a high level, the brain can be divided into the cerebrum, brainstem and cerebellum.

Cerebrum

The cerebrum (front of brain) comprises gray matter (the cerebral cortex) and white matter at its center. The largest part of the brain, the cerebrum initiates and coordinates movement and regulates temperature. Other areas of the cerebrum enable speech, judgment, thinking and reasoning, problem-solving, emotions and learning. Other functions relate to vision, hearing, touch and other senses.

Cerebral Cortex

Cortex is Latin for "bark," and describes the outer gray matter covering of the cerebrum. The cortex has a large surface area due to its folds, and comprises about half of the brain's weight.

The cerebral cortex is divided into two halves, or hemispheres. It is covered with ridges (gyri) and folds (sulci). The two halves join at a large, deep sulcus (the interhemispheric fissure, AKA the medial longitudinal fissure) that runs from the front of the head to the back. The right hemisphere controls the left side of the body, and the left half controls the right side of the body. The two halves communicate with one another through a large, C-shaped structure of white matter and nerve pathways called the corpus callosum. The corpus callosum is in the center of the cerebrum.

Brainstem

The brainstem (middle of brain) connects the cerebrum with the spinal cord. The brainstem includes the midbrain, the pons and the medulla.

Midbrain. The midbrain (or mesencephalon) is a very complex structure with a range of different neuron clusters (nuclei and colliculi), neural pathways and other structures. These features facilitate various functions, from hearing and movement to calculating responses and environmental changes. The midbrain also contains the substantia nigra, an area affected by Parkinson's disease that is rich in dopamine neurons and part of the basal ganglia, which enables movement and coordination.

Pons. The pons is the origin for four of the 12 cranial nerves, which enable a range of activities such as tear production, chewing, blinking, focusing vision, balance, hearing and facial expression. Named for the Latin word for "bridge," the pons is the connection between the midbrain and the medulla.

Medulla. At the bottom of the brainstem, the medulla is where the brain meets the spinal cord. The medulla is essential to survival. Functions of the medulla regulate many bodily activities, including heart rhythm, breathing, blood flow, and oxygen and carbon dioxide levels. The medulla produces reflexive activities such as sneezing, vomiting, coughing and swallowing.

The spinal cord extends from the bottom of the medulla and through a large opening in the bottom of the skull. Supported by the vertebrae, the spinal cord carries messages to and from the brain and the rest of the body.

Cerebellum

The cerebellum ("little brain") is a fist-sized portion of the brain located at the back of the head, below the temporal and occipital lobes and above the brainstem. Like the cerebral cortex, it has two hemispheres. The outer portion contains neurons, and the inner area communicates with the cerebral cortex. Its function is to coordinate voluntary muscle movements and to maintain posture, balance and equilibrium. New studies are exploring the cerebellum's roles in thought, emotions and social behavior, as well as its possible involvement in addiction, autism and schizophrenia.

Brain Coverings: Meninges

Three layers of protective covering called meninges surround the brain and the spinal cord.

The outermost layer, the dura mater, is thick and tough. It includes two layers: The periosteal layer of the dura mater lines the inner dome of the skull (cranium) and the meningeal layer is below that. Spaces between the layers allow for the passage of veins and arteries that supply blood flow to the brain.

The arachnoid mater is a thin, weblike layer of connective tissue that does not contain nerves or blood vessels. Below the arachnoid mater is the cerebrospinal fluid, or CSF. This fluid cushions the entire central nervous system (brain and spinal cord) and continually circulates around these structures to remove impurities.

The pia mater is a thin membrane that hugs the surface of the brain and follows its contours. The pia mater is rich with veins and arteries.

Lobes of the Brain and What They Control

Each brain hemisphere (parts of the cerebrum) has four sections, called lobes: frontal, parietal, temporal and occipital. Each lobe controls specific functions.

Frontal lobe. The largest lobe of the brain, located in the front of the head, the frontal lobe is involved in personality characteristics, decision-making and movement. Recognition of smell usually involves parts of the frontal lobe. The frontal lobe contains Broca's area, which is associated with speech ability.

Parietal lobe. The middle part of the brain, the parietal lobe helps a person identify objects and understand spatial relationships (where one's body is compared with objects around the person). The parietal lobe is also involved in interpreting pain and touch in the body. The parietal lobe houses Wernicke's area, which helps the brain understand spoken language.

Occipital lobe. The occipital lobe is the back part of the brain that is involved with vision.

Temporal lobe. The sides of the brain, temporal lobes are involved in short-term memory, speech, musical rhythm and some degree of smell recognition.

Deeper Structures Within the Brain

Pituitary Gland

Sometimes called the "master gland," the pituitary gland is a pea-sized structure found deep in the brain behind the bridge of the nose. The pituitary gland governs the function of other glands in the body, regulating the flow of hormones from the thyroid, adrenals, ovaries and testicles. It receives chemical signals from the hypothalamus through its stalk and blood supply.

Hypothalamus

The hypothalamus is located above the pituitary gland and sends it chemical messages that control its function. It regulates body temperature, synchronizes sleep patterns, controls hunger and thirst and also plays a role in some aspects of memory and emotion.

Amygdala

Small, almond-shaped structures, an amygdala is located under each half (hemisphere) of the brain. Included in the limbic system, the amygdalae regulate emotion and memory and are associated with the brain's reward system, stress, and the "fight or flight" response when someone perceives a threat.

Hippocampus

A curved seahorse-shaped organ on the underside of each temporal lobe, the hippocampus is part of a larger structure called the hippocampal formation. It supports memory, learning, navigation and perception of space. It receives information from the cerebral cortex and may play a role in Alzheimer's disease.

Pineal Gland

The pineal gland is located deep in the brain and attached by a stalk to the top of the third ventricle. The pineal gland responds to light and dark and secretes melatonin, which regulates circadian rhythms and the sleep-wake cycle.

Ventricles and Cerebrospinal Fluid

Deep in the brain are four open areas with passageways between them. They also open into the central spinal canal and the area beneath arachnoid layer of the meninges.

The ventricles manufacture cerebrospinal fluid, or CSF, a watery fluid that circulates in and around the ventricles and the spinal cord, and between the meninges. CSF surrounds and cushions the spinal cord and brain, washes out waste and impurities, and delivers nutrients.

Blood Supply to the Brain

Two sets of blood vessels supply blood and oxygen to the brain: the vertebral arteries and the carotid arteries.

The external carotid arteries extend up the sides of your neck, and are where you can feel your pulse when you touch the area with your fingertips. The internal carotid arteries branch into the skull and circulate blood to the front part of the brain.

The vertebral arteries follow the spinal column into the skull, where they join together at the brainstem and form the basilar artery, which supplies blood to the rear portions of the brain.

The circle of Willis, a loop of blood vessels near the bottom of the brain that connects major arteries, circulates blood from the front of the brain to the back and helps the arterial systems communicate with one another.

Cranial Nerves

Inside the cranium (the dome of the skull), there are 12 nerves, called cranial nerves:

Cranial nerve 1: The first is the olfactory nerve, which allows for your sense of smell.

Cranial nerve 2: The optic nerve governs eyesight.

Cranial nerve 3: The oculomotor nerve controls pupil response and other motions of the eye, and branches out from the area in the brainstem where the midbrain meets the pons.

Cranial nerve 4: The trochlear nerve controls muscles in the eye. It emerges from the back of the midbrain part of the brainstem.

Cranial nerve 5: The trigeminal nerve is the largest and most complex of the cranial nerves, with both sensory and motor function. It originates from the pons and conveys sensation from the scalp, teeth, jaw, sinuses, parts of the mouth and face to the brain, allows the function of chewing muscles, and much more.

Cranial nerve 6: The abducens nerve innervates some of the muscles in the eye.

Cranial nerve 7: The facial nerve supports face movement, taste, glandular and other functions.

Cranial nerve 8: The vestibulocochlear nerve facilitates balance and hearing.

Cranial nerve 9: The glossopharyngeal nerve allows taste, ear and throat movement, and has many more functions.

Cranial nerve 10: The vagus nerve allows sensation around the ear and the digestive system and controls motor activity in the heart, throat and digestive system.

Cranial nerve 11: The accessory nerve innervates specific muscles in the head, neck and shoulder.

Cranial nerve 12: The hypoglossal nerve supplies motor activity to the tongue.

The first two nerves originate in the cerebrum, and the remaining 10 cranial nerves emerge from the brainstem, which has three parts: the midbrain, the pons and the medulla.

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The brain is an important organ that controls thought, memory, emotion, touch, motor skills, vision, respiration, and every process that regulates your body.

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How your brain works

The brain and nervous system

The brain contains billions of nerve cells arranged in patterns that coordinate thought, emotion, behavior, movement and sensation.

A complicated highway system of nerves connects the brain to the rest of your body, so communication can occur in seconds. Think about how fast you pull your hand back from a hot stove. While all the parts of the brain work together, each part is responsible for a specific function - controlling everything from your heart rate to your mood.

Cerebrum

The cerebrum is the largest part of the brain. It's what you probably visualize when you think of brains in general. The outermost layer of the cerebrum is the cerebral cortex, also called the "gray matter" of the brain. Deep folds and wrinkles in the brain increase the surface area of the gray matter, so more information can be processed.

The cerebrum is divided by a deep groove, also known as a fissure. The groove divides the brain into two halves known as hemispheres. The hemispheres communicate with each other through a thick tract of nerves called the corpus callosum at the base of the groove. In fact, messages to and from one side of the body are usually handled by the opposite side of the brain.

Lobes of the brain

The brain's hemispheres have four lobes.

The frontal lobes help control thinking, planning, organizing, problem-solving, short-term memory and movement.

The parietal lobes help interpret feeling, known as sensory information. The lobes process taste, texture and temperature.

The occipital lobes process images from your eyes and connect them to the images stored in your memory. This allows you to recognize images.

The temporal lobes help process information from your senses of smell, taste and sound. They also play a role in memory storage.

Cerebellum and brainstem

The cerebellum is a wrinkled ball of tissue below and behind the rest of the brain. It works to combine sensory information from the eyes, ears and muscles to help coordinate movement. The cerebellum activates when you learn to play the piano, for example.

The brainstem links the brain to the spinal cord. It controls functions vital to life, such as heart rate, blood pressure and breathing. The brainstem also is important for sleep.

The inner brain

Structures deep within the brain control emotions and memories. Known as the limbic system, these structures come in pairs. Each part of this system is present in both halves of the brain.

The thalamus acts as a gatekeeper for messages passed between the spinal cord and the cerebrum.

The hypothalamus controls emotions. It also regulates your body's temperature and controls functions such as eating or sleeping.

The hippocampus sends memories to be stored in areas of the cerebrum. It then recalls the memories later.

Peripheral nervous system

All of the nerves in your body that are outside of the brain and spinal cord make up the peripheral nervous system.

It relays information between your brain and your extremities, such as your arms, hands, legs or feet. For example, if you touch a hot stove, pain signals travel from your finger to your brain in a split second. Your brain tells the muscles in your arm and hand to quickly take your finger off the hot stove.

Nerve cells

Nerve cells, known as neurons, send and receive nerve signals. They have two main types of branches coming off their cell bodies. Dendrites receive messages from other nerve cells. Axons carry outgoing messages from the cell body to other cells - such as a nearby neuron or muscle cell.

Interconnected with each other, neurons provide efficient, lightning-fast communication.

Neurotransmitters

A nerve cell communicates with other cells through electrical impulses when the nerve cell is stimulated. Within a neuron, the impulse moves to the tip of an axon and causes the release of chemicals, called neurotransmitters, that act as messengers.

Neurotransmitters pass through the gap between two nerve cells, known as the synapse. They then attach to receptors on the receiving cell. This process repeats from neuron to neuron as the impulse travels to its destination. This web of communication that allows you to move, think, feel and communicate.

Show references

See more In-depth

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How your brain controls everything from your heart rate to your mood.

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Which part of your brain does what? Take a tour.

