Role of gonadal steroids in stress-sensitive neural circuits

项目摘要 社会压力是几种与压力有关的精神病理学的危险因素，包括创伤后精神障碍。 应激障碍（PTSD）。然而，大多数遭受创伤的人不会发展出与压力有关的 精神病理学和以前的社会经验有可能改善应对策略， 强调恢复力。有助于压力恢复力发展的一种社会经历是一种占主导地位的 在社会等级中的地位。在这个提议中，我们使用了一个叙利亚仓鼠模型，其中占优势的动物显示， 与压力相关的行为比下属少。我们的初步数据显示 优势种在背侧雄激素受体（AR）阳性细胞中显示c-Fos免疫反应性增加 后内侧杏仁核（MePD）相比，他们的下属同行。此外，它们还显示， MePD细胞中c-Fos免疫反应性增加，投射到纹状体床核的后部区域 终端（BNSTp）相比，下属。与雄性不同，占主导地位的雌性仓鼠有更大的 MePD中雌激素受体α（ERα）阳性细胞的数量与下属相比。然而，在这方面， 优势雌性在BNSTp投射的MePD细胞中没有显示出升高的c-Fos免疫反应性， 下属总之，这些发现表明，虽然MePD-BNSTp通路中的AR表达可能是 雄性仓鼠应激脆弱性的状态依赖性差异的关键，MePD-1中的ERα表达， BNSTp通路可能不会导致雌性仓鼠应激易感性的状态依赖性差异。 由于这些性别差异，我们在这个提议中有两个独立的假设。我们假设 MePD-BNSTp通路中的AR+神经元对应激相关的状态依赖性差异至关重要。 雄性仓鼠的行为此外，我们假设MePD中的ERα+细胞是状态- 雌性仓鼠的压力相关行为的依赖性差异。我们将使用依赖Cre的AAV载体 其表达AR的短发夹RNA（shRNA）以选择性地敲低MePD-BNSTp中的AR受体。 通路此外，我们将使用AAV-shRNA敲低非Cre细胞中MePD中的ERα受体。 在女性和男性的依赖方式。总的来说，这个项目将研究细胞机制， 以及性腺类固醇激素受体参与状态依赖性变化的神经回路， 压力脆弱性。这一系列的研究将确定社会经验是如何产生神经可塑性的， 选择神经合奏，从而改变压力的脆弱性，在性别依赖的方式。

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.