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

项目摘要 除了运动和经典的条件反射功能外，小脑还有助于激励和奖励。 构成复杂行为基础的过程。影响非运动过程，如进食和食物- 在寻找行为时，人们认为小脑调节皮质和皮质下的摄食中心。唯一的 小脑影响摄食控制的途径是通过深部的小脑输出回路。 小脑核(DCN)。然而，关于DCN电路是如何组织的以及是否存在不同的路径，人们知之甚少 它们致力于觅食和觅食行为。DCN离散子集的最新识别 投射到丘脑、丘脑下部和下丘脑脑区的神经元表明神经的存在 小脑输出量的亚型组织。基于已发表的和初步的数据，主要假设 这一建议是：1)不同的DCN介导的途径投射到已知的喂养中心，以影响食物 摄取；以及2)这些特征识别对于进食和/或新陈代谢至关重要的不同的DCN回路；最后， 3)DCN介导的专用通路在摄食过程中参与，并影响特定个体的神经活动。 关键摄食中心的神经元亚型。这项提案将通过三个目标来检验这些假设。目标1 描绘了特定DCN电路在目标选择性方面的差异。我们将使用有条件的病毒跟踪，以及 确定DCN亚群与摄食中心输出连通性的遗传命运图谱方法 (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相连。在目标2中，我们将定义 DCN回路通过光遗传激活和沉默在离散神经元的摄食控制中的作用 DCN中的亚群。具体地说，我们将研究选择性神经操作如何在解剖学上- 确定的DCN通路影响食物的摄取和代谢，并解离运动控制的输出通路。 最后，目标3中的实验将确定离散的DCN神经元亚群的活性分布，以及 在自由活动的小鼠中，这些亚群中的活动如何改变已知摄食回路的神经活动 在食物摄取过程中使用大脑深部成像。通过定义小脑的解剖和功能组织 输出路径及其与摄食行为相关的活动动态，这些目的提供了更多的洞察 小脑如何控制动机和奖励回路的一般机制，并建立了一个框架 探索小脑更神秘的认知角色。更全面地了解 小脑功能将提供更多关于神经系统疾病和损伤是如何扰乱食物摄入的洞察， 并为开发肥胖症和饮食失调的新治疗策略奠定了基础。

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.