Mechanisms underlying CSC-induced breakdown of HPA axis functions

慢性社会心理压力是各种躯体和情感障碍发展的公认危险因素。越来越多的证据表明，应激诱导的低皮质而非高皮质与这些疾病的发病机制有因果关系。我们可以证明，19天的慢性从属群体住房（CSC），一种建立和临床相关的雄性小鼠慢性社会心理应激源，导致肾上腺工作不足。初步数据表明，慢性社会心理压力还会影响下丘脑-垂体-肾上腺（HPA）轴的较高水平，包括参与负反馈抑制的大脑区域。在当前的项目中，我们的目标是在肾上腺、垂体、下丘脑和海马水平上剖析csc诱导的HPA轴功能破坏的详细机制。我们将使用宏观、微观和分子技术，在体内和体外，研究CSC是否以及在多大程度上诱导HPA轴这些不同水平的结构和/或功能变化，包括糖皮质激素（GC）反馈调节。为了分别检测可能的体侧特异性和持续时间依赖性效应，这些参数将在CSC暴露期间的不同时间点分别在左侧和右侧体侧进行评估。为了揭示基因x应激环境的相互作用，我们将在选择性饲养的应激反应性差异或特质焦虑差异的小鼠中分析选定的csc相关参数。

Chronic psychosocial stress is an acknowledged risk factor for the development of various somatic and affective disorders. There is growing evidence that stress-induced hypo- rather than hypercorticism is causally involved in the pathogenesis of these disorders. We could show that 19 days of chronic subordinate colony housing (CSC), an established and clinically relevant chronic psychosocial stressor for male mice, results in insufficiently working adrenals. Preliminary data indicate that chronic psychosocial stress affects also higher levels of the hypothalamo-pituitary-adrenal (HPA) axis including brain regions involved in negative feedback inhibifion. In the current project we aim to dissect the detailed mechanisms underlying the CSC-induced breakdown of HPA axis functions at the levels of the adrenal glands, pituitary, hypothalamus, and hippocampus. We will use macroscopic, microscopic and molecular techniques, both in vivo and in vitro, to investigate whether and to what extent CSC induces structural and/ or functional changes at these different levels of the HPA axis including glucocorticoid (GC) feedback regulation. To detect possible body side-specific and duration-dependent effects, respectively, these parameters will be assessed at the left and right body side separately at different time points during the CSC exposure. In order to reveal gene x stress environment interactions, selected CSC-relevant parameters will be analysed in mice selectively bred for either differences in stress reactivity or differences in trait anxiety.