Monday, November 25, 2024
11/25/2024
Project Summary Recently, we identified the cerebellum as a novel satiation center in the brain. Yet, little is known about the pathways and circuit mechanisms through which the cerebellum regulates food intake. The major research goal of this proposal is to define cerebellar à striatal circuits that regulate food intake and better understand the physiological changes mediated by activity in this circuit. We have recently identified a subset of molecularly and topographically-distinct neurons in the lateral nucleus of the mouse anterior deep cerebellar nuclei (aDCN-lat) that are activated by food intake (Low et al., 2021). Our functional assessment of these neurons demonstrates that activation of aDCN-lat neurons dramatically decreases food intake by reducing meal size without compensatory changes to metabolic rate. We discovered that activity in aDCN-lat neurons reduces the phasic dopamine response to additional food, likely curbing the urge to eat by reducing the reward value of additional food (Low et al., 2021). Based on published and preliminary data, the central hypotheses of this proposal are that: 1) food- and nutrient-sensing aDCN-lat neurons are polysynaptically linked to the striatum through subcortical pathways to influence striatal dopamine levels, and these neurons have a unique molecular profile that changes during obesity; 2) aDCN-lat mediated dopamine changes influence neural activity in a subset of striatal neurons and regulate affective and motivational desire for food; and, 3) aDCN-striatal circuits and DA signaling are disrupted in obesity. This proposal will test these hypotheses through three aims. Aim 1 delineates the pathways through which aDCN-lat neurons can act on striatal dopamine and defines transcript changes in aDCN-lat neurons of diet-induced obese mice. We will use viral tools (AAVretro and rabies) to determine the intermediate targets of aDCN-lat neurons (hypothesized to be linked by ventral tegmental area and substantia nigra) and single nuclei RNA-sequencing to identify changes in transcripts of aDCN-lat neurons in obese mice. In Aim 2, we will examine the influence of aDCN-mediated changes in striatal DA levels on the neural activity of specific striatal neuron subtypes (D1R and D2R). These experiments will allow us to examine how cerebellar activity influences the striatal response to food anticipation, consumption and gastric nutrients. Finally, the experiments in Aim 3 will assess how diet-induced obesity impacts aDCN-mediated changes in striatal neural activity at a single cell level, and more importantly test the hypothesis that silencing the DCN leads to an ‘obesity- like’ pattern of neural activity in the striatum. By defining cerebellar-striatal pathways, how cerebellar activity controls striatal neuron function, and how this circuitry might be disrupted in obesity, this work will reveal circuit mechanisms that regulate food reward processing with added translational value of guiding the development of non-invasive cerebellar stimulation and cell-type specific pharmacological manipulation of striatal neurons for long-term body weight management.
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