The hormone ghrelin displays several well-characterized functions, including some with pharmaceutical interest. The receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), is expressed in the hypothalamic paraventricular nucleus (PVH), a critical hub for the integration of metabolic, neuroendocrine, autonomic, and behavioral functions. Here, we performed a neuroanatomical and functional characterization of the neuronal types mediating ghrelin actions in the PVH of male mice. We found that fluorescent ghrelin mainly labels PVH neurons immunoreactive for nitric oxide synthase 1 (NOS1), which catalyze the production of nitric oxide [NO]). Centrally injected ghrelin increases c-Fos in NOS1 PVH neurons and NOS1 phosphorylation in the PVH. We also found that a high dose of systemically injected ghrelin increases the ghrelin level in the cerebrospinal fluid and in the periventricular PVH, and induces c-Fos in NOS1 PVH neurons. Such a high dose of systemically injected ghrelin activates a subset of NOS1 PVH neurons, which do not express oxytocin, via an arcuate nucleus-independent mechanism. Finally, we found that pharmacological inhibition of NO production fully abrogates ghrelin-induced increase of calcium concentration in corticotropin-releasing hormone neurons of the PVH whereas it partially impairs ghrelin-induced increase of plasma glucocorticoid levels. Thus, plasma ghrelin can directly target a subset of NO-producing neurons of the PVH that is involved in ghrelin-induced activation of the hypothalamic-pituitary-adrenal neuroendocrine axis.

中文翻译：

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Ghrelin 在雄性小鼠 PVH 中的作用：可及性、神经元靶标和 CRH 神经元激活。

生长激素释放肽显示出多种明确的功能，其中包括一些具有制药意义的功能。生长素释放肽的受体，即生长激素促分泌素受体 (GHSR)，在下丘脑室旁核 (PVH) 中表达，PVH 是代谢、神经内分泌、自主神经和行为功能整合的关键枢纽。在这里，我们对雄性小鼠 PVH 中介导生长素释放肽作用的神经元类型进行了神经解剖学和功能表征。我们发现荧光生长素释放肽主要标记与一氧化氮合酶 1 (NOS1) 发生免疫反应的 PVH 神经元，NOS1 催化一氧化氮 [NO] 的产生。集中注射的生长素释放肽会增加 NOS1 PVH 神经元中的 c-Fos 和 PVH 中 NOS1 的磷酸化。我们还发现，全身注射高剂量的 ghrelin 会增加脑脊液和脑室周围 PVH 中的 ghrelin 水平，并在 NOS1 PVH 神经元中诱导 c-Fos。如此高剂量的全身注射生长素释放肽通过弓形核独立机制激活 NOS1 PVH 神经元的子集，这些神经元不表达催产素。最后，我们发现，对NO产生的药理学抑制完全消除了生长素释放肽诱导的PVH促肾上腺皮质激素释放激素神经元中钙浓度的增加，同时它部分削弱了生长素释放肽诱导的血浆糖皮质激素水平的增加。因此，血浆生长素释放肽可以直接靶向PVH中产生NO的神经元子集，该神经元参与生长素释放肽诱导的下丘脑-垂体-肾上腺神经内分泌轴的激活。