Neural mechanisms underlying REM sleep regulation by MCH neurons

 描述(由申请人提供)：考虑到许多神经精神障碍(例如，严重抑郁障碍和创伤后应激障碍)中PS的失调以及PS抑制的不利健康后果，理解控制快速眼动睡眠(或异相睡眠；PS)的神经机制至关重要。在下丘脑外侧区，表达黑色素浓缩激素(MCH)的神经元被认为在PS调节中发挥着不可或缺的作用，但它们在这一功能中的确切作用尚不清楚。这项拟议的工作旨在解决这一问题，并描绘神经元电路的MCH神经元的影响，以调节PS。为了证明MCH神经元在PS控制中的特殊作用，在目标1中，我们将使用一种新的药物遗传学工具-设计者受体(DREADD)选择性地激活和沉默MCH神经元，并研究选择性PS剥夺后基线PS和PS反弹的变化(PS稳态)。因为MCH神经元的激活增加了PS，而MCH神经元本质上是抑制性的，我们假设MCH神经元抑制PS，抑制中脑导水管周围灰质腹外侧区(VlPAG)/桥脑外侧被盖(LPT)中的神经元以促进PS。在目标2中，我们将通过研究体内光遗传刺激v1PAG/LPT中的MCH终末后PS的变化和b)光遗传抑制v1PAG/LPT中的MCH终末并同时用DREADS刺激MCH细胞体来验证这一假说。最后，为了确定神经化学上不同的vlPAG/LPT神经元亚群，将MCH PS促进的输入传递到SLD，我们将激活和沉默a)特异性投射到SLD的vlPAG/LPT神经元，以及b)使用DREADDS激活和沉默vlPAG/LPT中的谷氨酸和GABA能神经元，并研究PS和PS稳态的变化(目标3)。根据我们的初步结果，我们预测投射到SLD的vlPAG/LPT中的GABA能神经元与PS抑制密切相关，因此它们被MCH神经元抑制可能促进PS。

 DESCRIPTION (provided by applicant): Understanding the neural mechanisms controlling rapid eye movement sleep (or paradoxical sleep; PS) is critical considering the dysregulation of PS in many neuropsychiatric disorders (e.g. major depressive disorder and post-traumatic stress disorder) and the adverse health consequences of PS suppression. In the lateral hypothalamus (LH), neurons expressing melanin concentrating hormone (MCH) are thought to play an integral role in PS regulation but their precise role in this function is unclear. The proposed work is aimed to address this question and to delineate the neuronal circuitry MCH neurons impact in order to regulate PS. To demonstrate the specific role of MCH neurons in PS control, in Aim 1, we will selectively activate and silence the MCH neurons using a novel pharmacogenetic tool - Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) - and study the changes in baseline PS and PS rebound following selective PS deprivation (PS homeostasis). Because MCH neuronal activation increases PS and MCH neurons are inhibitory in nature, we hypothesize that the MCH neurons inhibit PS suppressing neurons in the ventrolateral periaqueductal grey (vlPAG)/lateral pontine tegmentum (LPT) to facilitate PS. We will test this hypothesis, in Aim 2, by studying the changes in PS a) following i vivo optogenetic stimulation of the MCH terminals in the vlPAG/LPT and b) following optogenetic inhibition of the MCH terminals in the vlPAG/LPT with concurrent stimulation of MCH cell bodies by DREADDs. Finally, in order to identify the neurochemically distinct subset of vlPAG/LPT neurons that relay MCH PS promoting inputs to the SLD, we will activate and silence a) the vlPAG/LPT neurons specifically projecting to the SLD and b) glutamatergic and GABAergic neurons in the vlPAG/LPT using DREADDs and study the changes in PS and PS homeostasis (Aim 3). We predict, based on our preliminary results that GABAergic neurons in the vlPAG/LPT projecting to the SLD are critically involved in PS suppression and hence their inhibition by MCH neurons may promote PS.