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Felipe Mora-Bermúdez, 1,† Farhath Badsha, 1,† Sabina Kanton, 2,† J Gray Camp, 2,† Benjamin Vernot, ² Kathrin Köhler, ² Birger Voigt, ³ Keisuke Okita, ⁴ Tomislav Maricic, ² Zhisong He, ⁵ Robert Lachmann, ⁶ Svante Pääbo, 2,* Barbara Treutlein, 1, 2,* and Wieland B Huttner 1,*

Andrea Musacchio, Reviewing editor

Andrea Musacchio, Max Planck Institute of Molecular Physiology, Germany;

Abstract

Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we have searched for such differences by analysing cerebral organoids from human and chimpanzees using immunohistofluorescence, live imaging, and single-cell transcriptomics. We find that the cytoarchitecture, cell type composition, and neurogenic gene expression programs of humans and chimpanzees are remarkably similar. Notably, however, live imaging of apical progenitor mitosis uncovered a lengthening of prometaphase-metaphase in humans compared to chimpanzees that is specific to proliferating progenitors and not observed in non-neural cells. Consistent with this, the small set of genes more highly expressed in human apical progenitors points to increased proliferative capacity, and the proportion of neurogenic basal progenitors is lower in humans. These subtle differences in cortical progenitors between humans and chimpanzees may have consequences for human neocortex evolution.

DOI: http://dx.doi.org/10.7554/eLife.18683.001

Research Organism: Human, Mouse, Other

eLife digest

The human brain is about three times as big as the brain of our closest living relative, the chimpanzee. Moreover, a part of the brain called the cerebral cortex - which plays a key role in memory, attention, awareness and thought - contains twice as many cells in humans as the same region in chimpanzees. Networks of brain cells in the cerebral cortex also behave differently in the two species.

How these species differences arise is not clear, but it likely occurs in the earliest phases of development when brain stem and progenitor cells divide and give rise to cerebral cortex cells in the growing brain. To study the earliest stages of brain development, researchers often use human brain cells grown in the laboratory. Under the right conditions, cells collected from adult humans and other animals can be reprogrammed to behave like brain stem cells. Recently, researchers have been able to use these reprogrammed cells to make tissue that resembles the brain in petri dishes, known as brain organoids.

Mora-Bermúdez, Badsha, Kanton, Camp et al. have now analysed brain organoids grown from reprogrammed human, chimpanzee and orangutan cells. The experiments showed that the human and chimpanzee brain organoids were remarkably similar in many ways including in the mix of cell types and in how these cells were arranged.

Mora-Bermúdez et al. then used live microscopy to show that progenitor cells that form the human cerebral cortex spend around 50% more time in a stage of the cell division process called metaphase compared to the same cells from chimpanzees or orangutans. Metaphase is the part of the division process when the cell makes sure that structures called chromosomes, which carry the cell's DNA, can be separated and distributed equally between the two daughter cells. Mora-Bermúdez et al. also found that progenitor cells more likely to become neurons sooner had a shorter metaphase than progenitor cells more likely to remain proliferating as stem cells for longer. This suggests that a longer metaphase may be a feature of brain stem cells.

Further studies are now needed to find out how the length of time these progenitor cells spend in metaphase affects how chimpanzee and human brains develop; and whether this can help explain why the human brain is so much larger.

DOI: http://dx.doi.org/10.7554/eLife.18683.002

Introduction

The expansion of the neocortex during primate evolution is thought to contribute to the higher cognitive capacity of humans compared to our closest living relatives, the great apes, and notably the chimpanzees ( Geschwind and Rakic, 2013; Rakic, 2009; Striedter, 2005). Neocortex expansion in humans relative to chimpanzees involves an increase in the number of cortical neurons generated during fetal development ( Borrell and Reillo, 2012; Florio and Huttner, 2014; Herculano-Houzel, 2009; Lui et al., 2011). This reflects primarily a greater and prolonged proliferative capacity of human neural stem and progenitor cells (NSPCs) within the germinal zones of the developing neocortex ( Lewitus et al., 2013). Unravelling differences between human and chimpanzee NSPC behaviour is therefore a key issue, yet very little is known about such differences.

The neocortex develops from two principal germinal zones, the ventricular zone (VZ) and the subventricular zone (SVZ) ( Angevine et al., 1970). In primates developing a folded (gyrencephalic) neocortex, and notably in humans, an inner SVZ (iSVZ) and an outer (oSVZ) can be distinguished ( Dehay et al., 2015; Smart et al., 2002). Correspondingly, the VZ and SVZ harbour the cell bodies of two principal classes of NSPCs, called apical progenitors (APs) and basal progenitors (BPs), respectively, each of which comprise several distinct NSPC types ( Borrell and Reillo, 2012; Götz and Huttner, 2005; Lui et al., 2011; Taverna et al., 2014). APs (neuroepithelial cells, apical radial glia, and apical intermediate progenitors) divide at the ventricular surface, keep ventricular contact and exhibit apical cell polarity, whereas BPs (basal (or outer) radial glia and basal intermediate progenitors) lack this contact and type of cell polarity ( Taverna et al., 2014).

Studies dissecting the switch between NSPC proliferation and differentiation have demonstrated that a central aspect of the cell division process, the orientation of the mitotic spindle, has a pivotal role, particularly in the case of APs ( Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al., 2014; Shitamukai and Matsuzaki, 2012). The orientation of the spindle relative to the apical-basal axis of cell polarity in mitotic apical radial glia, the major cortical neural stem cells ( Götz and Huttner, 2005; Kriegstein and Alvarez-Buylla, 2009), can determine whether their division is symmetric or asymmetric, and whether it is proliferative or neurogenic, with regard to their progeny ( Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al., 2014; Shitamukai and Matsuzaki, 2012). Comparing spindle orientation in mitotic APs may therefore provide insight into the cell biological basis underlying the differences between humans and chimpanzees in NSPC proliferation versus differentiation during neocortex development.

Protocols to generate structured cerebral tissue (cerebral organoids) from pluripotent stem cells in vitro constitute a major advance for studying neocortex development, in particular with regard to humans and non-human primates where fetal brain tissue is hard or impossible to obtain and manipulate ( Kadoshima et al., 2013; Lancaster and Knoblich, 2014; Lancaster et al., 2013; Mariani et al., 2015; Qian et al., 2016). Human cerebral organoids form a variety of tissues that resemble specific brain regions, including the cerebral cortex, ventral forebrain, midbrain-hindbrain boundary, hippocampus, and retina. Moreover, their cerebral cortex-like regions exhibit distinct germinal zones, that is, a VZ containing APs and an SVZ containing BPs, as well as basal-most neuronal layers. Cerebral organoid APs include apical radial glia-like NSPCs that contact a ventricle-like lumen, express radial glia marker genes, undergo interkinetic nuclear migration, and divide at the apical surface, similar to their in vivo counterparts, and cerebral organoid BPs comprise both basal radial glia-like and basal intermediate progenitor-like NSPCs ( Lancaster et al., 2013). Finally, we have previously shown by single-cell RNA sequencing that the gene expression programs controlling neocortex development in human cerebral organoids are remarkably similar to those in the developing fetal tissue ( Camp et al., 2015). Together, these findings suggest that cerebral organoids constitute a valid system to explore potential differences in NSPC proliferation versus differentiation between humans and chimpanzees ( Otani et al., 2016), in particular with regard to spindle orientation in mitotic APs.

Here, we have generated cerebral organoids from chimpanzee-derived induced pluripotent stem cells (iPSCs), and used single-cell transcriptomics, immunohistofluorescence and live imaging to compare relevant features of chimpanzee NSPCs to human NSPCs in cerebral organoids and fetal neocortex. While most NSPC characteristics are found to be similar, we show that the prometaphase-metaphase in mitotic APs is longer in humans than in chimpanzees, indicating that a fundamental difference exists in the regulation of mitosis during neocortex development between the two species. Our data also provide a resource for further studies on human and chimpanzee differences in cortical development, and demonstrate the usability of cerebral organoids as a means to be able to perform such studies.

Results

Chimpanzee cerebral organoids recapitulate cortex development

We generated cerebral organoids from iPSCs derived from chimpanzee fibroblasts and lymphocytes ( Figure 1A left, Figure 1-figure supplement 1 ). These chimpanzee cerebral organoids formed complex tissue structures that resembled the developing primate brain ( Figure 1A right), as reported previously for human cerebral organoids ( Lancaster et al., 2013). Similar to human iPSC-derived cerebral organoids ([ Camp et al., 2015], Figure 1B,C right), within the chimpanzee organoids grown for 52 days (D52), we observed cortex-like regions ( Figure 1A right) with PAX6-positive APs (such as radial glia) residing predominantly in the apical-most zone facing a ventricular lumen ( Figure 1B left), similar to the ventricular zone (VZ) of developing primate neocortex at an early-mid stage of neurogenesis. Consistent with this, cells immunoreactive for the deep-layer neuron marker CTIP2 were observed in the basal region of the developing cortical wall ( Figure 1B left), corresponding to an early cortical plate. TBR2 (also known as EOMES) positive BPs (presumably mostly basal intermediate progenitors) were concentrated in a zone between the PAX6+ progenitors and the CTIP2+ neurons, corresponding to the subventricular zone (SVZ). In the context of the time-lapse live imaging of apical mitoses described below, we observed apically directed nuclear migration prior to, and basally directed nuclear migration after, mitosis, consistent with the existence of interkinetic nuclear migration. Our results suggest that chimpanzee cerebral organoids recapitulate important aspects of fetal chimpanzee brain development and allow comparisons with cerebral cortex development in human cerebral organoids and fetal neocortex.

We next compared the proportion of various NSPC types, as revealed by expression of PAX6 and/or TBR2, and neurons at a very early (D28) and a mid-neurogenic (D52-D54) stage between human and chimpanzee cerebral organoid cortices ( Figure 2 ). In both species, we observed a decrease in PAX6+TBR2- apically located NSPCs (presumably proliferating APs) from D28 to D52, concomitant with an increase in PAX6+TBR2+ and PAX6-TBR2+ basally located NSPCs (presumably neurogenic BPs) ( Figure 2A,B ). Notably, whereas no significant differences were observed at D28, at D52-D54, the proportion of PAX6+TBR2+ NSPCs in the chimpanzee organoids was nearly twice that in the human organoids, and the proportion of PAX6+TBR2- NSPCs was correspondingly lower, whereas no significant difference between human and chimpanzee was observed for PAX6-TBR2+ NSPCs ( Figure 2B ). In line with what would be expected with regard to neuron production, the proportion of PAX6-TBR2- cells, located in the basal-most zones of the developing cortical wall, was very low at D28 but increased by D52-D54 to about a third of the total cells for both, human and chimpanzee cerebral organoids ( Figure 2B ). Immunostaining for CTIP2 corroborated the neuronal identity of these cells (data not shown).

Cell composition and lineage relationships in chimpanzee cerebral organoids

To survey the cellular composition and cell type-specific transcriptomes of the chimpanzee organoids, we analysed 344 single cell transcriptomes from 7 organoids ranging in age from 45 to 80 days ( Figure 1D , Figure 1-source data 1). We combined all transcriptomes and identified the genes most informative for defining cell populations by principal component analysis (PCA) ( Figure 1-source data 2). Using these genes, we used tSNE analysis to cluster cells into transcriptionally distinct groups representing cerebral cortex, hindbrain, ventral midbrain and peripheral mesenchyme ( Figure 1-figure supplement 2 ). These groups are similar to those identified in human cerebral organoids ( Camp et al., 2015). We identified 178 cortex-like cells based on strong expression of canonical NSPC and neuron marker genes (i.e., NSPCs and neurons: FOXG1, NFIA, NFIB; NSPCs: PAX6, SOX2, GLI3; neurons: NEUROD6) and the lack of expression of the ventral and medial telencephalic markers OTX2 and RSPO2 ( Figure 1-figure supplement 2 ).

We sub-classified the 178 cerebral cortex-like cells based on the correlation between their transcriptomes and the bulk transcriptomes of laser-capture microdissected VZ, iSVZ, oSVZ, and cortical plate of fetal human neocortex ( GSE38805, [ Fietz et al., 2012]). We found that groups of cells correlated best with one of the four zones, suggesting that the range of cell types present in the human fetal and organoid cerebral cortex are represented in our chimpanzee data ( Figure 1E ). Consistent with this, each chimpanzee cell represents a cell state on a continuum from NPSCs to neurons based on gene expression signatures extracted from fetal human cerebral cortex transcriptomes ( Figure 1F , Figure 1-figure supplement 3 ) ( Camp et al., 2015).

