Inhibitory Cell Types and Circuits in the Lateral Hypothalamus

外侧下丘脑的抑制细胞类型和电路

• 批准号: 10522510
• 负责人: Alexander Choi Jackson
• 金额: $ 58.53万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522510
• 关键词: Ablation; Address; Affect; Amygdaloid structure; Anatomy; Animals; Arousal; Axon; Behavior; Behavior assessment; Behavioral; Biological; Brain; Clinical; Data; Dimensions; Disease; Dissection; Dissociation; Electrophysiology (science); Environment; Exhibits; Feeding behaviors; Foundations; Generations; Genetic; Genetic Transcription; Goals; Grant; Hypothalamic structure; In Vitro; Investigation; Knowledge; Lateral; Lateral Hypothalamic Area; Link; Literature; Memory; Mental Health; Metabolic Diseases; Methods; Molecular; Mus; Negative Valence; Neurokinin B; Neuromedin K Receptor; Neurons; Neuropeptides; Neurotransmitters; Output; Patients; Peripheral; Personal Satisfaction; Physiological; Physiology; Population; Population Heterogeneity; Positioning Attribute; Positive Valence; Post-Traumatic Stress Disorders; Property; Quality of life; Receptor Signaling; Rewards; Shapes; Signal Pathway; Signal Transduction; Sleep; Sleep Disorders; Source; Stress; Structure; System; TACR3 gene; Tachykinin; Taxonomy; Techniques; Therapeutic Intervention; Viral; Work; addiction; base; behavioral study; cell type; differential expression; experimental study; feeding; gamma-Aminobutyric Acid; genetic approach; improved; in vivo; inhibitory neuron; melanin-concentrating hormone; motivated behavior; neural circuit; neurochemistry; neuropsychiatric disorder; neuropsychiatry; neuroregulation; neurotransmission; neurotransmitter release; novel; optogenetics; relating to nervous system; response; sleep behavior; targeted treatment; therapeutic target; tool; transcriptomics; transmission process

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to define the cellular diversity, connectivity and function of inhibitory neurons in the lateral hypothalamic area (LHA). The LHA is a linchpin in the orchestration of fundamental aspects of behavior owing to its unique position at the intersection of multiple neural and humoral systems. LHA GABAergic neurons in particular have emerged as potent actuators of arousal, goal-directed behavior as well as both negative and positive valence behavior. Within this broad class of inhibitory LHA neurons lie poorly resolved but functionally important subpopulations, which may differentially determine behavioral output. Important among these is a population of putative inhibitory neurons that express the neuropeptide melanin-concentrating hormone (MCH). LHA MCH-expressing neurons (LHAMCH) display remarkable functional diversity, sending extensive projections throughout the brain and coordinating a broad range of physiological functions and behaviors, including the modulation of sleep-wake states, feeding, motivated behavior, stress and memory. However, experimental manipulations of LHAMCH neurons are largely interpreted in the context of LHAMCH neurons being a monolithic, neuromodulatory projection system, creating a profound knowledge gap as to the source of their functional diversity. There is, therefore, a critical need to delineate the unique cellular, circuit-level and behavioral impact of LHAMCH diversity. In the previous grant cycle, we made significant progress towards our long-term goal of defining the population structure of LHA GABAergic neurons, including the generation of the most comprehensive cellular taxonomy to date of molecularly distinct LHA cell types in the mouse. Here, we will build upon that progress through our investigation of: 1) two transcriptomically-distinct LHAMCH subpopulations that differentially express the neurokinin 3 receptor (NK3R), the receptor for neurokinin B (NKB); 2) and a novel projection from NKB neurons in the central extended amygdala to the LHA. In Aim 1, we will determine whether distinct LHAMCH subpopulations give rise to functional sub-circuits that project to different targets in the brain and release different neurochemicals using a precise intersectional viral strategy based on the enrichment of NK3R in one LHAMCH subpopulation over the other. In Aim 2, we will explore whether differential engagement of LHAMCH subpopulations elicits distinct behavioral repertoires using two parallel intersectional strategies for optogenetically targeting LHAMCH subpopulations and then subjecting animals to a suite of behavioral assessments. In Aim 3, we will investigate the biological mechanisms underlying NKB/NK3R signaling in the central extended amygdala–LHA circuit through a detailed electrophysiological investigation of NKB/GABA co- transmission onto LHAMCH neurons, and by studying the behavioral impact of these projections. Together, the proposed experiments will address outstanding questions concerning the cellular and circuit-level functions of LHAMCH neuron diversity, which is necessary both for a mechanistic understanding of LHA circuit function, and as a critical precursor for identifying therapeutic targets for neuropsychiatric, sleep and metabolic disorders.

项目概要/摘要 该提案的目标是定义抑制性神经元的细胞多样性、连接性和功能 下丘脑外侧区（LHA）。 LHA 是协调行为基本方面的关键 由于其在多个神经和体液系统交叉点的独特位置。 LHA GABA能神经元 特别是已经成为唤醒、目标导向行为以及消极和消极行为的有效执行者。 正价行为。在这一大类抑制性 LHA 神经元中，分辨率较差，但功能正常 重要的亚群，可能会不同地决定行为输出。其中重要的是 表达神经肽黑色素浓缩激素（MCH）的推定抑制性神经元群体。 LHA MCH 表达神经元 (LHAMCH) 显示出显着的功能多样性，发送广泛的预测 整个大脑并协调广泛的生理功能和行为，包括 调节睡眠-觉醒状态、进食、动机行为、压力和记忆。然而，实验 LHAMCH 神经元的操作很大程度上是在 LHAMCH 神经元是一个整体的背景下解释的， 神经调节投射系统，在其功能来源方面造成了深刻的知识差距 多样性。因此，迫切需要描述独特的细胞、电路级和行为影响 LHAMCH 多样性。在上一个资助周期中，我们在实现长期目标方面取得了重大进展 定义 LHA GABA 能神经元的群体结构，包括最 迄今为止，对小鼠分子上不同的 LHA 细胞类型进行了全面的细胞分类。在这里，我们将打造 通过我们的调查取得了进展：1）两个转录组学上不同的 LHAMCH 亚群 差异表达神经激肽 3 受体 (NK3R)、神经激肽 B (NKB) 受体； 2）和一本小说 中央延伸杏仁核中的 NKB 神经元投射到 LHA。在目标 1 中，我们将确定是否 不同的 LHAMCH 亚群产生功能子电路，投射到大脑中的不同目标， 使用基于 NK3R 富集的精确交叉病毒策略释放不同的神经化学物质 一个 LHAMCH 亚群优于另一个亚群。在目标 2 中，我们将探讨 LHAMCH 的差异化参与是否 亚群使用两种平行的交叉策略来引发不同的行为库 以光遗传学方式瞄准 LHAMCH 亚群，然后对动物进行一系列行为 评估。在目标 3 中，我们将研究 NKB/NK3R 信号转导的生物学机制。 通过对NKB/GABA co-的详细电生理学研究，中央扩展杏仁核-LHA回路 传输到 LHAMCH 神经元，并研究这些投射的行为影响。在一起， 拟议的实验将解决有关细胞和电路级功能的突出问题 LHAMCH 神经元多样性，这对于理解 LHA 回路功能的机制和 作为确定神经精神、睡眠和代谢疾病治疗靶点的关键先导。