The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, 77030.
The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas Health Science Center at Houston, Houston, TX, 77030
J Neurosci. 2018 Feb 21;38(8):1874-1890. doi: 10.1523/JNEUROSCI.1492-17.2017. Epub 2018 Jan 19.
Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) initiate hypothalamic-pituitary-adrenal axis activity through the release of CRF into the portal system as part of a coordinated neuroendocrine, autonomic, and behavioral response to stress. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. Here, we characterize the electrophysiological and molecular properties of PVN-CRFR1 neurons and interrogate their monosynaptic connectivity using rabies virus-based tracing and optogenetic circuit mapping in male and female mice. We provide evidence that CRF neurons in the PVN form synapses on neighboring CRFR1 neurons and activate them by releasing CRF. CRFR1 neurons receive the majority of monosynaptic input from within the hypothalamus, mainly from the PVN itself. Locally, CRFR1 neurons make GABAergic synapses on parvocellular and magnocellular cells within the PVN. CRFR1 neurons resident in the PVN also make long-range glutamatergic synapses in autonomic nuclei such as the nucleus of the solitary tract. Selective ablation of PVN-CRFR1 neurons in male mice elevates corticosterone release during a stress response and slows the decrease in circulating corticosterone levels after the cessation of stress. Our experiments provide evidence for a novel intra-PVN neural circuit that is activated by local CRF release and coordinates autonomic and endocrine function during stress responses. The hypothalamic paraventricular nucleus (PVN) coordinates concomitant changes in autonomic and neuroendocrine function to organize the response to stress. This manuscript maps intra-PVN circuitry that signals via CRF, delineates CRF receptor type 1 neuron synaptic targets both within the PVN and at distal targets, and establishes the role of this microcircuit in regulating hypothalamic-pituitary-adrenal axis activity.
促肾上腺皮质释放因子 (CRF) 神经元位于下丘脑室旁核 (PVN)，通过将 CRF 释放到门脉系统中，启动下丘脑-垂体-肾上腺轴活动，这是应激条件下神经内分泌、自主和行为反应的协调组成部分。最近的发现表明，表达 CRF 受体 1（CRFR1）的神经元位于 PVN 内的 CRF 神经元附近，这些神经元表达 CRF 受体 1，提示 CRF 也在神经内分泌系统内传递信号，以协调应激反应的各个方面。在这里，我们描述了 PVN-CRFR1 神经元的电生理和分子特性，并使用狂犬病毒追踪和光遗传电路映射技术，在雄性和雌性小鼠中探讨了它们的单突触连接。我们提供的证据表明，PVN 中的 CRF 神经元与邻近的 CRFR1 神经元形成突触，并通过释放 CRF 激活它们。CRFR1 神经元主要从下丘脑接收大多数单突触传入，主要来自 PVN 本身。局部地，CRFR1 神经元在 PVN 内的小细胞和大细胞上形成 GABA 能突触。PVN 中的 CRFR1 神经元还在自主神经核（如孤束核）中形成长程谷氨酸能突触。选择性消融雄性小鼠的 PVN-CRFR1 神经元会升高应激反应期间的皮质酮释放，并减缓应激停止后循环皮质酮水平的下降。我们的实验提供了证据，证明存在一种新的 PVN 内神经回路，该回路由局部 CRF 释放激活，并在应激反应期间协调自主和内分泌功能。下丘脑室旁核 (PVN) 协调自主和神经内分泌功能的同时变化，以组织对压力的反应。本文绘制了通过 CRF 信号传递的 PVN 内回路，描绘了 CRF 受体 1 神经元在 PVN 内和远端靶标上的突触靶点，并确定了该微回路在调节下丘脑-垂体-肾上腺轴活动中的作用。
