Advances in the Neurobiology of Mental Illness

Depression is a common, chronic, and debilitating syndrome, which involves dysregulation throughout the brain’s limbic circuitry. Our laboratory has focused on stable changes in gene expression within this circuitry that control life-long vulnerability to different forms of stress and the induction of depression-related behavioral abnormalities in mouse models. We concentrate on transcriptional pathways, deduced from large RNA-sequencing datasets of RNAs that show altered expression in several limbic brain regions of mice as a consequence of stress exposures across the life cycle. Parallel work examines transcriptional mechanisms in homologous regions in the brains of depressed humans examined postmortem. A major interest in the animal and human studies are sex differences in stress responses, given the >2-fold greater prevalence of depression in females.

Current studies are exploring the detailed mechanisms by which specific transcriptional abnormalities identified in mouse models and human depression contribute to a depression-like state. We are particularly interested in how stress causes life-long changes in gene expression and hypothesize that such changes are mediated via so-called chromatin scars. We are approaching this question by studying a range of chromatin mechanisms genome-wide, including post-translational modifications of histones, DNA methylation, nucleosome positioning, and the 3-dimensional structure of chromatin. These studies are identifying the most prominent molecular abnormalities induced in limbic brain regions by chronic stress and depression. We are also studying how such molecular derangements alter the functioning of individual cell types within these brain regions and their larger circuits, thus linking transcriptional and chromatin regulation to neural and behavioral plasticity associated with depression. Another major interest is understanding mechanisms of natural resilience, that is, the transcriptional and chromatin mechanisms that make certain individuals more resistant to the deleterious effects of chronic stress.

This work establishes transcriptional and chromatin regulation as important mechanisms underlying the ways in which a history of stress causes lasting changes in targeted limbic brain regions which result in depression-related behavioral abnormalities in vulnerable individuals. The long-term goal is to use these insights to develop improved diagnostic tests and treatments for depression and related syndromes.

Funded by the National Institute of Mental Health and Hope for Depression Research Foundation.

The genetic analysis of mental disorders is meeting with success but is revealing a dauntingly complex polygenic risk architecture that involves thousands of DNA sequence variants affecting many hundreds of genes.  We are also learning that risk associated genes are shared across multiple mental disorders.  It is a daunting challenge to transform such complex genetic and phenotypic information into useful insights that will elucidate disease mechanisms and provide clues for discovering much needed new therapeutics.  I will discuss new technologies and model systems including human cellular and brain organoid models that make it possible for neurobiology to rise to the challenge.

Posttraumatic stress disorder (PTSD) is a serious public health concern in the military and civilian sectors, where it is associated with functional impairment and increased risk for suicide. The neurobiology of PTSD is being increasingly understood, with current theories of its pathophysiology focused on altered fear learning. As a disorder caused by exposure to traumatic stress, PTSD could be amenable to early interventions in individuals at high risk. The identification of genetic risk factors for PTSD (and PTSD symptom domains) may provide important insights into the biological basis of vulnerability and comorbidity. It is anticipated that these discoveries will translate into novel therapeutics for PTSD, either through repurposing of existing drugs or through the development of new compounds targeted at key nodes in its pathophysiology. These therapeutic advances are much needed, as are efforts to delineate a precision medicine approach to PTSD.

Despite public health and research efforts to improve prevention, assessment and management of suicidal behavior, suicide rates in the United States have remained stubbornly high.  To the contrary, they have increased dramatically over the past 30 years. Suicidal thoughts and behaviors are transdiagnostic arising even in the absence of other diagnosable mental health disorders, but they are far from homogeneous. Genetic, neurobiological, and psychological factors are associated with suicidal behavior, but these risk factors have limited clinical utility and modest statistical power. Thus, suicidal behavior is more likely a final common pathway of multiple separate neuropathological processes.  Developing distinct phenotypes of suicidal behavior that represent neurobiological subtypes may yield better strategies for identifying robust biomarkers to predict this tragic outcome.

Millions of individuals worldwide suffer from bipolar disorder (BD) and many will lose their lives to suicide. BD is characterized by acute episodes of the severe emotional highs of manias and lows of depressions. Dr. Blumberg will present multimodality magnetic resonance imaging research demonstrating advances in understanding of the structural and functional differences in brain circuitry in BD. This will include demonstration of differences in the functioning of emotional brain circuitry in individuals while they experience manic or depressive symptoms, as well as structural differences in gray matter nodes and integrity of the white matter wiring in emotion brain circuitry that underlie the differences in functioning. She will present data from integrative approaches with neuroimaging to show negative influences of genetic variations and early life stress (such as child abuse and neglect), and salutary influences of pharmacological and non-pharmacological interventions, on the structure and function of the circuitry. This will include presentation of differences in brain circuitry features of BD across the lifespan and features that are most associated with risk for suicide. Finally, she will discuss how this knowledge is being translated to new methods for prevention and treatment.