Stress plasticity of CRH neurons

CRH 神经元的应力可塑性

• 批准号: 10214477
• 负责人: JEFFREY G TASKER
• 金额: $ 41.1万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214477
• 关键词: Address; Adrenal Glands; Affective; Anxiety; Anxiety Disorders; Astrocytes; Behavior; Behavioral; Biochemical; Blood; Brain; Brain Stem; Cell Line; Cells; Chronic stress; Coping Behavior; Corticotropin-Releasing Hormone; Dependence; Equilibrium; Etiology; Feedback; Female; Genomics; Glucocorticoids; Glutamates; Health Status; Homeostasis; Hormones; Hypothalamic structure; Immune; Knowledge; Lead; Mediating; Mental Depression; Mental Health; Mental disorders; Mus; Neurobiology; Neurons; Neurosecretory Systems; Norepinephrine; Output; Pathway interactions; Pharmacogenetics; Physiological; Physiology; Pituitary Gland; Play; Psychological Stress; Regulation; Role; Signal Transduction; Slice; Specificity; Stress; Stress and Coping; Synapses; Synaptic plasticity; Vasopressins; anxiety-like behavior; behavior test; behavioral phenotyping; biological adaptation to stress; brain circuitry; chronic neurologic disease; desensitization; excitatory neuron; hormone regulation; hypothalamic-pituitary-adrenal axis; imaging approach; in vivo; live cell imaging; male; mental development; nerve supply; neural circuit; non-genomic; noradrenergic; novel; optogenetics; paraventricular nucleus; patch clamp; postsynaptic; psychologic; psychological stressor; receptor; response; stressor; trafficking; transmission process; traumatic stress

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.

概括 下丘脑-垂体-肾上腺 (HPA) 轴失调和循环糖皮质激素水平改变 与心理健康障碍密切相关。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，并直接调节压力和焦虑 相关行为。由可塑性变化引起的 CRH 神经元兴奋-抑制平衡的改变 突触回路导致 HPA 活性改变并改变循环糖皮质激素，从而导致 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 神经元活动和 HPA 激活，但对其机制知之甚少 去甲肾上腺素 (NE) 通过应激来调节 CRH 神经元或其可塑性。我们的初步调查结果 揭示了 PVN CRH 神经元树突体积传递的新机制，该机制由 NE 和 由星形细胞逆行中继和胶质细胞传递介导，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会导致 NE 激活的快速抑制。 PVN CRH 神经元由 α1 肾上腺素受体脱敏介导。这种快速的糖皮质激素作用是 可能有助于 HPA 轴的反馈抑制，但其对生理与生理的特异性。 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，我们将使用一个 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 将重点关注 CRH 神经元的突触前和突触后机制 负责 α1 肾上腺素受体诱导的神经元-胶质细胞逆行信号传导的脑切片 激活上游谷氨酸电路。目标 2 将确定应激诱导的细胞机制 通过探索 α1 的快速糖皮质激素调节来研究 CRH 神经元活动的 NE 调节的可塑性 肾上腺素受体运输和信号传导。目标 3 将采用体内方法来检查 NE 的作用 通过生理和心理输入激活 HPA 的传入，并研究压力的影响 CRH 神经元的 NE 调节对核心应激行为表型焦虑的可塑性。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 控制CRH神经元的中枢回路的应激可塑性及其生理和行为 输出。