One thing that has clearly emerged from contemporary brain research is the link between mental health and processes that occur while the brain is developing, prior to birth.

The emergence and "wiring up" of the prenatal brain is orchestrated—in ways still only partly known—by our genes. Every one of our body cells, including over 100 billion cells in the brain, contains the full human genome, made up of over 20,000 genes packed tightly in the cell nucleus. In various combinations and at different moments, specific genes are activated in cells across the brain, underlying the organ's development and function.

Research also has shown that errors or irregularities in this highly patterned, pre-programmed developmental process likely have a causal role in certain brain and behavior disorders, including schizophrenia and autism spectrum disorder (ASD).

To better understand the brain when it malfunctions, and to more clearly identify specific conditions which give rise to malfunctions, are major motivations for some of the most sophisticated basic research on the brain that is now in progress. One example is a project led by 2018 BBRF Young Investigator Tomasz J. Nowakowski, Ph.D., of the University of California, San Francisco.

In the journal Nature, Dr. Nowakowski and colleagues including Seth Ament, Ph.D., a 2014 BBRF Young Investigator, recently published results of a multi-year project focusing on an aspect of gene regulation called chromatin dynamics. It is centrally involved in the patterned development of the human brain. Irregularities in chromatin dynamics likely contribute to neurodevelopmental illnesses including schizophrenia, ASD, and learning disabilities.

Chromatin consists of DNA which forms the genome plus certain specialized proteins that help to organize it in the three-dimensional space of the cell nucleus. Each human cell's DNA would stretch out over 6 feet if unfurled and laid end-to-end. Yet this material is packaged tightly in the microscopic nucleus of each cell—a triumph of billions of years of evolution. Dr. Nowakowski's team specifically studied “chromatin accessibility," which accounts for how different parts of the genome are packed or unpacked.

When chromatin in a given genome location is accessible, genes encoded by that DNA can be activated by specialized cellular machinery. Conversely, when chromatin is tightly packed, or inaccessible, the corresponding genes tend to be silenced. In their study, the team focused on mapping chromatin accessibility in glutamate neurons, and progenitors from which these cells arise during development. Glutamate neurons, the most prevalent type of excitatory neurons in the brain, are mostly generated during development.

If genes whose expression are essential in a particular phase of neuronal development are in fact inaccessible, that cell's fate may be altered, with potentially consequential post-birth mental health implications.

The research reported by Dr. Nowakowski's team and led by graduate student Ryan Ziffra was based on scrutiny of over 77,000 human brain cells sampled from post-mortem developmental specimens. The cells were sourced from key parts of the cerebral cortex in the forebrain, and included cells and progenitors of many different types. Advanced technologies enabled the team to analyze the relationship between changes in the accessibility of chromatin and various aspects of cell development at the level of individual cells, including determination of the cell's type and its ultimate fate specification in the mature brain.

The team was able to identify places in the genome that undergo extensive changes in chromatin accessibility during neurogenesis, the process in which new neurons are born. These changes were correlated with specific cell types and brain regions. By systematically comparing chromatin accessibility across brain regions, the team also found an "unexpected diversity" among neural progenitor cells in the cerebral cortex. Signaling by a molecule called retinoic acid (RA), which is derived from the common dietary supplement vitamin A, was tied to the process in which a developing neuron's fate specification—its identity, say, as an excitatory neuron of the prefrontal or visual cortical areas—was determined within the cortex.

The RA discovery is intriguing, Dr. Nowakowski says, in light of evidence that over-supplementation with vitamin A during pregnancy, particularly through topical retinoids, has been linked to severe birth defects. "Our study highlights the unmet need to explore how environmental factors, including diet, during pregnancy, can impact human brain development," he notes.

The team said their results also provided "a blueprint for evaluating the fidelity and robustness" of cerebral organoids. These are assemblages of stem cell-derived brain cells grown in culture dishes in the lab. Cerebral organoids are used by researchers to study brain development and the emergence of pathologies which contribute to mental illness, as well as the action of potential drugs to treat psychiatric illness.

In follow-up studies, the team hopes to probe how disease-associated DNA variants in regulatory regions of the genome act to modify cell-fate decisions in the developing cortex. The ultimate aim, they say, is "complete reconstruction" of the processes in which regulators of the genome determine how the brain develops, including how specific DNA mutations alter normal development, resulting in disease.