The Role of Genetic Sex in Affect Regulation

描述（由申请人提供）：生长抑素是一种在大脑中抑制性神经元亚群中表达的神经肽，在人类多种脑部疾病中，包括精神分裂症、双相抑郁症和阿尔茨海默病，都会减少。在重度抑郁症患者中，生长抑素也被下调，而且在女性抑郁症患者中下调幅度更大，因此反映了女性抑郁症患病率的增加。这一提议是对候选人Marianne Seney博士最近的发现的跟进，她指出XY基因性别在调节焦虑类行为和生长抑素表达方面的作用，以及成年睾酮对XY基因性别的行为影响的相反作用。这些转化小鼠研究直接由人类死后发现提供信息，并将专门研究(i) XY遗传性别和成人循环睾酮对焦虑样行为和分子相关物的“相反”作用，以及（ii）操纵表达生长抑素的抑制性神经元的功能是否会影响遗传性别和循环睾酮在成人行为结果中的平衡。候选人Marianne Seney博士基于她之前在神经内分泌学和啮齿动物大脑两性异形领域的研究经验，是进行拟议研究的理想人选。导师Etienne Sibille博士将提供翻译方法方面的专业知识，以研究变异的因果关系

DESCRIPTION (provided by applicant): 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.