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Neural mechanisms underlying REM sleep regulation by MCH neurons

MCH 神经元调节 REM 睡眠的神经机制

基本信息

批准号：
9234081
负责人：
Vetrivelan Ramalingam
金额：
$ 38.06万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9234081
关键词：
Acute Address Animal Behavior Attenuated Brain Brain Stem Cell Nucleus Cells Clozapine Cognitive Development Disease Electroencephalogram Generations Genetic Glutamates Health Heating Homeostasis Hormone Antagonists Huntington Disease Hypothalamic structure Implant Injectable Injection of therapeutic agent Interneurons Intraperitoneal Injections Knowledge Lateral Lesion Ligands Major Depressive Disorder Mediating Mental disorders Metabolic Methods Mood Disorders Mus Nature Neurologic Neurons Neurotransmitters Outcome Oxides Pathway interactions Pharmacogenetics Physiologic pulse Physiological Play Pontine structure Population Post-Traumatic Stress Disorders Procedures REM Sleep Regulation Rodent Role Sleep Slow-Wave Sleep Techniques Tegmentum Mesencephali Testing Tissues Transgenic Mice Work adeno-associated viral vector base deprivation designer receptors exclusively activated by designer drugs improved in vivo inhibitory neuron intraperitoneal light effects melanin-concentrating hormone midbrain central gray substance nervous system disorder neural circuit neurochemistry neuromechanism neuronal circuitry neuropsychiatric disorder neuropsychiatry neurotoxic novel optogenetics public health relevance retrograde transport sleep regulation tool

项目摘要

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.

描述（由申请人提供）：考虑到许多神经精神疾病（例如重度抑郁症和创伤后应激障碍）中PS的失调以及PS抑制的不良健康后果，了解控制快速眼动睡眠（或异相睡眠; PS）的神经机制至关重要。在外侧下丘脑（LH）中，表达黑色素浓集激素（MCH）的神经元被认为在PS调节中起着不可或缺的作用，但其在该功能中的确切作用尚不清楚。拟议的工作旨在解决这个问题，并描绘神经元回路MCH神经元的影响，以调节PS。为了证明MCH神经元在PS控制中的特定作用，在目标1中，我们将使用一种新的药物遗传学工具选择性地激活和沉默MCH神经元-由设计药物独家激活的设计受体（DREADD）-并研究选择性PS剥夺（PS稳态）后基线PS和PS反弹的变化。因为MCH神经元激活增加PS，并且MCH神经元本质上是抑制性的，所以我们假设MCH神经元抑制腹外侧导水管周围灰质（vlPAG）/外侧脑桥被盖（LPT）中的PS抑制神经元以促进PS。在目的2中，我们将通过研究PS的变化来测试该假设：a）在vlPAG/LPT中MCH末端的体内光遗传学刺激之后，和B）在vlPAG/LPT中MCH末端的光遗传学抑制与DREADD对MCH细胞体的同时刺激之后。最后，为了鉴定将MCH PS促进输入中继到SLD的vlPAG/LPT神经元的神经化学上不同的子集，我们将使用DREADD激活和沉默a）特异性投射到SLD的vlPAG/LPT神经元和B）vlPAG/LPT中的谷氨酸能和GABA能神经元，并研究PS和PS稳态的变化（目的3）。根据我们的初步结果，我们预测，投射到SLD的vlPAG/LPT中的GABA能神经元在PS抑制中起关键作用，因此MCH神经元对它们的抑制可能促进PS。