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.
The rising prevalence of obesity and eating disorders is a significant public health crisis, and dysfunctions of cortical and subcortical circuits important for motivation and reward processing have been implicated. This proposal will address how cerebellar circuits influence food seeking and consumption. Through a combination of molecular-genetic tools, imaging and quantitative behavioral and metabolic analysis, we will dissect the connectivity and function of a newly-identified brain center that regulates feeding behavior, with a long-term goal of exploring the efficacy of drugs and behavioral modifications as effective therapeutics for body weight control.
