Cellular Plasticity and HPA Axis Dysfunction

描述（由申请人提供）：慢性压力和抑郁导致下丘脑-垂体-肾上腺（HPA）轴激活持续增加，循环HPA激素（包括糖皮质激素）水平强直性升高。在实验模型和人类中，慢性应激的后遗症包括下丘脑轴对应激刺激的超敏反应，以及下丘脑轴对循环糖皮质激素负反馈调节的敏感性降低。慢性应激诱导的HPA轴超敏性和HPA激素持续高分泌的可能原因是对触发HPA轴激活的细胞（室旁核（PVN）的促肾上腺皮质激素释放激素（CRH）神经元）的兴奋性突触驱动增加和对糖皮质激素的敏感性降低。CRH神经元的突触激活似乎涉及谷氨酸能、gaba能和去甲肾上腺素能系统之间的相互作用，这表明这些系统的结构变化可能是慢性应激和抑郁期间HPA轴反应性改变的原因。糖皮质激素的快速反馈抑制作用似乎部分是通过激活PVN内的内源性大麻素释放和由此产生的谷氨酸释放到PVN CRH神经元的逆行抑制介导的。通过研究下丘脑轴的研究者合作网络，我们获得了初步的解剖学和分子数据，表明暴露于慢性应激下PVN CRH神经元的突触神经支配在结构上发生了改变。该提案是IRPG应用的细胞生理学组成部分，旨在解决慢性应激导致突触回路和糖皮质激素反馈的长期分子，解剖和功能变化，这些突触回路和糖皮质激素反馈调节PVN CRH神经元和下丘脑对应激的反应。我们将使用全细胞膜片钳记录和基因组分析来确定暴露于慢性应激是否通过改变谷氨酸能、gaba能和/或去甲肾上腺素能突触输入，和/或2)通过减少糖皮质激素抑制反馈调节，导致PVN CRH神经元兴奋性增加。这些研究将对慢性压力下大脑发生的功能变化提供重要的见解，并将为某些与压力相关的情感障碍（如严重抑郁症）的临床治疗提供潜在的目标。

DESCRIPTION (provided by applicant): Chronic stress and depression lead to a sustained increase in the activation of the hypothalamic-pituitary adrenal (HPA) axis and tonically elevated levels of circulating HPA hormones, including glucocorticoids. Sequelae of chronic stress in experimental models and in humans include hypersensitivity of the HPA axis to stressful stimuli, and reduced sensitivity of the HPA axis to negative feedback regulation by circulating glucocorticoids. Likely causes of the chronic stress-induced hypersensitivity of the HPA axis and sustained hypersecretion of HPA hormones is an increased excitatory synaptic drive to and a reduced sensitivity to glucocorticoids of the cells that trigger HPA axis activation, the corticotropin releasing hormone (CRH) neurons of the paraventricular nucleus (PVN). Synaptic activation of the CRH neurons appears to involve an interaction between glutamatergic, GABAergic and noradrenergic systems, suggesting that structural changes in these systems may be responsible for the altered responsiveness of the HPA axis during chronic stress and depression. Rapid feedback inhibitory actions of glucocorticoids appear to be mediated, in part, by activation of endocannabinoid release within the PVN and a resulting retrograde suppression of glutamate release onto the PVN CRH neurons. Through a collaborative network of investigators studying the HPA axis, we have acquired preliminary anatomical and molecular data to suggest that the synaptic innervation of PVN CRH neurons is structurally altered by exposure to chronic stress. This proposal is the cellular physiology component of an IRPG application designed to address the overarching hypothesis that chronic stress leads to long-term molecular, anatomical and functional changes in the synaptic circuitry and glucocorticoid feedback that regulate PVN CRH neurons and the hypothalamic response to stress. We will use whole-cell patch-clamp recordings and genomic analyses to determine whether exposure to chronic stress causes an increase in the excitability of PVN CRH neurons 1) by altering glutamatergic, GABAergic and/or noradrenergic synaptic inputs, and/or 2) by reducing glucocorticoid inhibitory feedback regulation. These studies will provide important insight into the functional changes that occur in the brain during chronic stress, and will offer potential targets for the clinical treatment of certain stress-related affective disorders, such as severe depression.