We next classified the chimpanzee cerebral cortex cells by determining the fetal cell type with which each cell most strongly correlates, resulting in 73 APs, 25 BPs, and 80 neurons. Analysis of known cell type markers revealed expression patterns consistent with what has been observed in human organoid and fetal cerebral cortex ( Figure 1G ) ( Camp et al., 2015). Though this classification is convenient to describe the cell types present in the chimpanzee organoid, we note that many of the cells can be described as intermediates between APs, BPs, and different stages of neuron maturation. We inferred lineage relationships among the chimpanzee cerebral cortex in an adjacency network based on pairwise correlations between cells ( Figure 1H ), revealing a structured topology where VZ-APs connect to cortical plate neurons through SVZ-BPs. These lineage relationships were corroborated using a minimal spanning tree algorithm ( Figure 1-figure supplement 3G ) ( Trapnell et al., 2014). Together, these data allowed reconstruction of the chimpanzee organoid cerebral cortex from single-cell transcriptomes.

Chimpanzee and human gene expression in the developing cerebral cortex

To further explore transcriptome similarities and differences between chimpanzee and human cerebral cortex cells, we compared them to the single-cell transcriptomes of 220 fetal human cortex cells (12-13 weeks post-conception (wpc), published in ( Camp et al., 2015), GSE75140) and 207 cortex-like cells from human cerebral organoids (40-80 days, 155 single-cell transcriptomes published in ( Camp et al., 2015), GSE75140; 52 single-cell transcriptomes acquired as part of this study) ( Figure 3-source data 1). In a PCA, the first principal component (PC1) separated NSPCs and neurons, whereas PC2 separated species ( Figure 3A ). Hierarchical clustering of organoid and fetal cells showed that human and chimpanzee organoid and human fetal cells were distributed together within the two main sub-clusters representing NSPCs and neurons (not shown), and showed highly correlated expression of marker gene patterns ( Figure 3B ).

We constructed an intercellular correlation network, which revealed a VZ sub-network of human and chimpanzees APs that link through BPs expressing iSVZ and oSVZ markers to cortical plate neurons. Generally, APs, BPs, and neurons from human and chimpanzee intermixed, confirming that cells in the chimpanzee organoid cortices have a zonal organization consistent with what is observed histologically ( Figure 3C,D ). In conclusion, the major proportion of the variation in these data is not between in vitro and in vivo tissues or between species, but among cell states during neurogenesis, confirming that the major features of the genetic programs regulating the NSPC-to-neuron lineage are conserved between human and chimpanzees, and are recapitulated in cerebral organoids.

To identify genes differentially expressed between chimpanzee and human cortex-like cells, we remapped all single-cell transcriptome reads to a consensus human-chimpanzee genome and used human annotations to identify 1-to-1 orthologous genes. We then used a Bayesian approach to identify differentially expressed genes by comparing cerebral organoid APs and neurons between species (ignoring BPs due to the low number of BPs identified). We identified 297 and 279 genes that were more highly expressed in human APs and neurons, respectively, and 283 and 314 genes that were more highly expressed in chimpanzee APs and neurons, respectively ( Figure 3E , Figure 3-source data 2). In addition to the between-species comparisons, we identified genes differentially expressed between human or chimpanzee APs and neurons to identify cell-type specific genes (for human: 1328 AP-specific, 1132 neuron-specific; for chimpanzee: 1501 AP-specific, 1166 neuron-specific). The vast majority (94%) of genes that are AP-specific and neuron-specific in humans are not differential between human and chimpanzee ( Figure 3E , Figure 3-figure supplement 1 ). Of the differentially expressed genes between species, we identified 93 genes that are strongly upregulated in human organoid APs and 72 genes upregulated in human organoid neurons. Gene ontology enrichments suggest that the proteins encoded by some of these genes are integral to cell membranes and involved in intercellular signalling ( Figure 3F , Figure 3-source data 2), for example integrin beta 8 (ITGB8) in APs and insulin receptor (INSR) in human neurons. This upregulation of ITGB8 specific to human APs and INSR specific to human neurons is also observed in comparisons between human and mouse ( Florio et al., 2015) ( Figure 3G ).

When comparing these results to bulk RNA-seq data from mouse APs and neurons ( Florio et al., 2015), we find that 75% of the genes with expression specific to APs or neurons in humans are also specific to each cell type in the mouse, suggesting that these gene expression programs were already established and likely present in the common ancestor of mouse, human and chimpanzee some 90 million years ago ( Figure 3F ). Notably, a similar proportion of AP- and neuron-specific genes were gained on the chimpanzee and human branch subsequent to their separation, suggesting that our analysis did not have a strong human bias. About 12% of these genes specific to AP or neurons in both human and chimpanzee were not specific to these cell types in the mouse ( Florio et al., 2015), suggesting that they may be involved in developmental processes specific to the primate cerebral cortex.

Live imaging of NSPC mitoses in human fetal neocortex and cerebral organoids

We used an established live imaging method ( Mora-Bermudez et al., 2014) to compare dividing cortical APs, i.e. cells undergoing mitosis at the ventricular surface (presumably mostly aRG), in slice cultures of both 11-13 wpc human fetal neocortex and human D30 cerebral organoids. We did not observe signs of strong perturbation during live image acquisition in either system, such as mitotic arrest ( Figure 4A,C,E ; see also Figure 5A-C and Video 1) or lack of nuclear movements and cell death. Chromosome dynamics and spindle orientation of APs, as revealed by the orientation of the metaphase plate, were similar in human developing neocortex and human organoids, both before anaphase ( Figure 4A-D,G ) and during anaphase ( Figure 4A-D,H,I ), when cell cleavage initiates. This strongly suggests that cerebral organoids are a suitable model to study live NSPC division and spindle orientation dynamics.

Spindle orientation dynamics are similar in human and chimpanzee NSPCs

Spindle orientation can determine symmetric vs. asymmetric NSPC division ( Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al., 2014; Shitamukai and Matsuzaki, 2012) and is therefore a major candidate mechanism to explain the approximately 3-fold expansion of the neocortex in humans compared to great apes. We compared spindle orientation dynamics between human and chimpanzee APs in cerebral organoids. However, our data revealed no clear differences in spindle orientation, either during metaphase ( Figure 4C-G ) or shortly after anaphase onset ( Figure 4C-F, I-J ). As deduced from the orientation of the chromosome plates, most APs in both human and chimpanzee divided with a cleavage orientation largely perpendicular to the apical, ventricular surface, showing deviations of fewer than 30° from a perfect orthogonal cleavage. Oblique and near-horizontal orientations were also observed, but at a much lower abundance and at similar frequencies in chimpanzee and human organoids ( Figure 4H-J ). This shows that the frequency of asymmetric cell division caused by oblique spindle orientation is most likely not a major difference between human and chimpanzee APs.

Longer prometaphase-metaphase in human than great ape APs

We noticed, however, unexpected differences between human and chimpanzee APs in their progression through mitosis. Specifically, measurement of the length of the various phases of mitosis (for details, see Materials and methods) revealed that APs in 11-13 wpc fetal human neocortex and D30 cerebral organoids remained approximately 5 min longer in prometaphase-metaphase than APs in chimpanzee organoids ( Figure 5A-C,E ; Video 1). By comparison, prometaphase-metaphase of APs in slice culture of mouse neocortex, a well-characterized model system for neurogenesis, lasted for only approximately half the amount of time than human APs ( Figure 5D,E ; Figure 5-source data 1).

To trace the specific phase of mitosis when this difference arises, we used chromosome morphology and dynamics to determine the time chromosomes spent congressing toward the equatorial plane of the cell (defined here as 'prometaphase') and the time they spent tightly aligned as a metaphase plate (defined here as 'metaphase'). Remarkably, the longer prometaphase-metaphase of human than chimpanzee APs was specifically due to a ∼40-60% lengthening of metaphase ( Figure 5A-C,G ), whereas prometaphase was not significantly different ( Figure 5A-C,F ; Video 1). By contrast, in mouse APs, both prometaphase and metaphase were found to be significantly shorter than the respective mitotic phases in human and chimpanzee APs ( Figure 5D,F,G ; Figure 5-source data 1).

None of the other mitotic phases (prophase, anaphase, telophase) differed in length between APs in human fetal neocortex and human cerebral organoids vs. chimpanzee organoids. However, anaphase of mouse APs was found to be significantly shorter than that of human and chimpanzee APs ( Figure 5-figure supplement 1A ; Figure 5-source data 1). These differences between species in the individual mitotic phases were reflected in the cumulative length of total mitosis, which was significantly shorter in mouse APs than human and chimpanzee APs ( Figure 5-figure supplement 1B ).

We also generated cerebral organoids from an orangutan iPSC line and determined the length of AP prometaphase-metaphase. This revealed that the length of prometaphase-metaphase in orangutan D30 organoid APs was similar to that of chimpanzee APs and significantly shorter than that of human organoid APs ( Figure 5-figure supplement 3A,B ). As was the case for the human-chimpanzee AP comparison, the shorter prometaphase-metaphase of orangutan than human APs was due to a shorter metaphase ( Figure 5-figure supplement 3A,D ) rather than prometaphase ( Figure 5-figure supplement 3A,C ; Figure 5-source data 1). Together, these data indicate that human APs specifically lengthen prometaphase-metaphase as compared to great ape APs.

The prometaphase-metaphase lengthening in humans occurs upon neural differentiation

Longer prometaphase-metaphase in proliferative than neurogenic mouse APs

To investigate potential functions of prometaphase-metaphase lengthening, we asked whether mitotic phases were different between proliferating and neurogenic APs. To this end, we measured mitotic phase lengths in a transgenic mouse line where EGFP is expressed under the promoter of the pan-neurogenic marker Tis21 in neurogenic but not proliferative NSPCs ( Haubensak et al., 2004; Iacopetti et al., 1999). This revealed that prometaphase-metaphase was longer in proliferative AP divisions (Tis21-) than in neurogenic AP divisions (Tis21+ ), whereas the separate phases were not significantly different ( Figure 7 ; Figure 5-source data 1). These results suggest that a lengthening of prometaphase-metaphase may be characteristic of proliferating NSPCs.

Gene expression in human and chimpanzee mitotic APs

We used the single-cell RNA-seq data to identify organoid APs in different phases of the cell cycle ( Figure 8A , Figure 8-figure supplement 1 ) and searched for genes that might be involved in human-specific lengthening of the metaphase. We compared human organoid APs in G1 with APs in G2-M and identified 395 genes with enriched expression in G2-M ( Figure 8B ). We next compared human APs in G2-M with human iPSCs (TkDA3-4) and an endothelial cell line (HUVEC; both single-cell RNA-seq data sets in GSE81252) to understand the specificity of G2-M regulation in APs. We found that nearly all genes upregulated in human APs in G2-M compared with human APs in G1 were also upregulated during G2-M in iPSCs and endothelial cells ( Figure 8C ). Therefore, the expression level of these genes is unlikely to contribute to the specificity of mitotic control of human APs in G2-M. However, we identified many genes that were highly expressed throughout the human AP cell cycle and were specific to APs. Genes with the highest specificity score encoded canonical cerebral cortex patterning transcription factors such as PAX6, ID4, and GLI3, as well as proteins involved in cell adhesion and ECM signalling (CDH4, EFNB1/2, COL4A2). Notably, no genes associated with cell cycle, kinetochore, or spindle terms were specific to human APs ( Figure 8C , inset). Of genes specific to APs, a subset were also differentially expressed between human and chimpanzee cerebral organoids (APOLD1, BICC1, EFNB1, GSTM1, IFI44L, ITGB8, SDK2, SEMA5A, SLC35F1, ZNF516), which makes them candidates for the unique regulation of AP proliferation in humans ( Figure 8D ).

Discussion

We have characterized cerebral organoids generated from chimpanzee iPSCs, including a newly generated iPSC line, and shown that their cytoarchitecture, cell type composition, and neurogenic gene expression programs are remarkably similar to human cerebral organoids and to human fetal neocortex. This extends a very recent study ( Otani et al., 2016) and establishes cerebral organoids as a valid system to compare human and chimpanzee NSPC behaviour. Using this system, we have shown that human and chimpanzee APs differ in that prometaphase-metaphase is longer in humans than in chimpanzees. This difference was also observed between human and orangutan and reflects a greater extent of prometaphase-metaphase lengthening that occurs as human APs are generated during cerebral organoid development from IPSCs. There are two intriguing implications as to the biological significance of this prometaphase-metaphase lengthening in human APs.

