Stress plasticity of CRH neurons

摘要 下丘脑-垂体-肾上腺(HPA)轴调节失调和循环糖皮质激素水平改变 与精神健康障碍密切相关。大鼠促肾上腺皮质激素释放激素(CRH)神经元 下丘脑室旁核(PVN)控制HPA轴的激活，并控制直接应激和焦虑。 关联的行为。可塑性改变对CRH神经元兴奋性-抑制性平衡的影响 突触回路导致HPA活性改变和循环中糖皮质激素的转移，这可能导致 生理动态平衡和行为输出的变化。传入去甲肾上腺素能回路对 控制CRH神经元活性和HPA激活，但对其机制知之甚少 去甲肾上腺素(NE)在应激状态下调节CRH神经元或其可塑性。我们的初步调查结果 揭示去甲肾上腺素和肾上腺皮质激素激活的下丘脑室旁核CRH神经元树突体积传递的新机制 通过星形胶质细胞逆行传递和神经胶质传递来刺激局部兴奋性突触回路。 我们还发现，应激诱导的糖皮质激素引起去甲肾上腺素(NE)激活的快速抑制。 下丘脑室旁核促肾上腺皮质激素释放激素神经元是由-1肾上腺素受体脱敏介导的。这种快速的糖皮质激素效应是 可能参与了对HPA轴的反馈抑制，但其对生理的和对健康的特异性。 心理压力输入及其在压力相关行为中的作用尚不清楚。在这里，我们将使用 结合膜片钳记录、活细胞成像、生化分析和行为测试 解决三个具体目标。目标1将重点研究CRH神经元突触前和突触后的机制。 负责1肾上腺素受体诱导的神经元-神经胶质细胞逆行信号的脑片 激活上游谷氨酸回路。目标2将确定应激诱导的细胞机制 从-1对糖皮质激素的快速调节看去甲肾上腺素调节促肾上腺皮质激素释放激素神经元活性的可塑性 肾上腺素受体的运输和信号传递。Aim 3将采用活体方法来研究NE的作用 传入神经通过生理和心理输入激活HPA，并研究应激的影响 去甲肾上腺素调节CRH神经元对核心应激行为表型焦虑的可塑性。加在一起，这些 研究将填补我们对HPA调节和去甲肾上腺素能机制理解的一个重要空白 CRH神经元中枢环路的应力可塑性及其生理行为 产出。

Summary Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and altered circulating glucocorticoid levels are closely associated with mental health disorders. Corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) control activation of the HPA axis, and direct stress- and anxiety- associated behaviors. Alterations of the CRH neuron excitatory-inhibitory balance caused by plastic changes in synaptic circuits result in altered HPA activity and shifting circulating glucocorticoids, which can lead to changes in physiological homeostasis and behavioral outputs. Afferent noradrenergic circuits are critical for controlling CRH neuron activity and HPA activation, yet little is known about the mechanism by which norepinephrine (NE) regulates the CRH neurons or its plasticity with stress exposure. Our preliminary findings reveal a novel mechanism of dendritic volume transmission in PVN CRH neurons that is activated by NE and mediated by an astrocytic retrograde relay and gliotransmission to stimulate local excitatory synaptic circuits. We have also found that stress-induced glucocorticoids cause a rapid suppression of the NE activation of the PVN CRH neurons that is mediated by 1 adrenoreceptor desensitization. This rapid glucocorticoid effect is likely to contribute to the feedback inhibition of the HPA axis, but its specificity to physiological vs. psychological stress inputs and its role in stress-associated behaviors are not known. Here, we will use a combination of patch clamp recordings, live-cell imaging, biochemical analysis, and behavioral testing to address three specific aims. Aim 1 will focus on the pre- and postsynaptic mechanisms in CRH neurons in brain slices that are responsible for 1 adrenoreceptor-induced neuronal-glial retrograde signaling that activates upstream glutamate circuits. Aim 2 will determine the cellular mechanisms of the stress-induced plasticity of the NE regulation of CRH neuron activity by probing the rapid glucocorticoid regulation of 1 adrenoreceptor trafficking and signaling. Aim 3 will take an in vivo approach to examine the role of the NE afferents in HPA activation by physiological and psychological inputs, and to study the impact of the stress plasticity of NE regulation of CRH neurons on a core stress behavioral phenotype, anxiety. Together, these studies will fill an important gap in our understanding of the noradrenergic mechanisms of HPA regulation and the stress plasticity of central circuits controlling the CRH neurons and their physiological and behavioral outputs.