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：
10557199
负责人：
John Nicholas Betley
金额：
$ 56.87万
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/10557199
关键词：
Anatomy Appetite Stimulants Association Learning Behavior Behavior Therapy Behavioral Biological Assay Body Weight Brain Brain imaging Brain region Cerebellar Nuclei Cerebellum Cerebral cortex Cognitive Complex Consumption Data Dedications Development Dissociation 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 Rabies virus Rewards Rodent Role Satiation Signal Transduction Stomach Structure Structure of nucleus infundibularis hypothalami Synapses Testing Thalamic structure Therapeutic Viral Weight maintenance regimen calcium indicator cerebellar lesion drug efficacy drug modification experimental study feeding food consumption genetic approach insight limb movement motivational processes motor control nervous system disorder neural novel obese patients optogenetics paraventricular nucleus reduced food intake reward processing satiety center skills 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.

项目摘要除了运动和经典条件功能外，小脑还有助于动力和奖励构成复杂行为的过程。影响非运动过程，例如喂养和食物 - 寻求行为，人们认为小脑会调节皮质和皮质下喂养中心。唯一的小脑可以影响进食控制的路径是深处的小脑输出电路小脑核（DCN）。然而，关于DCN电路的组织方式以及是否不同的途径知之甚少致力于喂养和寻求食物的行为。 DCN的离散子集的最新鉴定向丘脑，丘脑和下丘脑脑区域投射的神经元表明存在神经小脑输出的亚型组织。根据已发布和初步数据，主要假设该建议是：1）DCN介导的途径不同进气2）这些特征确定了对喂养和/或代谢必不可少的DCN电路；最后， 3）专用DCN介导的途径在进食过程中参与并影响特定的神经活动关键喂养中心中的神经元亚型。该建议将通过三个目标检验这些假设。目标1 描述特定DCN电路的目标选择性的区分。我们将采用有条件的病毒追踪，并遗传命运映射方法来定义DCN亚群到喂养中心的输出连接（室室核，下丘脑侧，弧形核和Zona incerta），我们假设影响喂养行为。此外，我们将确定是否主要的神经元的主要亚类（例如POMC 或Agrp）与特定的Cre-line和反式突触狂犬病病毒相关。在AIM 2中，我们将定义 DCN电路通过光学激活和离散神经元的沉默在进食控制中的作用 DCN中的亚群。具体而言，我们将研究解剖学的选择性神经操纵如何定义的DCN途径会影响食物摄入量和代谢，并解离运动控制的输出途径。最后，AIM 3中的实验将确定离散DCN神经元亚群的活性特征，并确定这些亚群中的活性如何改变自由移动小鼠中已知喂养电路的神经活动在食物摄入期间，使用深脑成像。通过定义小脑的解剖学和功能组织输出途径及其在喂养行为中涉及的活动动态，这些目的提供了更多信息小脑如何控制动机和奖励电路的一般机制，并建立一个框架探索小脑更神秘的认知作用。对小脑功能将为神经系统疾病和伤害如何破坏食物的摄入量提供更多的了解，并为制定肥胖症和饮食失调的新型治疗策略的基础奠定了基础。