One is related to the fate of the progeny arising from AP division. Mouse Tis21::GFP-negative APs, which are known to undergo proliferative divisions to generate more APs, have a longer prometaphase-metaphase than Tis21::GFP-positive APs, which are known to undergo neurogenic divisions to generate BPs ( Haubensak et al., 2004). The longer prometaphase-metaphase in human than chimpanzee APs would therefore be consistent with a greater tendency for proliferative than neurogenic divisions. In this respect, other changes in progeny fate have also been recently observed in a different context, upon an experimentally induced and considerable prolongation of AP mitosis in embryonic mouse neocortex ( Pilaz et al., 2016).

Another set of observations are consistent with the notion that the longer prometaphase-metaphase in human than chimpanzee APs may indicate a greater tendency for proliferative than differentiative divisions. The human vs. chimpanzee prometaphase-metaphase difference decreased in the course of organoid cortical development from D30 to D52, when one would expect proliferative AP divisions to decrease and differentiative AP divisions to increase.

Further support for this notion was obtained by analysis of the interphase of the cell cycle, specifically S-phase. Mouse Tis21::GFP-negative (proliferative) APs have previously been shown to have a longer S-phase than Tis21::GFP-positive (differentiative) APs ( Arai et al., 2011). The substantially longer S-phase of human than chimpanzee APs observed here is therefore also in line with human APs having a greater tendency for proliferative divisions.

Finally, the changes in the abundance of NSPC types in the course of cerebral organoid development yielded data supporting a greater AP proliferation in human than chimpanzee. Specifically, the proportion of PAX6+TBR2- NSPCs, located in the VZ and thus constituting proliferating APs, decreased in both human and chimpanzee cerebral organoids, but the value reached in human organoids was slightly higher than that in chimpanzee organoids ( Figure 2B ). Conversely, the proportion of PAX6+TBR2+ NSPCs, located in the basal VZ and SVZ and constituting BPs with neurogenic potential, showed a greater increase in chimpanzee than human cerebral organoids. In sum, two independent lines of evidence, the detailed analysis of AP mitosis phase lengths and the determination of the proportions of the various NSPC types, support the concept that a longer neurogenic period ( Lewitus et al., 2014), which in turn implies a longer phase of NSPC proliferation ( Otani et al., 2016), contributes to the greater expansion of the neocortex in humans than the great apes.

The second implication as to the biological significance of the longer prometaphase-metaphase in human than chimpanzee APs concerns the fact that these are the phases of mitosis when chromosomes prepare for segregation, to ensure that only one copy of each chromosome is distributed to each nascent daughter cell ( Musacchio and Salmon, 2007). The longer duration of prometaphase-metaphase in human than chimpanzee APs, in particular of the metaphase plate stage ( Figure 5B ), may therefore reflect some difference between the two species with regard to the preparation for chromosome segregation.

If the longer prometaphase-metaphase in human than chimpanzee APs reflects a greater tendency for proliferative than neurogenic divisions in the human NSPCs, why did we not detect significant differences between human and chimpanzee APs in spindle orientation, a parameter previously shown to affect the mode of AP division ( Lancaster and Knoblich, 2012; Mora-Bermudez and Huttner, 2015; Mora-Bermudez et al., 2014; Shitamukai and Matsuzaki, 2012)? This may be due to spindle orientation variability between individual APs being greater than potential inter-species differences. This suggests that, in the cell types and stages analysed, spindle orientation may not play a key role in human vs. chimpanzee neurogenesis. Alternatively, this may reflect the fact that differences in proliferative versus neurogenic AP divisions can occur without a change in spindle orientation ( Konno et al., 2008; Kosodo et al., 2004; Mora-Bermudez and Huttner, 2015). In this context, differences between human and chimpanzee NSPCs of relevance for neocortex expansion are likely to be small. Consistent with this view, our single-cell transcriptome analyses revealed only few differences between human and chimpanzee, and the differences in the proportions of organoid NSPC populations were in the range of a few percentage points. Furthermore, the ~5 min longer prometaphase-metaphase in human than chimpanzee APs constituted only a fraction of the total duration of their mitosis. These small differences nevertheless provide a set of clues as to which NSPC features may underlie the differential extent of neocortex expansion in humans versus apes, and are consistent with a scenario in which the accumulation of such small differences during evolution may have resulted in the distinct chimpanzee and human neocortices.

Materials and methods

Neocortex tissue

Human fetal brain tissue (11-13 weeks post conception (wpc)) was obtained with informed written maternal consent followed by elective pregnancy termination, and neocortex was dissected at room temperature, as described previously ( Florio et al., 2015). Research involving human fetal brain was approved by the Ethical Review Committee of the Universitätsklinikum Carl Gustav Carus of the Technische Universität Dresden (reference number EK100052004). In addition, research was approved by the Institutional Review Board of the Max Planck Institute of Molecular Cell Biology and Genetics.

Mice were kept pathogen-free at the Biomedical Services Facility of the MPI-CBG. All mouse embryos were heterozygotes of the Tis21::GFP knock-in line ( Haubensak et al., 2004). Imaging was performed in the dorsolateral telencephalon of E14.5 embryos, at a medial position along the rostro-caudal axis. Embryonic day (E) 0.5 was defined as noon of the day of vaginal plug identification. All experiments using mice were performed according to the German Animal Welfare Legislation.

Cell lines and organoid culturing

Two human iPSC lines (409b2, SC102A-1), two chimpanzee iPSC lines (PR818-5, Sandra A), and one orangutan iPSC line (Toba) were used to generate cerebral organoids in this study. 409b2 was purchased from the RIKEN BRC cell bank and SC102A-1 was purchased from System Biosciences. PR818-5 (0818) was obtained as a kind gift from F. Gage ( Marchetto et al., 2013) from the Salk Institute for Biological Studies (La Jolla, CA). Sandra A and Toba were generated in collaboration with Shinya Yamanaka following a nonviral transfection method ( Okita et al., 2013). Briefly, blood was collected from a chimpanzee and an orangutan, both housed at the Leipzig Zoo, and leukocytes were isolated by Ficoll gradient centrifugation, which were then used for reprogramming to iPSCs. DNA sequencing revealed no chromosome aberrations, and RNA-seq and immunohistochemistry confirmed pluripotent gene and protein expression signatures. Primate blood samples used to generate iPSCs were obtained by certified veterinarians during annual medical examinations or other necessary medical interventions, meaning that no invasive procedures were performed on primates for the sole purpose of our research project. The Max Planck Institute for Evolutionary Anthropology has an institutional permit for the transport of biological material derived from endangered species (DE216-08, see http://cites.org/common/reg/si/e-si-beg.shtml). Human iPSC line TkDA3-4 ( Takebe et al., 2013) was used to generate iPSC single-cell transcriptomes. iPSC lines were cultured under standard iPSC culturing methods on matrigel (BD Biosciences) using mTeSR1 (Stemcell Technologies). Human endothelial cells. (HUVECs, Lonza, Basel, Switzerland) were maintained in endothelial growth medium (EGM) (Lonza) at 37°C in a humidified 5% CO2 incubator. Single cell transcriptome analysis confirmed the identity of human and chimpanzee iPSCs and human endothelial cells, and showed no contamination with other cell lines. B-cell lines were generated from blood obtained from three human (A144, A156, A158) and three chimpanzee (Dorien, Jahaga, Ulla) individuals. Withdrawal and processing of blood samples was performed according to approved protocols, and was performed for chimpanzee during necessary veterinary interventions. Lymphocytes were isolated from blood using a Ficoll gradient centrifugation. Immortalization was performed by adding Epstein Barr virus (EBV) supernatant to the lymphocytes and further cultivation of the cells until colonies of immortalized B-lymphocytes were established ( Tosato and Cohen, 2007). B-cells were maintained in RPMI with 10% FBS, 1% Glutamax and 2% penicillin/streptomycin. Cell lines were regularly tested for mycoplasma using a PCR-based test (Minerva Biolabs) and found to be negative.

Human and chimpanzee cerebral organoids were generated from the above iPSCs and cultured for the indicated times as described previously for human cerebral organoids ( Lancaster and Knoblich, 2014; Lancaster et al., 2013), with minor modifications ( Camp et al., 2015).

Single-cell RNA-seq experiments

Preparation of single-cell suspensions from cerebral organoids

To generate single-cell suspensions, cerebral organoids were either dissociated as a whole or first sliced using a vibratome to dissect cortical regions. Whole organoids were washed three times in PBS and incubated at 37°C in 2 ml Accutase (Sigma) plus 2 U/μl DNAse I (New England Biolabs) for ~45 min. For dissections, organoids were washed using PBS and embedded into 4% low-melting agarose (Sigma) and sliced into 150-μm sections using a vibrating microtome (Ci 7000 smz, Camden Instruments). Slices were kept in differentiation plus vitamin A (Diff +VA) medium ( Lancaster et al., 2013) and inspected under a stereomicroscope (Leica) to dissect cortical regions. Selected regions were washed three times with PBS and incubated in ~200 μl Accutase with DNAse I at 37°C for ~45 min. Additional mechanical dissociation was performed by triturating the tissue. Subsequently, cells were filtered through a 30-μm cell filter (Miltenyi Biotec), washed with Diff +VA medium and spun down at 300 × g for 5 min. The resulting pellet was resuspended in 30-50 μl (for cortical slices) or 250-500 μl (for whole organoids) of Diff +VA medium. In case of excessive debris being present, cells were cleaned using a Percoll (Sigma) gradient centrifugation and the resulting pellet was resuspended in 30-50 μl Diff +VA medium. Counting of cells was performed using a Countess automated cell counter (Invitrogen) and by staining with Trypan blue. For single-cell experiments, cell suspensions were diluted to a final concentration of 450-600 cells/μl.

Single-cell cDNA generation

These steps were performed as described ( Camp et al., 2015; Treutlein et al., 2014). Depending on the size distribution of the cells, cells were loaded at a concentration of 250-500 cells per μl onto small (5-10 μm) or medium (10-17 μm) integrated fluidic circuits (IFCs, Fluidigm). Lysis, reverse transcription and amplification were performed on the Fluidigm C1 platform using the SMARTer Ultra Low RNA Kit for the Fluidigm C1 system. External RNA Control Consortium (ERCC) spike-ins (Ambion) were added to the lysis mix at a dilution of 1:80,000. Resulting cDNA was quantified and checked for its size distribution using a capillary gel electrophoresis system (Fragment Analyzer, Advanced Analytical, 1-6000 bps High Sensitivity).

RNA-Seq library preparation and sequencing

Each cell's cDNA was diluted and libraries were prepared using Nextera XT DNA library preparation kits (Illumina). Up to 96 single-cell libraries were pooled and cleaned up using solid phase reversible immobilization (SPRI) beads (Thermo Scientific). Quantification and library size distribution was assessed on a Bioanalyzer (Agilent) platform using High Sensitivity DNA chips. Up to 192 cells were pooled and sequenced in 100-bp paired-end mode on one lane of an Illumina HiSeq 2500 platform (rapid mode).

Read processing, mapping and gene quantification

Base-calling, adaptor trimming and demultiplexing of reads was performed using a custom pipeline based on freeIbis ( Renaud et al., 2013), leeHom ( Renaud et al., 2014) and deML ( Renaud et al., 2015). Demultiplexed reads were mapped using TopHat v2.0.14, and FPKM (Fragments Per Kilobase of transcript per Million mapped reads) values per gene were quantified using Cufflinks v.2.2.1 ( Trapnell et al., 2012). Human reads were mapped to the hg38 reference genome (release 77) and chimpanzee reads were mapped to panTro4 (release 80). The raw FPKM data of all single cells were combined into one master table and transformed to log2 (FPKM +1). ( RStudio Team, 2015) was used to run ( R Development Core Team, 2010), scripts to perform principal component analysis (PCA, FactoMineR package), hierarchical clustering (stats package), differential expression analysis (SCDE package), and to construct heatmaps, scatter and line plots, dendrograms, bar graphs, pie charts and histograms. Generally, ggplot2 and gplots packages were used to visualize the data. Gene ontology enrichment analyses were performed using DAVID informatics Resources 6.7 of the National Institute of Allergy and Infectious Diseases ( Huang et al., 2009).

