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相关的心理病理的危险因素，包括创伤后 应激障碍(PTSD)。然而，大多数暴露在创伤中的人不会患上与压力有关的疾病。 精神病理学和既往的社会经验有可能改善应对策略并使 压力恢复力。一种有助于发展压力韧性的社会经验是占主导地位的 在社会等级制度中的地位。在这个方案中，我们使用了一个叙利亚仓鼠模型，在这个模型中，占主导地位的动物 与他们的下属相比，与压力相关的行为更少。我们的初步数据显示男性 优势种在背侧显示雄激素受体(AR)阳性细胞c-Fos免疫反应增强 杏仁后内侧核(MePD)与其下级对应区的比较。此外，他们还展示了 投射到纹床核后部的MePD细胞c-Fos免疫反应增强 终生(BNSTp)与下位的比较。与雄性不同，占主导地位的雌性仓鼠有更大的 雌激素受体α(ER-α)阳性细胞数与下级相比。然而， 与对照组相比，优势雌性投射BNSTp的MePD细胞中c-Fos免疫反应性不升高 下属。总之，这些发现表明，虽然AR在MePD-BNSTp途径中的表达可能是 ERα在雄性仓鼠应激易损性中的地位依赖差异起关键作用。 BNSTp通路可能对雌性仓鼠的应激易损性的状态依赖差异没有贡献。 由于这些性别差异，我们在这项提议中有两个不同的假设。我们假设 MePD-BNSTp通路中的AR+神经元是应激相关状态依赖性差异的关键 雄性仓鼠的行为。此外，我们还假设MePD中的ERα+细胞是状态所必需的- 雌性仓鼠应激相关行为的依赖差异。我们将使用依赖于Cre的AAV载体 表达AR的短发夹状RNA(ShRNA)，选择性地击倒MePD-BNSTp中的AR受体 路径。此外，我们将使用aav-shRNA来敲除非Cre-Cre-Mepd中的ERα受体。 女性和男性都有依赖的态度。总体而言，这个项目将研究细胞机制 性腺类固醇激素受体参与状态依赖性改变的神经回路 压力易损性。这一系列研究将决定社会经验如何产生神经可塑性。 选择神经集合，从而以性别依赖的方式改变应激脆弱性。