Scientists unveil detailed cell maps of the human brain and the nonhuman primate brain

A group of international scientists have mapped the genetic, cellular, and structural makeup of the human brain and the nonhuman primate brain. This understanding of brain structure, achieved by funding through the National Institutes of Health's Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, allows for a deeper knowledge of the cellular basis of brain function and dysfunction, helping pave the way for a new generation of precision therapeutics for people with mental disorders and other disorders of the brain. The findings appear in a compendium of 24 papers across Science, Science Advances, and Science Translational Medicine.

"Mapping the brain's cellular landscape is a critical step toward understanding how this vital organ works in health and disease," said Joshua A. Gordon, M.D., Ph.D., director of the National Institute of Mental Health. "These new detailed cell atlases of the human brain and the nonhuman primate brain offer a foundation for designing new therapies that can target the specific brain cells and circuits involved in brain disorders."

The 24 papers in this latest BRAIN Initiative Cell Census Network (BICCN) collection detail the exceptionally complex diversity of cells in the human brain and the nonhuman primate brain. The studies identify similarities and differences in how cells are organized and how genes are regulated in the human brain and the nonhuman primate brain. For example:

• Three papers in the collection present the first atlas of cells in the adult human brain, mapping the transcriptional and epigenomic landscape of the brain. The transcriptome is the complete set of gene readouts in a cell, which contains instructions for making proteins and other cellular products. The epigenome refers to chemical modifications to a cell's DNA and chromosomes that alter the way the cell's genetic information is expressed.
• In another paper, a comparison of the cellular and molecular properties of the human brain and several nonhuman primate brains (chimpanzee, gorilla, macaque, and marmoset brains) revealed clear similarities in the types, proportions, and spatial organization of cells in the cerebral cortex of humans and nonhuman primates. Examination of the genetic expression of cortical cells across species suggests that relatively small changes in gene expression in the human lineage led to changes in neuronal wiring and synaptic function that likely allowed for greater brain plasticity in humans, supporting the human brain's ability to adapt, learn, and change.
• A study exploring how cells vary in different brain regions in marmosets found a link between the properties of cells in the adult brain and the properties of those cells during development. The link suggests that developmental programming is embedded in cells when they are formed and maintained into adulthood and that some observable cellular properties in an adult may have their origins very early in life. This finding could lead to new insights into brain development and function across the lifespan.
• An exploration of the anatomy and physiology of neurons in the outermost layer of the neocortex -- part of the brain involved in higher-order functions such as cognition, motor commands, and language -- revealed differences in the human brain and the mouse brain that suggest this region may be an evolutionary hotspot, with changes in humans reflecting the higher demands of regulating humans' more complex brain circuits.

The core aim of the BICCN, a groundbreaking effort to understand the brain's cellular makeup, is to develop a comprehensive inventory of the cells in the brain -- where they are, how they develop, how they work together, and how they regulate their activity -- to better understand how brain disorders develop, progress, and are best treated.

"This suite of studies represents a landmark achievement in illuminating the complexity of the human brain at the cellular level," said John Ngai, Ph.D., director of the NIH BRAIN Initiative. "The scientific collaborations forged through BICCN are propelling the field forward at an exponential pace; the progress -- and possibilities -- have been simply breathtaking."

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Sugar is processed differently in the brains of obesity-prone vs. obesity-resistant rats

On a diet? Perhaps you're avoiding sweets or carbs altogether or curbing late-night munchies. These are examples of behavior modifications and when it comes to food, avoiding those diet triggers can be pretty hard to do.

To understand what drives people to overeat, scientists are looking more closely at a brain structure involved in motivation, called the nucleus accumbens. This small region drives reward-seeking behaviors underlying the pursuit of sex, recreational drugs like nicotine and alcohol, and food.

"These brain motivation centers evolved to help us survive; finding food and having sex are essential to the survival of an individual and of a species," said Carrie Ferrario, Ph.D., associate professor in the Department of Pharmacology at U-M Medical School.

"What was advantageous when food was hard to find has become a disadvantage and unhealthy in the current food dense environment. This is compounded by the over-abundance of over-processed, low nutrition foods that may satisfy our taste but leave our bodies unnourished. People don't tend to find it difficult to turn down an extra serving of broccoli, but just one more french-fry or making room for a bit of chocolate dessert...that's a different story. The real challenge is overcoming these urges and changing our behavior when it comes to food," Ferrario added.

Given the immense toll obesity takes on virtually all body systems, Ferrario, Peter Vollbrecht, Ph.D., of Western Michigan University, and their colleagues are using rat models to understand potential brain differences between animals who are prone to over-eating and obesity and those who are not.

