Role of gonadal steroids in stress-sensitive neural circuits

性腺类固醇在压力敏感神经回路中的作用

• 批准号: 10727406
• 负责人: Matthew A Cooper
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727406
• 关键词: Acute; Aggressive behavior; Amygdaloid structure; Androgen Receptor; Animals; Behavior; Biological Models; COVID-19 outbreak; Cells; Coping Skills; Data; Development; Dorsal; Environmental Risk Factor; Estrogen Receptor alpha; Exhibits; Exposure to; FOS gene; Family Relationship; Female; Fishes; Forcible intercourse; Generalized Anxiety Disorder; Goals; Gonadal Steroid Hormones; Hamsters; Human; Individual; Investigation; Major Depressive Disorder; Medial; Mesocricetus auratus; Modeling; Neuronal Plasticity; Neurons; Neurosecretory Systems; Pathway interactions; Pattern; Peer Group; Persons; Positioning Attribute; Post-Traumatic Stress Disorders; Primates; Psychopathology; Research; Resistance; Risk Factors; Rodent; Rodent Model; Role; Sex Differences; Social Behavior; Social Development; Social Dominance; Social Hierarchy; Social isolation; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Territoriality; Testing; Trauma; Viral; Withdrawal; Work; adeno-associated viral vector; anxiety-like behavior; assault; behavioral response; experience; immunoreactivity; improved; knock-down; male; neural; neural circuit; neural network; neuromechanism; prevent; receptor; receptor expression; response; sex; small hairpin RNA; social; social defeat; social stress; social stressor; steroid hormone receptor; stress reduction; stress resilience; stressor; therapy development; trauma exposure; traumatic stress

Project Summary Social stress is a risk factor for several stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, most individuals exposed to trauma do not develop stress-related psychopathologies and previous social experience has the potential to improve coping strategies and enable stress resilience. One social experience that contributes to the development of stress resilience is a dominant position in a social hierarchy. In this proposal, we use a Syrian hamster model in which dominant animals show less stress-related behavior than their subordinate counterparts. Our preliminary data indicate that male dominants show increased c-Fos immunoreactivity in androgen receptor (AR)-positive cells in dorsal aspects of the posterior medial amygdala (MePD) compared to their subordinate counterparts. In addition, they show increased c-Fos immunoreactivity in MePD cells projecting to posterior regions of the bed nucleus of the stria terminalis (BNSTp) compared to subordinates. Unlike males, dominant female hamsters have a greater number of estrogen receptor alpha (ERα)-positive cells in the MePD compared to subordinates. However, dominant females do not show elevated c-Fos immunoreactivity in BNSTp-projecting MePD cells compared to subordinates. Altogether, these findings suggest that while AR expression in a MePD-BNSTp pathway may be critical for status-dependent differences in stress vulnerability in male hamsters, ERα expression in MePD- BNSTp pathway may not contribute to status-dependent differences in stress vulnerability in female hamsters. Because of these sex differences, we have two separate hypotheses in this proposal. We hypothesize that AR+ neurons in a MePD-BNSTp pathway are essential for status-dependent differences in stress-related behavior in male hamsters. Also, we hypothesize that ERα+ cells in the MePD are necessary for status- dependent differences in stress-related behavior in female hamsters. We will use a Cre-dependent AAV vector that expresses a short hairpin RNA (shRNA) for AR to selectively knockdown AR receptors in a MePD-BNSTp pathway. In addition, we will use an AAV-shRNA to knockdown ERα receptors in the MePD in a non-Cre- dependent manner in both females and males. Overall, this project will investigate the cellular mechanisms and neural circuits by which gonadal steroid hormone receptors contribute to status-dependent changes in stress vulnerability. This line of research will determine how social experience generates neural plasticity in select neural ensembles and thereby changes stress vulnerability in a sex-dependent manner.

项目摘要 社会压力是几种与压力有关的心理病理学的危险因素，包括创伤后 应激障碍（PTSD）。但是，大多数接触创伤的人不会发展与压力有关 心理病理学和以前的社交经验有可能改善应对策略并实现 压力弹性。有助于发展压力弹性的一种社会经历是一个主导 在社会等级中的位置。在此提案中，我们使用叙利亚仓鼠模型，其中主导动物显示 与下属同行相比，与压力相关的行为少。我们的初步数据表明男性 在背面的雄激素受体（AR）阳性细胞中的C-FOS免疫反应性增加 与下属同级相比，后内侧杏仁核（MEPD）此外，他们表明 在投射到STRIA床核后区域的MEPD细胞中的C-FOS免疫反应性增加 与下属相比，末端（BNSTP）。与雄性不同，主导的女仓鼠有更大的 与下属相比，MEPD中雌激素受体α（ERα）阳性细胞的数量。然而， 与BNSTP预测的MEPD细胞相比 下属。总之，这些发现表明，虽然MEPD-BNSTP途径中的AR表达可能是 对于男性仓鼠的压力脆弱性依赖性差异至关重要，MEPD-中ERα表达 BNSTP途径可能不会导致女性仓鼠的压力脆弱性差异。 由于这些性别差异，我们在此提案中有两个单独的假设。我们假设这一点 MEPD-BNSTP途径中的AR+神经元对于与应力相关的状态差异至关重要 男性仓鼠的行为。另外，我们假设MEPD中的ERα+细胞对于状态是必需的 雌性仓鼠在压力相关行为的依赖差异。我们将使用依赖CRE的AAV矢量 为AR表示短发夹RNA（shRNA），可在MEPD-BNSTP中有选择地敲低AR受体 路径。此外，我们将使用AAV-shRNA在非循环中敲低MEPD中的ERα受体 女性和男性的依赖方式。总体而言，该项目将研究细胞机制 和神性立体观念受体受到状态依赖性变化的神经回路 强调脆弱性。这一研究将决定社交经验如何产生神经可塑性 选择神经合奏，从而以性依赖性方式改变压力脆弱性。