Analysis of chimpanzee single-cell RNA-seq data

The Seurat package ( Macosko et al., 2015) implemented in R was used to identify cell populations present in chimpanzee organoids ( Figure 1-figure supplement 2 ). T-distributed stochastic neighbour embedding (tSNE) was performed on all chimpanzee organoid cells using the most significant genes (p-value <10-3, with a maximum of 200 genes per principal component) that define the first 6 principal components of a PCA analysis on the data set. In Figure 1E we calculated for each chimpanzee organoid cortex cell the Spearman correlation of its transcriptome (all genes) with bulk transcriptome data from each of 4 microdissected human cortical zones (VZ, iSVZ, oSVZ, CP, mean expression value of each gene across 4 replicates from 13 weeks post conception, data published in ([ Fietz et al., 2012] GSE38805). We hierarchically clustered (Pearson's correlation distance metric) cells based on their correlation coefficient with germinal zones and visualized the clustering in a heatmap showing correlation coefficients scaled across zones (mean-centering and dividing by standard deviation). The scaling enables a better comparison between cells, since the maximum and minimum correlation for each cell is color-coded in the same way after scaling. We used this analysis to identify the zone with which each individual cell had a maximum correlation.

NSPC and neuron signatures ( Figure 1-figure supplement 3 , Figure 1F ) were defined by the top 100 genes correlating or anti-correlating with PC1 from PCA of human fetal neocortex, respectively. Each fetal, human organoid, and chimpanzee organoid cortex cell was scored for the NSPC or neuron signature by summing the number of genes from each signature that have an expression greater than log2 FPKM of 5, and normalizing by the number of all genes expressed above log2 FPKM of 5 for each cell. Lineage network analysis and visualizations were done using igraph implemented in R ( http://igraph.sf.net). To construct the chimpanzee cellular network, we computed a pairwise correlation matrix for all chimpanzee cerebral cortex cells and using genes discovered in PCA of fetal neocortex single cell transcriptomes ( Camp et al., 2015).These same genes had been used to infer lineage relationships in the fetal neocortex. We then generated a weighted adjacency network graph using the graph.adjacency() command and visualized cells as vertices connected to other cells via edges if the pairwise correlation between two cells was higher than 0.4. The fruchterman reingold layout was used to plot the network graph. The combined species network was constructed in a similar way using the same genes and a correlation threshold of 0.4, and was based on FPKM quantification of alignments to each respective species' reference genome. Monocle ( Trapnell et al., 2014) was used to establish pseudotime estimates and corroborate lineage relationships of chimpanzee cerebral cortex cells using the same genes as in the network analysis.

Human-chimpanzee consensus genome construction

We re-aligned reads from each cell to a human-chimpanzee consensus genome to account for mapping bias originating from the different genome qualities of the human and chimpanzee genome. The consensus genome was generated as previously described ( He et al., 2014). In brief, the consensus genome was constructed based on the chained and netted pairwise alignment of human (hg38) and chimpanzee (panTro4) obtained from UCSC. Discordant sites and indels including 6 bp upstream and downsteam of the indel position were masked (replacing the base with N). STAR v2.5.1a ( Dobin et al., 2013) was used to map all sequences to the consensus genome requiring a minimal fraction of 85% of mapped bases per read. For quantification, HTSeq ( Anders et al., 2015) v0.6.1.p1 was used applying the human GENCODE v.24 annotation. Resulting count files were combined into one master table containing all cells and genes.

Differential gene expression analysis

To identify differentially expressed genes between human and chimpanzee, cells were first annotated as AP, BP or neuron based on the fetal cortex cell type with which each cell maximally correlated. After cell type assignment, SCDE (Single Cell Differential Expression) ( Kharchenko et al., 2014), a Bayesian approach for finding differentially expressed genes accounting for noise inherent to single-cell data, was used to compare the orthologous cell type between human and chimpanzee. AP or neuronal specificity was defined as one standard deviation from the mean of z-scores from SCDE of APs and Neurons (Z.x). A more stringent threshold of twice the standard deviation of the z-score was used to define differential expression between human and chimpanzee (Z.y). For the differential gene expression analysis during mitotic phases, we aimed to identify relatively homogeneous clusters of human organoid APs, chimpanzee organoid APs, endothelial cells (ECs), or iPSCs in G2M or G1 phases. We hierarchically clustered cells (Pearson correlation) using expression of genes that correlated with PC1 from PCA on human fetal cortex progenitor cells ( Camp et al., 2015) and which are able to distinguish between cells in G2M and G1 phases. We selected the clusters with high or no expression and assigned them as G2/M or G1, respectively, and ignored the intermediate cells for SCDE. For the organoid APs, this assignment was consistent with an independent assignment using the method published by ( Scialdone et al., 2015).

Immunohistofluorescence

Cerebral organoids were fixed with 1% PFA in 120 mM phosphate buffer pH 7.4 for 20 min at room temperature and subjected to cryosectioning (14 µm) and immunofluorescence as described ( Camp et al., 2015). The following primary antibodies were used: rabbit anti-PAX6 (PRB-278P; Covance), sheep anti-TBR2 (AF6166; R+D systems), rat anti-CTIP2 (ab18465; Abcam), rabbit anti-KI67 (ab15580; Abcam). The secondary antibodies, used in combination with DAPI staining, were all donkey-derived and conjugated with Alexa 488, 555 or 647 (Life Technologies). Images were acquired with a Zeiss LSM 880 Airy inverted microscope, using 10X (0.45 NA) and 20X (0.8 NA) Plan-Apochromat objectives, and analysed using Fiji. Quantifications were carried out in cortical regions of D28 and D52-54 cerebral organoids by counting, from the ventricular to the pial surface, either all PAX6 and TBR2 positive and negative nuclei stained by DAPI in 50 μm and 100 μm wide fields, respectively, or all KI67-positive cells in 100 μm wide fields. An average of 350 cells per sample were counted. Statistical significance was calculated using the Mann-Whitney U-test.

Cumulative EdU labeling

EdU was added to 52 day old cerebral organoids at a final concentration of 1 μg/ml (added from a 1 mg/ml EdU stock in PBS). The organoids were supplied with fresh medium containing EdU every six hours for up to 48 hr. Organoids were then collected in triplicates at the indicated time points (1, 2, 6, 24, 30/36, 48 hr) and processed as described above. For EdU detection, the Click-iT EdU Alexa Fluor 647 Imaging Kit (Invitrogen C10340) was used according to the manufacturer's instructions. Cell cycle parameters were determined using linear regression based on a model described previously ( Nowakowski et al., 1989).

Live imaging

Live tissue imaging was performed as described previously ( Mora-Bermudez et al., 2014). In short, cerebral organoids or freshly dissected developing neocortex tissue were embedded in agarose (Sigma, Germany), sectioned with a vibratome (~200 µm, Leica, Germany), embedded in type Ia collagen (Cellmatrix, Japan), mounted in glass bottom microwell dishes (MatTek, Germany), and incubated with Hoechst 33342 (Sigma) as vital DNA dye. Tissue slices in the dish were further cultured for observation in a microscope stage incubation chamber (Pecon, Germany) kept at 37°C. iPSCs and B cells were likewise mounted in glass bottom microwell dishes previously coated for 1h with matrigel (BD Biosciecne) and poly-D-lysine (Sigma, Germany) respectively, and imaged under their respective standard culturing conditions (see above). Potential phototoxicity was stringently controlled as previously described ( Mora-Bermudez and Ellenberg, 2007).

Image analysis

Images were viewed and prepared with ImageJ ( http://imagej.nih.gov/ij/). Brightness and contrast of images were recorded and adjusted linearly. Spindle orientation analysis was performed as described ( Mora-Bermudez et al., 2014). In short, the degree values given in Figure 4 are deviations from a perfect orthogonality with the local apical surface plane, as seen from a coronal perspective ( Figure 4A-F ). For Figure 4G , the maximal range of orientations per every mitotic AP was calculated from the formation of a metaphase plate to anaphase onset.

Mitotic phase length determination

To measure the duration of mitotic phases, the start of each different phase was defined as follows, based on morphology, dynamics and condensation of chromosomes as reported by vital DNA staining ( Figures 5 and ​and6). 6 ). Prophase: the beginning of mitotic chromosome condensation; prometaphase + metaphase: the beginning of chromosome congression and alignment; anaphase: the beginning of chromosome segregation toward the mitotic poles of the dividing cell; telophase: the beginning of chromosome decondensation after maximal chromosome condensation in late anaphase and until a level indistinguishable from interphase was achieved. The total duration of mitosis was the sum of these phases. We note that our measurements of mitotic phases are limited by the use of chromosomes as markers. Nevertheless, the use of a single fluorescence channel allowed a very high time resolution (~1.1 min) for close monitoring of key chromosomal dynamics to delimit mitotic phases. Towards distinguishing between prometaphase and metaphase, we subdivided prometaphase + metaphase into 'prometaphase', defined here as the time in which chromosomes are congressing and aligning toward the formation of a metaphase plate, and 'metaphase', defined here as the time after every chromosome has been incorporated into a tight metaphase plate at the equatorial plane of the cell, and until anaphase onset.

Statistical analysis

Data were tabulated with Excel (Microsoft, Redmond, WA) and analysed with GraphPad Prism (La Jolla, CA). Statistical tests: for two groups of observations, the Mann-Whitney U-test was used. For three or more groups, the Kruskal-Wallis ANOVA in conjunction with Dunn's Multiple Comparison test for pair-wise comparisons was used. Results were interpreted as statistically significant when p<0.05.

Acknowledgements

We thank the Services and Facilities of the Max Planck Institute of Molecular Cell Biology and Genetics for outstanding support, notably Jussi Helppi and his team of the Animal Facility, and Jan Peychl and his team of the Light Microscopy Facility. We thank David Andrijevic and Anne Weigert for help with maintenance and characterization of iPSC lines. We thank Marta Florio for assistance with human tissue dissection. We thank Andrea Musacchio and members of the Huttner, Treutlein and Pääbo labs for helpful discussions. We thank Fred Gage and Rick Livesey for kindly donating the PR818-5 iPSC line. SK was supported by a PhD fellowship of the Boehringer Ingelheim Fonds. SP was supported by the Paul G. Allen Family Foundation. WBH was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, SFB 655, A2) and the European Research Council (ERC, 250197), by the DFG-funded Center for Regenerative Therapies Dresden, and by the Fonds der Chemischen Industrie. SP, BT and WBH were supported by the Max Planck Society.

Funding Statement

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Funding Information

This paper was supported by the following grants:

Boehringer Ingelheim Fonds to Sabina Kanton.

Paul G. Allen Family Foundation to Svante Pääbo.

Deutsche Forschungsgemeinschaft DFG, SFB 655, A2 to Wieland B Huttner.

European Research Council ERC, 250197 to Wieland B Huttner.

Deutsche Forschungsgemeinschaft to Wieland B Huttner.

Fonds der Chemischen Industrie to Wieland B Huttner.

Max Planck Society to Svante Pääbo, Barbara Treutlein, Wieland B Huttner.

Additional information

Competing interests

The authors declare that no competing interests exist.

Author contributions

FM-B, Conceived the study, Designed the experiments, Performed and analysed live imaging experiments, Wrote the paper.

FB, Conceived the study, Designed the experiments, Grew cerebral organoids, Performed and analysed organoid immunohistochemistry and cumulative EdU labelling, Wrote the paper.

SK, Conceived the study, Designed the experiments, Grew cerebral organoids, Performed single-cell RNA-seq experiments, Analysed single-cell RNA-seq data, Wrote the paper.

JGC, Conceived the study, Designed the experiments, Performed single-cell RNA-seq experiments, Analysed single-cell RNA-seq data, Wrote the paper.

BVe, Analysed single-cell RNA-seq data, Provided information relevant for the interpretation of the data.

KK, Prepared chimpanzee iPSC line Sandra A and orangutan iPSC line Toba, Provided information relevant for the interpretation of the data.

BVo, Prepared chimpanzee iPSC line Sandra A and orangutan iPSC line Toba, Provided information relevant for the interpretation of the data.