Previous research from Ferrario's lab pinpointed differences in the nucleus accumbens in obesity-prone and obesity-resistant rats. Their latest study, published in the Journal of Neurochemistry, tracked what was happening in real time in the brain when these animals were presented with glucose, a type of sugar, labeled with a tracer. The tracer allowed the researchers to measure this new sugar in the brain.

Sugar is the brain's main fuel source and once there, the molecule is broken down and used to create new molecules such as glutamine, glutamate, and GABA, each with an important role in influencing the activation of neurons in the brain and nervous system.

"Glucose that is consumed gets broken down and then its carbons get incorporated into neurotransmitters. We see those labelled carbons showing up in those molecules -- glutamate, glutamine, and GABA -- over time," explained Vollbrecht.

They found that glucose was taking longer to get into the nucleus accumbens of obesity-prone animals.

Furthermore, when measuring the concentration of the glutamate, glutamine, and GABA, they discovered excess levels of glutamate, an excitatory neurotransmitter. This, said the team, implied a defect in a neurotransmitter recycling process, typically maintained in the nervous system by star-shaped cells called astrocytes.

Normally, astrocytes will pull glutamate out of the space between neurons, called the synapse, convert it into glutamine, and then shuttle it back to cells that produce GABA or glutamate. This sequence is crucial for turning neurons off and on. "The findings suggest that we're getting too much glutamate and it's not being taken out of the synapse," said Vollbrecht.

Ferrario added, "The balance between glutamate and GABA (the main inhibitory transmitter) is really important for brain function and will influence activity of the neurons in the nucleus accumbens."

This balance, and therefore brain activity, is different in obesity-prone vs. obesity-resistant rats.

The fact that these rats are either prone to obesity or not is important for disentangling cause and effect, says Vollbrecht. "It allows us to remove diet as one of the variables."

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Differences in brain structure between siblings make some more susceptible to developing severe antisocial behavior

Structural differences in the area of the brain responsible for decision making could explain why two siblings living in the same family might differ in their risk of developing the condition conduct disorder.

Psychologists and neuroscientists have long puzzled over why siblings with seemingly the same upbringing and genetic makeup might differ so significantly in terms of their behaviour: how do some young people growing up in families with antisocial or criminal behaviour manage to stay out of trouble?

Researchers at the universities of Bath and Southampton investigated this question by studying different members of the same families -- some with the mental health condition conduct disorder, and some with no behavioural problems.

Conduct disorder is characterised by repetitive patterns of aggressive and antisocial behaviour. It results in substantial personal and financial costs for affected individuals, their families and society in general and is one of the most common reasons for referral to Child and Adolescent Mental Health Services in the UK.

Conduct disorder has a prevalence rate of around 5% among young people aged between 5 and 16, although there is a steep social class gradient: a 2004 survey revealed almost 40% of looked-after children, those who had been abused or on safeguarding registers, had conduct disorder. Despite all this, general awareness of the condition remains low and it is not recognised by many psychologists or psychiatrists.

The new study, published today in the journal Psychological Medicine, sought to understand underlying mechanisms which might determine someone's risk of developing the condition. The international team, including Dr Graeme Fairchild at the University of Bath, conducted MRI brain scans on 41 adolescents with conduct disorder, 24 unaffected siblings (who had a brother or sister with conduct disorder but did not show the condition themselves) and 38 typically developing controls with no family history of conduct disorder.

Their analysis found that young people with conduct disorder and their relatives both displayed structural differences in the brain -- in a part of the brain called the inferior parietal cortex. However, there were also structural changes in the brain that were specific to the conduct disorder group in brain regions responsible for empathy and cognitive control / inhibiting behaviour that were not found in the unaffected siblings.

In addition, the researchers also found changes in the prefrontal cortex, a brain area involved in planning and decision-making, that were specific to the unaffected sibling group -- which may explain why they are protected from showing antisocial behaviour despite growing up with either environmental or genetic risk factors for conduct disorder. Previous work from the same team found that despite differences in antisocial behaviour between siblings, both those with conduct disorder and their unaffected siblings had difficulties in recognising emotional facial expressions.

Dr Graeme Fairchild from the University of Bath's Department of Psychology explains: "Our study aimed to understand the root causes of conduct disorder, specifically what makes members of the same family differ in their antisocial behaviour and are there genetic risk markers for conduct disorder in the brain.

"This is one of the first family-based studies of conduct disorder and it confirms that the brain is important for distinguishing between members of the same family who are at higher risk of developing antisocial or criminal behaviour.

"Interestingly, whilst our previous work showed common impairments between affected and unaffected siblings in recognising facial expressions, this study suggests that key behavioural differences may be determined by small changes in the part of the brain responsible for executive functioning or decision-making. These differences could make some siblings more prone to risky behaviour and should now be a focus of future study."

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