Cellular Plasticity and HPA Axis Dysfunction

描述(申请人提供)：慢性压力和抑郁导致下丘脑-垂体肾上腺(HPA)轴的激活持续增加，循环中的HPA激素水平持续升高，包括糖皮质激素。慢性应激在实验模型和人类中的后遗症包括HPA轴对应激刺激的高敏感性，以及HPA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HPA轴高敏感性和HPA激素持续高分泌的可能原因是触发HPA轴激活的细胞对糖皮质激素的兴奋性突触驱动增加和敏感性降低，室旁核(PVN)的促肾上腺皮质激素释放激素(CRH)神经元。CRH神经元的突触激活似乎涉及谷氨酸、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时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内内源性大麻素的释放以及由此导致的对PVN CRH神经元谷氨酸释放的逆行抑制来实现的。通过研究HPA轴的研究人员的合作网络，我们已经获得了初步的解剖学和分子数据，表明PVN CRH神经元的突触神经支配在慢性应激下发生了结构性改变。这项建议是IRPG应用程序的细胞生理学部分，旨在解决最主要的假设，即慢性应激导致突触电路和糖皮质激素反馈的长期分子、解剖和功能变化，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慢性应激是否导致PVN CRH神经元兴奋性的增加：1)通过改变谷氨酸、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。这些研究将对慢性应激期间大脑中发生的功能变化提供重要的洞察，并将为某些与应激相关的情感障碍的临床治疗提供潜在的靶点，例如严重的抑郁症。

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.