KO, Prepared chimpanzee iPSC line Sandra A and orangutan iPSC line Toba, Provided information relevant for the interpretation of the data.

TM, Prepared chimpanzee iPSC line Sandra A and orangutan iPSC line Toba, Provided information relevant for the interpretation of the data.

ZH, Constructed human-chimpanzee consensus genome.

RL, Provided human fetal tissue, Provided information relevant for the interpretation of the data.

SP, Conceived the study, Designed the experiments, Provided intellectual guidance in the interpretation of the data, Wrote the paper.

BT, Conceived the study, Designed the experiments, Analysed single-cell RNA-seq data, Provided intellectual guidance in the interpretation of the data, Wrote the paper.

WBH, Conceived the study, Designed the experiments, Provided intellectual guidance in the interpretation of the data, Wrote the paper.

Ethics

Human subjects: Human fetal brain tissue (11-13 weeks post conception (wpc)) was obtained with informed written maternal consent followed by elective pregnancy termination. Research involving human tissue was approved by the Ethical Review Committee of the Universitaetsklinikum Carl Gustav Carus of the Technische Universitaet Dresden. In addition, research was approved by the Institutional Review Board of the Max Planck Institute of Molecular Cell Biology and Genetics.

Animal experimentation: Mice were kept pathogen-free at the Biomedical Services Facility of the MPI-CBG. All experiments using mice were performed according to the German Animal Welfare Legislation. In addition, research was approved by the Institutional Review Board of the Max Planck Institute of Molecular Cell Biology and Genetics.

Additional files

Major datasets

The following dataset was generated:

Kanton S,Camp G,Treulein B,2016,Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE86207,Publicly available at NCBI Gene Expression Omnibus (accession no: GSE86207)

References

R Development Core Team . Vienna, Austria: 2010. R: A language and environment for statistical computing. R Foundation for Statistical Computing. [Google Scholar]

RStudioTeam . Vienna, Austria: 2015.. R: A language and environment for statistical computing. R Foundation for Statistical Computing. [Google Scholar]

Striedter GF. Principles of Brain Evolution. Sinauer Associates Inc; 2005. [Google Scholar]

Articles from eLife are provided here courtesy of eLife Sciences Publications, Ltd

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Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development

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Human neocortex expansion likely contributed to the remarkable cognitive abilities of humans. This expansion is thought to primarily reflect differences in proliferation versus differentiation of neural progenitors during cortical development. Here, we ...

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The brain is divided into two halves, the right and left brain. Specific areas are responsible for different functions, but the brain works as a whole.

The human brain is an intricate organ. At approximately of your body weight, it contains about 85-100 billion neurons and of connections. Your brain is the command center for how you think and feel, and what you do.

Your brain is divided into two halves. These two sides look very much alike, but there's a difference in how they process information. Within each half, particular regions manage certain functions.

There's a myth that suggests some people are left-brained, while others are right-brained. This myth assumes that a person's motor, cognitive, and behavioral functions stem from the side of the brain that's most dominant.

It's estimated that of the general population in the United States support neuromyths, including this one.

However, despite their contrasting styles, the two halves of your brain are connected by brain fibers and work together.

Keep reading to learn more about the left brain vs. right brain myth, the functions of each side, and tips to keep your brain healthy.

The theory that you're either left-brained or right-brained suggests that one side of your brain is more dominant.

This theory is based on the fact that the brain's two hemispheres function differently. This first came to light in the 1960s, thanks to the research of psychobiologist and Nobel Prize winner, Roger W. Sperry.

According to Sperry's dated research, the left brain and right sides of your brain help you with the following:

This suggests that the left brain is more verbal, analytical, and orderly than the right brain. It's sometimes called the digital brain because it's better at things like reading, writing, and computations.

On the other hand, the right brain is more visual, intuitive, and creative.

So, if you're mostly analytical and methodical in your thinking, the theory suggests you're left-brained. If you tend to be more creative or artistic, you're right-brained.

A team of neuroscientists set out to test the left brain vs. right brain hypothesis.

In a 2013 review, they found no proof that this theory is correct. Magnetic resonance imaging of 1,000 people revealed that the human brain doesn't favor one side over the other, nor are the networks on one side stronger than on the other.

Bundles of nerve fibers tie the two hemispheres together, creating an information highway. The two sides function differently, but they work together and complement each other. You don't use only one side of your brain at a time.

For example, the left brain has traditionally been associated with handling mathematical equations. However, a 2023 review suggests that the right hemisphere helps with:

spatial awareness during complicated calculations

understanding numbers that contain zeros

representing numbers nonverbally

Similarly, people credit the left brain with language processing. However, the authors of a 2020 review found that the right brain plays a key role in understanding context and non-literal language, such as metaphors and irony. They also suggest that the right brain's spatial awareness helps us understand and visualize language.

General personality traits, individual preferences, or learning styles don't translate into the notion that you're left-brained or right-brained.

Still, certain areas of your brain do have specialties, though how each exact area functions may vary from person to person.

According to the Alzheimer's Association, keeping your brain and body active may have short- and long-term benefits for brain health. Here are some tips to help keep your brain sharp.

Thinking exercises: Some brain-thinking exercises may help improve and maintain cognitive function. These may include playing a puzzle, reading, trying a new skill, or playing memory games, among others.

Physical activity: A 2022 review suggests that aerobic exercise may help episodic memory among adults ages 55 years and older who have a dementia diagnosis.

Diet: Nutrition plays a in keeping your brain healthy. Some healthy beverages and foods for your brain may include coffee, whole grains, fresh vegetables, nuts, fatty fish, and poultry.

Sleep: According to the National Institute of Neurological Disorders and Stroke, sleep is vital for your brain to help neurons communicate with each other, remove toxin buildup, and improve your memory.

The Centers for Disease Control and Prevention (CDC) also suggests the following tips to help maintain brain health:

What is it like to be right-brained?

Some people say that if you're right-brained, you're more creative, artistic, and intuitive. Each side of the brain is responsible for different functions, but suggests there are no "left-brained" or "right-brained" people. That said, some people are stronger in right- or left-brain functions.

What is the difference between the right and left side of the brain?

The anatomy of the brain is complex. When people think of the left and right sides of the brain, they think of the two hemispheres that make up the cerebrum. The cerebrum controls many functions, such as your senses, vision, memory, cognition, and hearing. The left side of the cerebrum is associated with speech and processing language, while the right is associated with nonverbal memory and spatial awareness.

What is left-brain thinking?

Left-brain thinking refers to people who may be more analytical, calculated, and orderly.

What is right-brain weakness?

According to the American Stroke Association, if the right side of your brain is affected, such as from a stroke, you may experience memory and vision problems, paralysis on the left side of your body, and some behavioral changes.

Whether you work out a complicated algebraic equation or paint an abstract work of art, both sides of your brain actively participate and provide input.

No one is truly left-brained or right-brained, but you can play to your strengths and continue broadening your mental horizons.

A typical, healthy brain is capable of lifelong learning and boundless creativity, especially when it gets fuel from proper nutrition, a dose of physical exercise, and mental stimulation.

Read this article in Spanish.

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Left Brain vs. Right Brain: What's the Difference?

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The two sides of your brain may look alike, but there's a big difference in how they process information. Here's what left brain versus right brain means for you.

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The terms left-brained and right-brained refer to the two hemispheres of the brain's cerebrum. The left hemisphere generally focuses more on speech and language, while the right hemisphere manages creativity and spatial relation (e.g., the ability to focus on a rabbit in a forest without noticing each tree).

Some believe that certain people have certain personality traits or skills because one side of the brain is more dominant. But finding some skills challenging does not mean that one side of the brain is weak. Instead, skills or difficulties have more to do with how the two sides of the brain work together.

This article discusses the differences between the two sides of the brain, common misconceptions, and more.

Left and Right Brain Differences

The two hemispheres of the cerebrum serve different purposes. For example, logic, language, and speech are mostly the jobs of the left side, while creativity, intuition, spatial attention, and association are the jobs of the right side.

The cerebrum is also responsible for muscle function, with the left hemisphere controlling the muscles on the right side of the body and the right hemisphere controlling the muscles on the left.

What Is a Left-Brained Person Like?

Science credits the left hemisphere with strong attention to detail and quantitative thinking. Some believe certain people are more logical and analytical because the left brain is dominant, though that's not necessarily true. For example, children considered gifted in math tend to have right and left hemispheres that work well together as opposed to an exceptionally strong left.

What Are Right-Brained Thinkers Good At?

Right-brained people might think more freely, qualitatively, and intuitively and consider the big picture more often. Creativity and artistic abilities are sometimes credited to right-brain dominance, too.

People who experience damage to the right hemisphere, sometimes caused by stroke, may find it challenging to:

Associate with dates, times, and locations

Focus or pay attention

Make connections between problems and their effects

Organize or plan

Process jokes or social cues

Recognize or solve problems

Remember or learn new information

See or notice things on their right side

Though it may seem that those functions are processed on the right side of the brain after damage to the right hemisphere, it has more to do with how the two hemispheres are able to work together after brain damage.

Left Brain, Right Brain, Dominance Misconception

The two sides of the brain have different roles but work together to function properly. People who excel at skills associated with one side of the brain or the other actually have a strong connection between the two hemispheres.

Similarly, when people find certain things more challenging, it is not because the side of the brain responsible for those tasks is weaker. Instead, it is because the brain develops differently than it typically might. For example, the right side may perform a role that is typically the responsibility of the left side.

Recent Research

Recent research shows that the right side of the brain develops earlier than the left, leaving the left side more susceptible to environmental influences during development. Research also shows that it is healthy for the left and right hemispheres to develop differently, each with its own unique roles.

Genes and genetic mutations play a role in this healthy brain asymmetry and can change in people with autism, schizophrenia, and other physical and mental challenges. Further research is necessary, but it may help treat various health conditions.

How the Brain Works

The brain's primary job is to process information and regulate the body. It receives information from the body through its senses of sight, touch, hearing, smell, and taste. It uses that information to decide what to do (consciously or subconsciously) and carries out those actions.

The left and right sides of the brain focus on different roles, but they work together to make the body function.

People who are especially skilled in one area or a certain type of activity are often considered left or right brained. The thought behind this is that one side is stronger than the other, but that's not the case. Instead, each side is more or less responsible for certain roles or areas of focus.

For example, the left side is generally responsible for logic and language, while the right is responsible for creativity and intuition. In reality, both sides work together, and stronger skills result from the two hemispheres working well together.

Frequently Asked Questions

Which brain is more intelligent? Left or right?

Neither side of the brain is more or less intelligent than the other. They each focus on different roles, such as creativity or logic. Additionally, they both work together to perform tasks and carry out functions.

Which side of the brain controls speech?

The left side of the brain typically controls speech and language.

How do you know if you're left brained or right brained?

There are personality tests and evaluations to test for right-brain or left-brain dominance. However, these tests do not assess each hemisphere's strengths. Scientific research does not show that one side is dominant over another. People can also practice and hone skills they find challenging.

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Left Brain vs. Right Brain: Functions, Traits, and Misconceptions

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The terms left-brained and right-brained refer to the two hemispheres of the brain's cerebrum. The left hemisphere generally focuses more on speech and language, while the right hemisphere manages creativity and spatial relation (e.g., the ability to focus on a rabbit in a forest without noticing each tree).

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Columbia University Mailman School of Public Health

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It's no secret that our bodies change as we grow older. Over time, we feel aches and pains in the joints we once used to spring up and out of bed in the morning. But in addition to our bodies changing as they grow older, our brains are constantly transforming throughout our lives-and it's not as simple as you might think. Some functions like memory, processing speed, and spatial awareness deteriorate as we age, but other skills like verbal abilities and abstract reasoning actually improve.

Why does this happen, though? And what does the changing nature of our most complex organ tell us about our aging selves and our aging population from a public health perspective?

What Changes Occur When the Brain Ages?

In the early years of life, the brain forms more than a million new neural connections every second. By the age of 6, the size of the brain increases to about 90% of its volume in adulthood.

