Decoding the Mind: Basic Science Revolutionizes Treatment of Mental Illnesses

The Division of Neuroscience and Basic Behavioral Science (DNBBS) at the National Institute of Mental Health (NIMH) supports research on basic neuroscience, genetics, and basic behavioral science. These are foundational pillars in the quest to decode the human mind and unravel the complexities of mental illnesses.

At NIMH, we are committed to supporting and conducting genomics research as a priority research area. As the institute celebrates its 75th Anniversary, we are spotlighting DNBBS-supported efforts connecting genes to cells to circuits to behavior that have led to a wealth of discoveries and knowledge that can improve the diagnosis, treatment, and prevention of mental illnesses.

Making gene discoveries

Medical conditions often run in families. For instance, if someone in your immediate family has high blood pressure, you are more likely to have it too. It is the same with mental disorders—often they run in families. NIMH is supporting research into human genetics to better understand why this occurs. This research has already led to the discovery of hundreds of gene variants that make us more or less likely to develop a mental disorder.

There are two types of genetic variation: common and rare. Common variation refers to DNA changes often seen in the general population, whereas rare variation is DNA changes found in only a small proportion of the population. Individually, most common gene variants have only a minor impact on the risk for a mental disorder. Instead, most disorders result from many common gene variants that, together, contribute to the risk for and severity of that disorder.

NIMH is committed to uncovering the role of genes in mental disorders with the aim of improving the lives of people who experience them. One of the many ways NIMH contributes to the discovery of common gene variants is by supporting the Psychiatric Genomics Consortium (PGC) . The consortium of almost 1,000 scientists across the globe, including ones in the NIMH Intramural Research Program and others conducting NIMH-supported research, is one of the largest and most innovative biological investigations in psychiatry.

Global collaborations such as the PGC are critical to amassing the immense sample sizes needed to identify common gene variants. Data from the consortium’s almost one million participants have already led to transformative insights about genetic contributors to mental illnesses and the genetic relationships of these illnesses to each other. To date, studies conducted as part of the consortium have uncovered common variation in over a dozen mental illnesses.

In contrast to common gene variants, rare gene variants are very uncommon in the general population. When they do occur, they often have a major impact on the occurrence of an illness, particularly when they disrupt gene function or regulation. Rare variants involving mutations in a single gene have been linked to several mental disorders, often through NIMH-supported research. For instance, a recent NIMH-funded study found that rare variation in 10 genes substantially increased the risk for schizophrenia. However, it is important to note that genetics is not destiny; even rare variants only raise the risk for mental disorders, but many other factors, including your environment and experiences, play important roles as well.

Because of the strong interest among researchers and the public in understanding how genes translate to changes in the brain and behavior, NIMH has developed a list of human genes associated with mental illnesses. These genes were identified through rare variation studies and are meant to serve as a resource for the research community. The list currently focuses on rare variants, but NIMH plans to continue expanding it as evidence accumulates for additional gene variants (rare or common).

Moreover, mental illnesses are a significant public health burden worldwide. For this reason, NIMH investments in genomics research extend across the globe. NIMH has established the Ancestral Populations Network (APN) to make genomics studies more diverse and shed light on how genetic variation contributes to mental disorders across populations. APN currently includes seven projects with more than 100 researchers across 25 sites worldwide.

Connecting biology to behavior

While hundreds of individual genes have been linked to mental illnesses, the function of most of these genes in the brain remains poorly understood. But high-tech advances and the increased availability of computational tools are enabling researchers to begin unraveling the intricate roles played by genes.

In addition to identifying genetic variation that raises the risk for mental illnesses, NIMH supports research that will help us understand how genes contribute to human behavior. This information is critical to discovering approaches to diagnose, treat, and ultimately prevent or cure mental illnesses.

An NIMH-funded project called the PsychENCODE consortium  focuses on understanding how genes impact brain function. PsychENCODE is furthering knowledge of how gene risk maps onto brain function and dysfunction by cataloging genomic elements in the human brain and studying the actions of different cell types. The PsychENCODE dataset currently includes multidimensional genetic data from the postmortem brains of thousands of people with and without mental disorders.

Findings from the first phase of PsychENCODE were published as a series of 11 papers  examining functional genomics in the developing and adult brains and in mental disorders. A second batch of PsychENCODE papers will be published later this year. These findings help clarify the complex relationships between gene variants and the biological processes they influence.

PsychENCODE and other NIMH-supported projects are committed to sharing biospecimens quickly and openly to help speed research and discovery.

Facilitating these efforts is the NIMH Repository and Genomics Resource (NRGR) , where samples are stored and shared. NRGR includes hundreds of thousands of samples, such as DNA, RNA, and cell lines, from people with and without mental disorders, along with demographic and diagnostic information.

Another NIMH initiative to connect risk genes to brain function is Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene). This initiative uses cutting-edge techniques to characterize the biological functions of 250 mental health risk genes—within the cells where they are expressed—to better understand how those genes contribute to mental illnesses. By systematically characterizing the biological functions of risk genes in cells, SSPsyGene will empower researchers to learn about biological pathways that may serve as new targets for treatment.

Genes also affect behavior by providing the blueprint for neurons, the basic units of the nervous system. Neurons communicate with each other via circuits in the brain, which enables us to process, integrate, and convey information. NIMH supports many initiatives to study the foundational role of neural networks and brain circuits in shaping diverse mental health-related behaviors like mood, learning, memory, and motivation.

For instance, studies supported through a basic-to-translational science initiative at NIMH focus on modifying neural activity to improve cognitive, emotional, and social processing . Similarly, another new funding opportunity encourages studies in humans and animals examining how emotional and social cues are represented across brain circuits  to help address a core deficit in many mental disorders. These studies will increase understanding of the biological mechanisms that support behavior throughout life and offer interventions to improve these functions in healthy and clinical populations.

Developing treatments and therapeutics

The gene discovery and biology-to-behavior programs described here will lay the foundation for delivering novel therapeutics. To be prepared to rapidly implement findings from this research, NIMH supports several initiatives to identify behavioral and biological markers for use in clinical studies and increase our ability to translate research into practice.

Through its therapeutics discovery research programs, NIMH advances early stage discovery and development studies in humans and early efficacy trials for mental disorders. Taking these efforts a step further, NIMH supports the National Cooperative Drug Discovery/Development Groups for the Treatment of Mental Disorders, which encourage public–private partnerships to accelerate the discovery and development of novel therapeutics and new biomarkers for use in human trials. Moreover, NIMH is one of several institutes and centers in the NIH Blueprint Neurotherapeutics Network , launched to enable neuroscientists in academia and biotechnology companies to develop new drugs for nervous system disorders.

For the treatments of tomorrow, NIMH is building a new research program called Pre-Clinical Research on Gene Therapies for Rare Genetic Neurodevelopmental Disorders , which encourages early stage research to optimize gene therapies to treat disorders with prominent cognitive, social, or affective impairment. In parallel, NIMH’s Planning Grants for Natural History Studies of Rare Genetic Neurodevelopmental Disorders  encourage the analysis of pre-existing data from people with rare disorders to learn about disease progression and enable future clinical trials with these populations.

NIMH's Division of Neuroscience and Basic Behavioral Science supports many different research projects that help us learn about genes and gene functions, how the brain develops and works, and impacts on behavior. By investing in basic neuroscience, genetics, and behavioral research, we're trying to find new targets for treatment and develop better therapies for mental disorders. We're hopeful these efforts will lead to new ways to treat and prevent mental illnesses in the near future and, ultimately, improve the lives of people in this country and across the globe.