Defining the functional organization of cerebellar output circuits that control feeding behavior

定义控制进食行为的小脑输出电路的功能组织

基本信息

批准号：
10352402
负责人：
John Nicholas Betley
金额：
$ 55.79万
依托单位：
SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10352402
关键词：
Address Anatomy Appetite Stimulants Behavior Behavior Therapy Behavioral Biological Assay Body Weight Brain Brain imaging Brain region Cerebellar Nuclei Cerebellum Cerebral cortex Cognitive Complex Consumption Data Development Eating Eating Disorders Feeding behaviors Food Functional Magnetic Resonance Imaging Functional disorder Gastrointestinal tract structure Genetic Goals Hunger Hypothalamic structure Image Infusion procedures Lateral Link Logic Maps Measures Mediating Metabolic Metabolism Methods Molecular Molecular Genetics Motivation Motor Motor Pathways Mus Nervous System Trauma Neurons Nutrient Obesity Output Pathway interactions Pattern Physiological Population Prevalence Process Property Public Health Publishing Rabies virus Rewards Rodent Role Satiation Signal Transduction Stomach Structure Structure of nucleus infundibularis hypothalami Synapses Testing Thalamic structure Therapeutic Viral Weight maintenance regimen base calcium indicator cerebellar lesion classical conditioning drug efficacy drug modification experimental study feeding food consumption insight limb movement motivational processes motor control nervous system disorder novel obese patients optogenetics paraventricular nucleus rabies viral tracing reduced food intake relating to nervous system reward processing satiety center therapeutically effective tool treatment strategy zona incerta

项目摘要

Project Summary In addition to motor and classical conditioning functions, the cerebellum contributes to motivation and reward processes that underlie complex behaviors. To influence non-motor processes, such as feeding and food- seeking behaviors, it is thought that the cerebellum modulates cortical and subcortical feeding centers. The only path through which the cerebellum can influence feeding control is through cerebellar output circuits in the deep cerebellar nuclei (DCN). Yet little is known about how DCN circuits are organized and whether distinct pathways are dedicated to feeding and food-seeking behaviors. The recent identification of discrete subsets of DCN neurons that project to thalamic, subthalamic and hypothalamic brain regions indicates the existence of neural subtype organization to cerebellar output. Based on published and preliminary data, the primary hypotheses of this proposal are that: 1) distinct DCN-mediated pathways project to known feeding centers to influence food intake; and 2) these features identify distinct DCN circuits essential for feeding and/or metabolism; and finally, 3) dedicated DCN-mediated pathways are engaged during feeding, and influence the neural activity of specific neuronal subtypes in key feeding centers. This proposal will test these hypotheses through three aims. Aim 1 delineates distinctions in target selectivity of specific DCN circuits. We will employ conditional viral tracing, and genetic fate-mapping methods to define the output connectivity of DCN subpopulations to feeding centers (paraventricular nucleus, lateral hypothalamus, arcuate nucleus and zona incerta), which we hypothesize influence feeding behavior. Additionally, we will determine if major subclasses of arcuate neurons (e.g. POMC or AgRP) are linked to the DCN with specific Cre-lines and trans-synaptic rabies virus. In Aim 2, we will define the role of DCN circuits in feeding control through optogenetic activation and silencing of discrete neuronal subpopulations in the DCN. Specifically, we will examine how selective neural manipulation of anatomically- defined DCN pathways influences food intake and metabolism, and dissociate output pathways for motor control. Finally, the experiments in Aim 3 will determine the activity profile of discrete DCN neuronal subpopulations, and how activity in these subpopulations changes neural activity of known feeding circuits in freely moving mice during food intake using deep-brain imaging. By defining the anatomical and functional organization of cerebellar output pathways, and their activity dynamics involved in feeding behavior, these aims provide insight into more general mechanisms of how cerebellum controls motivation and reward circuits, and establish a framework for exploring the more enigmatic cognitive roles of the cerebellum. A more comprehensive understanding of cerebellar function will provide greater insight into how neurological disorders and injuries disrupt food intake, and lay the groundwork for development of novel treatment strategies for obesity and eating disorders.

项目概要除了运动和经典调节功能外，小脑还有助于动机和奖励复杂行为背后的过程。影响非运动过程，例如进食和食物- 人们认为，在寻求行为时，小脑调节皮质和皮质下进食中心。唯一的小脑影响进食控制的途径是通过深部的小脑输出电路小脑核（DCN）。然而，人们对 DCN 电路的组织方式以及是否有不同的路径知之甚少。致力于进食和寻找食物的行为。 DCN离散子集的最新识别投射到丘脑、下丘脑和下丘脑大脑区域的神经元表明神经元的存在小脑输出的亚型组织。根据已发表的初步数据，主要假设该提议是：1）不同的 DCN 介导的途径投射到已知的喂养中心来影响食物摄入量； 2) 这些特征确定了对于进食和/或新陈代谢至关重要的不同 DCN 回路；最后， 3）在进食过程中，专门的DCN介导的通路参与，并影响特定的神经活动主要喂养中心的神经元亚型。该提案将通过三个目标来检验这些假设。目标1 描述了特定 DCN 电路的目标选择性的差异。我们将采用有条件的病毒追踪，并且遗传命运图谱方法来定义 DCN 亚群与喂养中心的输出连接（室旁核、下丘脑外侧核、弓状核和未定带），我们假设影响进食行为。此外，我们将确定弓状神经元的主要亚类（例如 POMC 或 AgRP）通过特定的 Cre 系和跨突触狂犬病病毒与 DCN 连接。在目标 2 中，我们将定义 DCN 回路通过光遗传学激活和离散神经元沉默在进食控制中的作用 DCN 中的亚群。具体来说，我们将研究如何选择性地神经操纵解剖学- 定义的 DCN 通路影响食物摄入和代谢，并分离运动控制的输出通路。最后，目标 3 中的实验将确定离散 DCN 神经元亚群的活动概况，以及这些亚群的活动如何改变自由活动小鼠已知进食回路的神经活动使用深部脑成像在食物摄入期间。通过定义小脑的解剖和功能组织输出途径及其与进食行为有关的活动动态，这些目标提供了对更多信息的洞察小脑如何控制动机和奖励回路的一般机制，并建立一个框架探索小脑更神秘的认知作用。更全面的了解小脑功能将有助于更深入地了解神经系统疾病和损伤如何扰乱食物摄入，并为开发肥胖和饮食失调的新治疗策略奠定基础。