Then, in our 30s and 40s, the brain starts to shrink, with the shrinkage rate increasing even more by age 60. Like wrinkles and gray hair that start to appear later in life, the brain's appearance starts to change, too. And our brain's physical morphing means that our cognitive abilities will become altered. The following changes normally occur as we get older:

Brain mass: While brain volume decreases overall with age, the frontal lobe and hippocampus - specific areas of the brain responsible for cognitive functions - shrink more than other areas.
The frontal lobes are located directly behind the forehead. They are the largest lobes in the human brain and are considered to be the human behavior and emotional control centers for our personalities.
The hippocampus is a complex brain structure embedded deep into the temporal lobe. It plays a major role in learning and memory. Studies have shown that the hippocampus is susceptible to a variety of neurological and psychiatric disorders.

Cortical density: This refers to the thinning of the outer corrugated surface of the brain due to decreasing synaptic connections. Our cerebral cortex, the wrinkled outer layer of the brain that contains neuronal cell bodies, also thins with age. Cortical thinning follows a pattern similar to volume loss and is particularly pronounced in the frontal lobes and parts of the temporal lobe. Lower density leads to fewer connections, which could contribute to slower cognitive processing.

White matter: White matter consists of myelinated nerve fibers that are bundled into tracts and transmit nerve signals between brain cells. Researchers believe that myelin shrinks with age, slowing down processing and reducing cognitive function. White matter is a vast, intertwining system of neural connections that join all four lobes of the brain (frontal, temporal, parietal, and occipital), and the brain's emotion center in the limbic system.

Neurotransmitter systems: The brain begins to produce different levels of chemicals that affect neurotransmitters and protein production, ultimately leading to a decline in cognitive function.

With these changes, older adults might experience memory challenges like difficulty recalling names or words, decreased attention, or a decreased ability to multitask.

As the brain ages, neurons begin to die, and the cells also produce a compound called amyloid-beta. Amyloid beta is what is typically associated with Alzheimer's. It can also be found in the brain of an individual who is aging. If there are amyloid-beta plaques (prions) in the brain, it can be a sign of Alzheimer's disease. And when there are signs of plaque, but no prions, it may be a sign of normal aging.

Overall, as the brain ages, it does get more difficult for older individuals to care for themselves.

The Connection of Aging and Public Health

With life expectancy almost doubling over the last century and the aging population on the rise, our aging society is a public health issue. Here at the Columbia Mailman School of Public Health, we believe that meeting the needs of our aging society is one of the most significant public health challenges of the 21st century.

We need public health leaders in government, research institutions, and more to help us understand the societal implications of our aging society and establish policies and programs that ensure the well-being of the aging population.

One example of the intersection of aging and public health is the Healthy Brain Initiative. In 2005, the Alzheimer's Association and the Centers for Disease Control and Prevention (CDC) launched this initiative, developed to disseminate the understanding and support of cognitive aging as a central component of public health practice.

If you're passionate about the intersection of aging and public health, check out our Health of an Aging Society Certificate.

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The Columbia Mailman School of Public Health has been a strong voice and advocate for public health research and education. With numerous publications on issues concerning public health, community collaboration, and health research, we aim to educate and inform the public on public health and safety. Visit our program pages to learn more about our public health degree programs.

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Changes That Occur to the Aging Brain | Columbia Mailman

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Learn more about the changes that occur to the aging brain, what happens as we get older, and how our aging society is an important component of public health.

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What can I do to take care of my temporal lobe?

There are a number of things you can do to maintain how well your temporal lobe works, including:

Help your hearing. If you have hearing loss, it doesn't just make it harder for you to communicate with others or listen to sounds around you. It may also contribute to memory loss, dementia and even age-related degenerative brain diseases like Alzheimer's disease. That makes it important to see a hearing specialist, such as an audiologist, to have your hearing tested. And if you need hearing aids, use them.

Engage your brain. Your brain is like any other part of your body. To keep it healthy, you need to put it to work. Keeping your brain busy is a key way to delay age-related decline in mental abilities, especially your memory.

Get enough quality sleep. Your brain needs good, quality sleep to work correctly. Lack of sleep or poor-quality sleep can contribute to conditions like Alzheimer's disease. A lack of quality sleep, such as with sleep apnea, can also cause thinking and memory problems (and this is true for people of all ages). Making sleep a priority is a way to make your brain health a priority.

Use tools to aid your brain. Memory aids - including calendars, planners, alarms, smartphone apps, etc. - can help bolster your thinking and memory. While it might seem like they keep you from using your brain, they can actually help your brain stay active and keep up with the world around you.

There are many other ways to help maintain your brain health overall. While many brain conditions aren't preventable, you may be able to delay or reduce the severity of some conditions. Some things you can do for your brain health include:

Eat a balanced diet. What you eat directly impacts your circulatory system health. Your brain relies on your circulatory system (a stroke is an example of a condition that happens when circulatory problems affect your brain). Too much or too little of certain vitamins can also affect your brain.

Reach and maintain a weight that's healthy for you, and find ways to be physically active. Managing your weight and activity level can help you prevent or delay many chronic conditions - especially circulatory issues like high blood pressure - that can impact how your brain works. Your primary care provider can guide you on reaching and staying in a weight range that's healthy for you. Staying physically active is also good for your brain directly, as it stimulates the production of key signaling chemicals known as neurotransmitters.

Wear safety equipment as needed. Because of their location, your temporal lobes are prone to concussions and traumatic brain injuries, especially from side impacts and sudden movement changes. Helmets, safety restraints (such as seat belts) and other protective gear are essential to preventing brain injuries to your temporal lobe.

Manage your chronic conditions. Many conditions that affect your brain worsen over time. However, treating those conditions can sometimes stop them or delay how long it takes for them to worsen. Examples of conditions like this include Type 2 diabetes, epilepsy and more.

A note from Cleveland Clinic
Your brain's temporal lobe is a key part of understanding the world around you, communicating with others, processing feelings and emotions, and storing certain types of memories (including memories about facts like in this article). Taking care of your brain health, especially relating to your temporal lobe, is important. That way, you improve the odds that your temporal lobe will continue to help you appreciate the world around you, enjoy time with others and remember precious moments throughout your lifetime.

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Temporal Lobe: What It Is, Function, Location & Damage

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Your brain's temporal lobe is a paired set of areas at your head's left and right sides. It's key in sensory processing, emotions, language ability, memory and more.

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There are many different types of brain injury that a person can experience. Learn about the terminology associated with brain injury here.

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The brain is one of our most important organs, yet most people understand very little about it. Come with us as we explore the different parts of the brain, how they work and why they are important.

We can't live without our brain

The human brain is a complex organ and it controls almost every aspect of our lives.

A good example of all parts of our brain working together to complete a task is the act of sending a text message:

Parietal lobe helps us feel the phone in our hand, the tapping of the text and to read what we've typed.

Occipital lobe helps us recognise the phone and interpret the data on the screen.

Hippocampus helps us draw on our memory, the name of a friend and the story we want to tell.

Temporal lobe helps us to spell and form a sentence.

Limbic region could be involved if the text is emotional.

Frontal lobe was involved in planning to send the text and censoring any socially inappropriate statements.

Many different conditions can impact on the brain and cause dementia, as well as many other diseases similar to dementia. That's why it's so important be brain healthy and see your GP in the first instance if you have any concerns.

All parts of our brain are interconnected

Each part of our brain has a specialised function, but one part can't function well without the others because the brain sends messages in all directions for the human body to work. To function as human beings, there is constant communication across the brain.

Damage to any part of the brain can have a significant impact on a person's life. Imagine trying to send a text if your parietal lobe wasn't working properly (helps us feel the phone in our hand, the tapping of the text and to read what we've typed). You wouldn't be able to do it the way you are used to, even though all other lobes might be working perfectly fine.

For people with dementia, brain damage occurs unevenly. It can start in one area of the brain, but it can affect so many different daily tasks, because so many brain parts are involved in one simple task. Brain damage caused by dementia also spreads over time, so more and more brain parts become damaged, leading to more and more difficulties in daily life.

There are two distinct hemispheres in our brains

The brain has two hemispheres, left and right. Separately and together, each hemisphere allows us to maintain life and be unique.
Limbic region:

Development of emotions

Being able to understand our emotions

Being able to detect danger

Damage to the limbic region is common in most forms of dementia. It may change the way a person feels or would react to things. A person may feel more excited, anxious, sad or apathetic than before they developed dementia.

Damage to this part of the brain can also lead to delusions (strongly believing things that aren't true) - for example believing a stranger is in the house, or someone is stealing things from them.
Hippocampus:

Part of the limbic system

Memories are stored all over the brain but the actual ability to store memory occurs here

Damage to the hippocampus makes it difficult to learn new things. It is important for memory of events and experiences (episodic memory).

The brain is then further divided into several different areas, called lobes, which are responsible for different things.
Frontal lobes:

Knowing how to do things in a certain order

Making decisions and solving problems

Self-awareness (for example, knowing when you are thirsty)

Ability to control emotions

Keeping your own behaviour in check

Talking fluently

Keeping things "in mind"

Starting and stopping an action

Frontotemporal dementia is most closely linked to damage in the frontal lobes. Early symptoms of frontotemporal dementia can be changes in personality or behaviour. People may also have trouble with planning, organising and making decisions.

In other types of dementia, such as Alzheimer's disease, dementia with Lewy bodies and vascular dementia, the frontal lobes tend to be damaged later.
Parietal lobes:

Paying attention

Being sensitive to sounds, touch, taste and temperature

Reading and writing

Knowing where your body is in relation to other things

Damage to the parietal lobes is common in Alzheimer's disease. It can lead to problems with performing gestures and skilled movements when the person is trying to do things like tie shoelaces or put on clothes. It can also make doing tasks involving reading or writing much more difficult.
Occipital lobes:
Being able to understand what you see

Damage to the occipital lobes eventually occurs in most types of dementia, although not generally during the early stages. However, in posterior cortical atrophy (PCA), visual problems can be among the first symptoms.

When the occipital lobes become damaged, a person may experience difficulty working out what they see in front of them. Severe difficulties with visual perception can also contribute to visual hallucinations.
Temporal lobes:

Understanding words, sounds and language

Being able to manage hearing lots of sounds at the same time

The hippocampus is located within the temporal lobes

The temporal lobes help to understand what is being heard and damage to this area can make it more difficult for the hippocampus to form memories of what has been heard.

Not all conditions of the brain are dementia

A number of conditions produce symptoms similar to dementia and some of the can be treated. They include some vitamin and hormone deficiencies, depression, medication effects, infections and brain tumours.

It is essential to talk to your doctor when symptoms first appear. If you feel comfortable, take a relative or friend with you.

If the symptoms are caused by dementia, an early diagnosis means early access to support, information and, if it is available, medication.

If symptoms are not caused by dementia, early diagnosis will be helpful to treat other conditions.

If you are worried about your brain or want to know more about being brain healthy, please call us at any time on 1800 100 500.
Want to know more about brain health? Check out these articles:
Is dementia inevitable and should you do the gene test to find out?Actor Chris Hemsworth's announcement that he carries two copies of the ApoE4 gene, increasing his risk of developing Alzheimer's disease, has generated a lot of conversation. But does this mean dementia is inevitable and is gene testing a good idea?

How do we maintain a healthy brain?There is no sure way to prevent dementia but there are things we can do to get our brain healthy and keep it healthy.

Is there a way to track your brain health? We all have times where we don't feel ourselves, but how can we determine if it is temporary or if there is something more going on?

For more resources about brain health visit our library guide here: https://dementia-org.libguides.com/maintain-your-brain

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The brain is one of our most important organs, yet most people understand very little about it. Come with us as we explore the different parts of the brain, how they work and why they are important.

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HOW DO NEURONS SEND AND RECEIVE MESSAGES?

In biology, electricity is the flow of charged particles (ions) moving across the surface layer of a cell, which is called a membrane [ 1]. The movement of ions carries an electrical wave along the length of a nerve cell, which is called a neuron. The neuron has local branches (like a tree) that receive signals, which are called dendrites, and a longer, simpler projection (like a tree trunk) that sends signals, which is called an axon ( Fig. 1 ). How does the electrical signal jump from one neuron to another? Near the end of the axon, there are special communication junctions called synapses ( Fig. 1 ). A synapse releases chemical signals, which are called neurotransmitters. These signals travel to another neuron to create a new electrical wave in that cell.

