The Role of Genetic Sex in Affect Regulation

遗传性别在情感调节中的作用

• 批准号: 8932026
• 负责人: Marianne L Seney
• 金额: $ 15.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932026
• 关键词: Adult; Affect; Agonist; Alzheimer' s Disease; Androgen Receptor; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Autopsy; Behavior; Behavioral; Behavioral Mechanisms; Bioinformatics; Biological; Bipolar Depression; Brain; Brain Diseases; Brain region; Cell physiology; Cells; Chronic stress; Clinical; D Cells; Data Set; Dendrites; Designer Drugs; Development; Discipline; Disease; Environment; Enzymes; Equilibrium; Estradiol; Estrogen Receptors; Etiology; Exposure to; Feedback; Female; Functional disorder; Funding; Gender; Gene Proteins; Gene Transfer; Genes; Genetic; Genotype; Glutamate Decarboxylase; Glutamates; Grant; Health; Hormones; Human; Individual; Institution; Knowledge; Lead; Learning; Link; Location; Major Depressive Disorder; Mass Spectrum Analysis; Mediating; Mental Depression; Mentors; Mentorship; Messenger RNA; Methods; Molecular; Mood Disorders; Mus; Neuroendocrinology; Neurons; Neuropeptides; Outcome; Pathway interactions; Pharmacogenetics; Population; Prevalence; Prevention; Proteins; Proteomics; Psychiatry; Regulation; Reporting; Research; Research Personnel; Risk; Rodent; Rodent Model; Role; Schizophrenia; Sex Characteristics; Sex Chromosomes; Sex Functioning; Signal Transduction; Somatostatin; Specificity; Techniques; Testosterone; Training; Universities; Viral; Viral Vector; Woman; anxiety-like behavior; base; behavioral outcome; brain cell; cell type; depressive symptoms; effective therapy; experience; frontal lobe; gamma-Aminobutyric Acid; genetic variant; hippocampal pyramidal neuron; inhibitory neuron; insight; male; men; novel; programs; protective effect; receptor; sex; sexual dimorphism; skills; translational approach

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.

描述（由申请人提供）：生长抑素是一种在大脑抑制性神经元亚群中表达的神经肽，在多种脑部疾病（包括精神分裂症、双相抑郁症和阿尔茨海默氏病）中，人类的生长抑素水平会降低。生长抑素在重度抑郁症中也会下调，并且在患有抑郁症的女性中更为明显，因此反映了女性患病率的增加。该提案是对候选人 Marianne Seney 博士最近的研究结果的后续研究，表明 XY 遗传性别在调节焦虑样行为和生长抑素表达中的作用，以及成人睾酮对 XY 遗传性别的行为影响的相反作用。这些转化小鼠研究直接来自人类尸检结果，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。根据她之前在神经内分泌学和啮齿动物大脑性别二态性领域的研究经验，候选人玛丽安·塞尼博士是执行拟议研究的理想人选。导师 Etienne Sibille 博士将提供转化方法方面的专业知识，以研究改变的因果关系 抑郁症病理生理学中涉及的生物途径或细胞机制，共同提供了一个独特且协同的环境来研究抑郁和焦虑的性别差异。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。联合导师 George Tseng 博士将在使用最先进的生物信息学和统计方法解释大型行为和分子数据集方面提供关键支持。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以及情绪和焦虑症临床现实方面的额外培训。匹兹堡大学精神病学系提供资金充足的环境，作为一流研究机构在国内和国际上享有盛誉，使其成为 Seney 博士进行研究和获得必要培训的理想场所。该提案完成后，塞尼博士将准备领导她自己的研究项目，旨在利用转化方法来了解情绪和焦虑症的性别差异。