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，在人类多种大脑疾病中减少，包括精神分裂症、双相抑郁症和阿尔茨海默病。生长抑素在重度抑郁症中也下调，在女性抑郁症中更明显，因此反映了女性抑郁症患病率的增加。这项建议是对候选人玛丽安·塞尼博士最近发现的后续研究，该研究表明XY遗传性别在调节焦虑样行为和生长抑素表达方面的作用，以及成年睾酮对XY遗传性别行为影响的相反作用。这些转化小鼠研究直接由人类尸检结果提供信息，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性的“相反”影响，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成人行为结果中遗传性别和循环睾酮之间的平衡。候选人玛丽安·塞尼（Marianne Seney）博士是执行拟议研究的理想人选，这是基于她之前在神经内分泌学和啮齿动物大脑性二态性领域的研究经验。导师Etienne Sibille博士将提供翻译方法的专业知识，以研究改变的因果关系。 生物途径或细胞机制参与抑郁症的病理生理学，共同提供了一个独特的和协同的环境中，研究抑郁症和焦虑症的性别差异。共同导师Colleen McClung博士将提供啮齿动物药物遗传学技术的基本培训，以调节大脑中特定细胞群的功能。共同导师，乔治曾博士，将提供关键的支持，使用最先进的生物信息学和统计方法来解释大型行为和分子数据集。为了执行拟议的研究和解释结果，Seney博士将受益于一组内部和外部专家顾问，并将获得蛋白质组学方面的额外培训，以及接触情绪和焦虑症的临床现实。匹兹堡大学精神病学系提供资金充足的环境，作为首屈一指的研究机构享有国内和国际公认的声誉，使其成为Seney博士进行研究和获得必要培训的理想场所。在完成这项提案后，Seney博士将准备领导她自己的研究计划，旨在使用翻译方法来了解情绪和焦虑症的性别差异。

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.