Inhibitory cell types and circuits in the lateral hypothalamus

下丘脑外侧的抑制细胞类型和回路

• 批准号: 9291243
• 负责人: Alexander Choi Jackson
• 金额: $ 39.36万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291243
• 关键词: Address; Affect; Anatomy; Arousal; Behavior; Behavioral; Biological Markers; Brain; Brain Stem; Cell Extracts; Cells; Censuses; Characteristics; Clinical; Coupled; Data; Data Analyses; Disease; Dissection; Electrophysiology (science); Environment; Equilibrium; Exhibits; Feeding behaviors; Foundations; Genetic; Genetic Transcription; Goals; Health; Hypothalamic structure; Interneurons; Ion Channel; Knowledge; Lateral; Lateral Hypothalamic Area; Maps; Membrane; Mental Health; Metabolic Diseases; Methods; Molecular; Neuromodulator; Neurons; Neuropeptides; Neurotransmitters; Output; Patients; Pattern; Peripheral; Pharmacology; Phenotype; Physiological; Physiology; Population; Population Heterogeneity; Positioning Attribute; Post-Traumatic Stress Disorders; Property; Quality of life; Research; Resolution; Resources; Rewards; Role; Shapes; Signal Transduction; Sleep Disorders; Slice; Stress; Structure; Synapses; System; Techniques; Therapeutic Intervention; addiction; base; cell type; design; feeding; gamma-Aminobutyric Acid; improved; intersectionality; locus ceruleus structure; molecular marker; motivated behavior; neural circuit; neurochemistry; neuropsychiatry; neuroregulation; noradrenergic; novel; optogenetics; patch clamp; programs; relating to nervous system; response; targeted treatment; therapeutic target; tool; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to develop a circuit-level understanding of GABAergic neurons in the lateral hypothalamic area (LHA) by resolving their molecular and functional diversity and local and long-range connectivity. The LHA is a linchpin in the orchestration of fundamental aspects of behavior including arousal, stress, feeding and motivated behavior. Owing to its unique position at the intersection of multiple neural and humoral systems, the LHA drives essential behavioral programs that maintain homeostatic balance in physiology and behavior. Underlying the diverse functions of the LHA is an exceptionally heterogeneous population of neuronal cell types, of which few have been identified. Inhibitory GABAergic neurons in the LHA (LHAGABA) have emerged as potent actuators of feeding, reward and stress. However, within this broad class of neurons lie poorly resolved but functionally important subpopulations, which may differentially determine behavioral output. Conventional methods are limited in their ability to decipher the molecular and functional diversity of LHAGABA neurons, which represents a major barrier in our understanding of the role of LHA circuits in health and disease. There is, therefore, a critical need to systematically delineate the neurochemical identity, cellular properties and connectivity of functional subpopulations of LHAGABA neurons as a prerequisite to circuit-level behavioral analyses. To fill this knowledge gap, we will establish the first large-scale and systematic molecular, cellular and connectivity analysis of LHAGABA neurons at single-cell resolution using an integrated approach of electrophysiological phenotyping, optogenetics-based circuit mapping and single-cell transcriptional profiling. Our central hypothesis is that LHAGABA neurons can be classified into distinct functional subtypes according to key molecular markers, electrical signatures and patterns of synaptic connectivity. We will probe this hypothesis in three Specific Aims. Aim 1 will systematically define the electrophysiological and neuromodulatory phenotypes of candidate LHAGABA neuron populations and refine these characteristics based on long-range projections to the locus coeruleus (LC). Aim 2 will determine the synaptic connectivity between populations of LHAGABA neurons and key, arousal-related targets, both within the LHA and the LC, using patch-clamp electrophysiology and optogenetics. Aim 3 will apply cutting-edge quantitative single-cell transcriptional profiling methods to decipher novel, molecularly distinct populations of LHAGABA neurons. Impact: As the first comprehensive neurochemical, electrophysiological and anatomical census of inhibitory cell types in the LHA, this project will yield functional subpopulations of LHAGABA neurons that, in turn, will allow the identification of key markers for the design of novel cre driver lines and intersectional genetic tools for circuit-specific dissection of LHAGABA circuits in behavior. Furthermore, a deeper understanding of LHAGABA cell types and circuits holds the promise of identifying therapeutic targets for neuropsychiatric illnesses, addiction, post-traumatic stress disorder, sleep and metabolic disorders.

项目摘要/摘要 该提案的目的是在横向中建立对GABA能神经元的电路级别的理解 下丘脑区域（LHA）通过解决其分子和功能多样性以及局部和远程 连接性。 LHA是行为基本方面的编排，包括唤醒， 压力，喂养和动机行为。由于其在多个神经和 LHA的体液系统驱动了维持生理稳态平衡的基本行为计划 和行为。 LHA的各种功能是基本的，是一个异常异构的人群 神经元细胞类型，其中很少被鉴定出来。 LHA（Lhagaba）中的抑制性GABA能神经元具有 成为喂养，奖励和压力的有效执行者。但是，在这一广泛的神经元中，神经元较差 解决但功能上重要的亚群，这可能会差异地确定行为输出。 传统方法的破译能力受到限制 神经元是我们对LHA电路在健康和疾病中的作用的理解的主要障碍。 因此，有系统地描绘神经化学身份，细胞特性和 拉加巴神经元功能亚群的连通性，作为电路级行为的先决条件 分析。为了填补这一知识空白，我们将建立第一个大规模和系统的分子，细胞和 使用单细胞分辨率的lagaba神经元的连通性分析使用的集成方法 电生理表型，基于光遗传学的电路映射和单细胞转录分析。 我们的核心假设是，lagaba神经元可以根据 关键分子标记，电特征和突触连通性的模式。我们将探究这个假设 在三个具体目标中。 AIM 1将系统地定义电生理和神经调节表型 候选lhagaba神经元种群的大量，并根据长期预测来完善这些特征 基因座（LC）。 AIM 2将确定lhagaba神经元种群之间的突触连通性 以及使用Patch-Clamp电生理学和LHA和LC内部的唤醒相关靶标 光遗传学。 AIM 3将应用最先进的定量单细胞转录分析方法来解密 新颖的，分子截然不同的神经元种群。影响：作为第一个全面的神经化学， LHA中抑制性细胞类型的电生理和解剖学普查，该项目将产生功能 拉加巴神经元的亚群，反过来允许识别新颖的关键标记 CRE驾驶员线和交叉遗传工具，用于行为中lagaba电路的电路特异性解剖。 此外，对撒哈巴细胞类型和电路的更深入的理解有望识别 神经精神疾病，成瘾，创伤后应激障碍，睡眠和代谢的治疗靶标 疾病。