How does an electrical wave travel down a neuron? The cell membrane contains gated protein channels that can open and shut, to allow ions to enter or leave the cell (permeability) [ 1]; like the automatic sliding doors at the grocery store. When such a channel opens, it lets ions flood into the cell, carrying electrical charge ( Fig. 2 ). This causes the next channel along to open, and then the next, such that the electrical wave moves along the cell. To return to rest, a different channel opens more slowly to allow the ions to leave the cell [ 1]. This ends the electrical wave, setting the stage for the next electrical wave to start the cycle again. The movement of ions continues along the axon to reach synapses near the axon terminus ( Fig. 2 ).

HOW DOES A SYNAPSE WORK TO COMMUNICATE BETWEEN CELLS?

The electrical wave causes the neuron to release small chemical neurotransmitters at the synapse [ 1], which then travel across to the other cell to attach to proteins on the cell surface, which is called a membrane ( Fig. 2 ). These proteins are called receptors. Neurotransmitters are packaged inside little round spheres called vesicles, which can fuse with the outside membrane to release the signal ( Fig. 2 ). When these vesicles fuse with the cell membrane, they release the chemicals outside of the cell ( Fig. 2 ). These chemicals then move through the space between the sender cell and the receiver cell [ 1]. This happens very quickly because the space is very, very narrow ( Fig. 2 ). When the chemical neurotransmitter reaches the receiver cell, it binds to special receptors in that membrane, which causes new channels to open ( Fig. 2 ). Ions flow into the receiver cell and this creates a new electrical message [ 2].

This is also how our neurons communicate with our muscles, telling us when to move. The special movement synapse is called the neuromuscular junction ( Fig. 2 ) [ 3]. In people, the neurotransmitter here is acetylcholine, and the muscle receptor is the acetylcholine receptor. Just like in neurons, the binding of the neurotransmitter causes receptors to open as channels in the muscle, allowing ions to flood into the muscle ( Fig. 2 ) [ 3]. In the muscle, this electrical message causes the muscle to contract or shorten. Think about catching a ball: your brain tells a neuron to send an electrical signal to the neuromuscular junction synapse, and this causes neurotransmitter to be released onto your finger muscles, so that they contract to catch the ball.

HOW DO SYNAPSES ALLOW ME TO SEE AND HEAR?

Our senses detect the world around us and transduce the many external forms of energy (light, sound, movement) into electrical messages in our neurons. In our eyes, for example, there are light-detecting neurons called photoreceptors that respond to the things we see [ 1]. Some of these special neurons detect colored light (red, green, blue) and some detect just black and white; like an old-fashioned photograph. Light causes channels to open in these different light-detecting neurons, which sends an electrical message to the synapses of neurons inside your brain ( Fig. 3 ). Signals travel along the optic nerve to carry information into your brain [ 1]. This information is then processed in visual center synapses to interpret the light images.

For us to hear, sensory receptors in our ears are actually activated by movement, as sound is movement vibrations travelling through the air. These air vibrations move tiny hairs on our ear nerve cells [ 1]. This movement opens channels, allowing ions to flood into the cell and create the electrical message ( Fig. 2 ). As a result, neurotransmitters are released at the synapse between the hair cell and a brain neuron ( Fig. 2 ). How loud the sound is depends on how many hairs are bent. Greater bending causes more neurotransmitter to be released at the synapse, which then creates more electrical messages into the brain ( Fig. 3 ). These signals travel along the auditory nerve, which connects through synapses to brain neurons interpreting smells [ 1].

HOW DO SYNAPSES ALLOW ME TO LEARN AND REMEMBER?

One of the most important things about our brains is that synapses change when we use them. These changes in our synapses (plasticity) allow us to learn new information, and then remember what we have learned [ 2]. The number and size of synapses can change as we use them. If we use our synapses a lot, many more can form ( Fig. 3 ). If we do not use them as much, synapses can shrink or decrease in number [ 2]. The strength of communication between synapses can also change depending on how much we use them. If we use them a lot, this can increase the amount of neurotransmitter released, or neurotransmitter receptors on the receiving cell ( Fig. 2 ) [ 2]. Synapses are like muscles; they are strengthened by use.

If we use our synapses a lot for a long time, synapse strengthening can also be maintained for a very long time. This process is known as long-term potentiation [ 2]. If we use our synapses a lot, it can create new synapses that remain in place for many years, even decades. Long-term potentiation is what happens when we form long-term memories, and what happens when we convert short-term memories into long-term memories [ 2]. As you know, you can remember things for years; think of your mother's face, or your best friend in the first grade. Since your synapses are so important for moving, sensing, learning and remembering, it is easy to see how problems with synapses can cause diseases and disabilities [ 4- 6].

WHAT HAPPENS WHEN SYNAPSES DO NOT WORK PROPERLY?

When synapses do not work properly, your brain cannot communicate within itself and with your body muscles. Movement disorders often result from problems at the neuromuscular junction [ 4]. Diseases result from problems in sending or receiving neuromuscular junction signals ( Fig. 2 ). For example, one disease is caused by the neurotransmitter acetycholine not being cleared out of the synapse. Acetylcholine is released at the neuromuscular junction synapse to cause muscles to contract ( Fig. 2 ). If it is not properly removed afterwards, then acetycholine will continue to bind muscle receptors ( Fig. 2 ). This will cause improper muscle contraction and movement, later loss of the receptors, and eventually the loss of the muscles [ 4].

Similarly in our senses, problems with synapses can cause a loss our sensory perception. Deafness can occur due to problems in synapses in our ear hair cells and the overactivation of auditory neurons [ 5]. If our hearing neurons are activated over and over again, it takes a stronger electrical message to continue to activate them. As a result, ear hair cells in people with hearing problems need to feel a louder sound in order to pass on the message to neurons in the auditory nerve [ 5]. This is known as an increased hearing threshold. In cases of blindness, photoreceptor synapse problems can cause photoreceptor cells to disappear completely [ 6]. Thus, light cannot be turned into electrical signals, and the information is not carried into the brain.

Finally, problems with the plasticity of brain synapses can cause thinking disabilities and autism [ 1, 2]. Perhaps you know someone with autism spectrum disorder? This problem causes a state of reduced social interaction and abilities to communicate with your friends and family. One clear cause of autism is that synapses do not change as much as they should when they are used [ 1, 2]. In this condition, new synapses do not form as well as usual and therefore communication between neurons is weakened. Although the causes of autism are still being determined, it is clear that it is related to our genes. One problem that can decrease the plasticity of synapses occurs in people with Down's syndrome.

WHY DO WE NEED TO KNOW ABOUT SYNAPSES?

So many functions of your body are carried out based on synapse communication between cells! Right now, as you are reading this, literally trillions of synapses are sending signals whizzing around your brain and into the rest of your body. Neurons are driving movement in your muscles through neuromuscular junction synapses; allowing your eyes to move and your fingers to tap! Your brain synapses are receiving sensory information from your eyes, your ears and your other senses, and you are using this blizzard of information to make the best decisions about what you should do. Your synapses are changing to allow you to learn, and to remember what you learn. Hopefully, the information in this article will stay in your brain synapses as long-term memory!

GLOSSARY

Ions

positive or negative charged salt particles that move through your cell membranes

Permeability

the number of ions moving through a cell membrane over a period of time

Neuromuscular junction

the special synapse between a motor neuron and a muscle cell

Transduce

to turn one type of energy into another type of energy; like light to electricity

Plasticity

the ability of all your synapses to change based on the amount you use them

AUTHOR BIOGRAPHIES

Athira Sivadas: I am a pre-med undergraduate student at Vanderbilt University in Nashville, Tennessee. My interests lie in the molecular basis of neurological disorders, such as Autism and Down's syndrome. I am especially interested in environmental effects on brain structure and plasticity. In my free time, I volunteer for the American Red Cross.

Kendal Broadie: I am the Stevenson Professor of Neurobiology at Vanderbilt University. I have studied synapses for more than 30 years, including synapse development (synaptogenesis), synapse function (neurotransmission), and use-dependent synapse change (synaptic plasticity). I also model synaptic diseases, such as Autism Spectrum Disorder (ASD).

REFERENCES

[1] Reece JB, Urry LA, Cain MC, Wasserman SA, Minorsky PV, Jackson RB Campbell Biology. 10th edition Glenview: Pearson Education, 2014. [ Google Scholar]

[4] Merzendorfer H 2005. Muscular dystrophies: a novel player. Journal of Experimental Biology. 208: 7. doi: 10.1242/jeb.01388. [[ CrossRef] Google Scholar]

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HOW DOES MY BRAIN COMMUNICATE WITH MY BODY?

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In biology, electricity is the flow of charged particles (ions) moving across the surface layer of a cell, which is called a membrane [ 1]. The movement of ions carries an electrical wave along the length of a nerve cell, which is called a neuron.

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For hundreds of years, scientists have tried to understand the human brain - known as the most complex organ in the universe.

The average human brain contains about 86 billion nerve cells, called neurons. These are the building blocks of your brain. Neurons communicate with each other by sending chemical and electrical signals.

Each neuron is connected with other neurons across tiny junctions called "synapses". Impulses rush along tiny fibres, like electrical wires, from one neuron to the next.

Every time you recognise a familiar face, hear a voice, learn something new or read a word like this, millions of neurons are communicating with each other through hundreds of millions of synapses.
Curious Kids is a series by The Conversation, which gives children the chance to have their questions about the world answered by experts. If you have a question you'd like an expert to answer, send it to curiouskids@theconversation.com. We won't be able to answer every question, but we'll do our very best.
Making sense

The brain is the body's control centre: it sends messages to your body through a network of nerves called "the nervous system", which controls your muscles, so that you can walk, run and move around.

The nervous system extends through your body from your spinal cord, which runs from your brain down your backbone, like the branches of a tree.

Read more: Curious Kids: how can we see what we are imagining as well as what's in front of us?

The brain is also in charge of the way you experience the world around you. Imagine you're walking in a forest. The light bouncing off the trees enters your open eyes; the chirping sounds of the birds reach your ears; and the damp smell of the forest soil wafts up your nose.

The nerve cells in your eyes, ears and nose detect these sensations, and send signals to different parts of your brain, which turn them into what you see, hear and smell - all in a matter of milliseconds.

Sending signals

As well as sending electrical signals through the nervous system, the brain also uses chemical signals to control processes in the body.

Have you ever wondered why you feel sleepy? When the sun goes down, a part of your brain called the pineal gland produces a hormone called melatonin, which makes you feel tired.

Melatonin is produced a few hours later in teenagers than it is in adults and children. This makes teenagers want to go to bed and wake up later than adults and children.

Read more: The biological reason why it's so hard for teenagers to wake up early for school

Teenagers are not lazy: it's all to do with how the brain sends signals to the body.

A sense of self

As well as allowing us to move around and understand what's going on in the world, the brain gives us a sense of who we are - a "sense of self", that's different to other people.

Scientists don't quite yet understand how the brain creates each person's sense of self. But research has shown that when people think they are being watched by others, certain parts of their brains are busy. This part - called the "medial prefrontal cortex" - is what makes you feel self-conscious.

The human brain, with its billions of neurons working together, is sending signals to your body to determine how you feel, from one moment to the next.

The brain is always trying to find ways to explain the sensations that we feel in our body. And the same sensation can have different meanings in different contexts. Here's an example: when you see a delicious piece of cake and your stomach churns, your brain might send signals to your body that you're hungry and excited.

But if you're about to have a test at school, your brain may give a different meaning to that churning stomach and create feelings of fear or anxiety.

The experiences you have become part of how your brain makes sense of what is happening to you. This means that people have more control over their emotions than they might think, because the brain can learn how to respond to experiences differently. As author Wayne Dyer said: "If you change the way you look at things, the things you look at change."

From perceiving the world through the five senses, to creating our sense of self, uncovering how the human brain sends signals to our body is one of the biggest mysteries in science.
Children can have their own questions answered by experts - just send them in to Curious Kids, along with the child's first name, age and town or city. You can: Here are some more Curious Kids articles, written by academic experts:

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Curious Kids: how does our brain send signals to our body?

# data[].attributes.attachment_link.description
For hundreds of years, scientists have tried to understand the human brain - known as the most complex organ in the universe. The average human brain contains about 86 billion nerve cells, called neurons. These are the building blocks of your brain. Neurons communicate with each other by sending chemical and electrical signals.