Stress plasticity of CRH neurons

总结 下丘脑-垂体-肾上腺（HPA）轴调节异常和循环糖皮质激素水平改变， 与精神疾病密切相关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，并直接应激和焦虑， 相关行为。脑可塑性改变引起CRH神经元兴奋-抑制平衡的改变 突触回路导致HPA活性改变和循环糖皮质激素转移，这可能导致 生理稳态和行为输出的变化。传入去甲肾上腺素能回路对于 控制CRH神经元的活动和HPA激活，但很少有人知道的机制， 去甲肾上腺素（NE）调节CRH神经元或其应激可塑性。我们的初步研究结果 揭示了PVN CRH神经元中树突体积传递的新机制，该机制由NE激活， 由星形胶质细胞逆行中继和胶质传递介导，以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NE激活的快速抑制， PVN CRH神经元是由β 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 可能有助于HPA轴的反馈抑制，但其对生理与 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 膜片钳记录、活细胞成像、生化分析和行为测试的组合， 提出三个具体目标。目的1将集中在CRH神经元的突触前和突触后机制， 脑切片负责β 1肾上腺素受体诱导的神经元-神经胶质逆行信号传导， 激活上游谷氨酸回路目的2将确定应激诱导的细胞机制， 通过探索CRH神经元活性的NE调节的可塑性 肾上腺素受体运输和信号传导。目的3将采取体内方法来检查NE的作用 传入神经在HPA激活中的生理和心理输入，并研究应激的影响 CRH神经元的NE调节对核心应激行为表型焦虑的可塑性。所有这些 这些研究将填补我们对HPA调节的去甲肾上腺素能机制的理解中的一个重要空白， 控制CRH神经元的中枢回路的应激可塑性及其生理和行为 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.