Somatostatin, a neuropeptide expressed in a subset of inhibitory neurons in the brain, is decreased in humans across multiple brain disorders, including schizophrenia, bipolar depression and Alzheimer's disease. Somatostatin is also down-regulated in major depressive disorder, and more robustly so in women with depression, hence mirroring the increased female prevalence of the disorder. This proposal follows up on recent findings from the candidate, Dr. Marianne Seney, indicating a role for XY genetic sex in regulating anxiety-like behaviors and expression of somatostatin, and of an opposing effect of adult testosterone on the behavioral effects of XY genetic sex. These translational mouse studies are directly informed by human postmortem findings and will specifically investigate (i) the opposing effect of XY genetic sex and adult circulating testosterone on anxiety-like behavior and on molecular correlates, and (ii) whether manipulating the function of inhibitory neurons that express somatostatin will affect the balance between genetic sex and circulating testosterone in adult behavioral outcomes. The candidate, Dr. Marianne Seney, is the ideal individual to perform the proposed research, based on her previous research experience in the fields of neuroendocrinology and of sexual dimorphism in the rodent brain. The mentor, Dr. Etienne Sibille, will provide expertise in the translational approach to study causality of altered biological pathways or cellular mechanisms involved in the pathophysiology of depression, together offering a unique and synergistic environment in which to study sex differences in depression and anxiety. The co-mentor, Dr. Colleen McClung, will provide essential training in rodent pharmacogenetic techniques to modulate function of specific cell populations in the brain. Co-mentor, Dr. George Tseng, will provide critical support in using state of the art bioinformatics and statistical approaches to interpret large behavioral and molecular datasets. To perform the proposed research and interpret results, Dr. Seney will benefit from a group of internal and external expert consultants, and will obtain additional training in proteomics and in exposure to clinical realities of mood and anxiety disorders. The Department of Psychiatry at the University of Pittsburgh offers a well-funded environment with a nationally and internationally recognized reputation as a premier research institution, making it the ideal location for Dr. Seney to perform her research and gain essential training. At completion of this proposal, Dr. Seney will be poised to lead her own research program aimed at using translational approaches to understand sex differences in mood and anxiety disorders.
Evidence suggests that gender/sex differences in mood and anxiety disorders are due to biological differences between men and women, but the underlying mechanisms are poorly characterized. Understanding the molecular mechanisms of increased vulnerability in women is critical for developing novel more effective treatments. Here we will use a translational rodent model, where we can dissect the contributions of developmental hormones, adult circulating hormones, and X/Y genetic sex to the function of a specific brain cell type that is affected in depression. Applications of this knowledge relating to mechanism(s) underlying female vulnerability may be critical to developing successful sex-specific treatments or even prevention of major depression and other mood disorders.
