Melanin-concentrating hormone and the neural regulation of feeding

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Project Summary/Abstract Obesity and its associated comorbidities pose a major burden to public health, and existing therapeutics are only minimally effective or have major adverse consequences. The brain plays a central role in mediating energy balance. Melanin-concentrating hormone (MCH), a neuropeptide produced primarily in the lateral hypothalamic area (LHA) increases energy intake and body weight gain, and therefore there is recent interest in developing obesity therapeutics that block the hyperphagic effects of MCH. Preliminary data herein suggest that in addition to generally increasing food intake, MCH contributes to excessive feeding via conditioned appetitive mechanisms, such as food impulsivity and conditioned place preference for palatable food. Furthermore, these mechanisms can be attributed to specific nodes of MCH neuronal circuitry such as the ventral hippocampus (vHP), a region that contains high levels of MCH receptor but where the function of MCH with regard to feeding behavior has not previously been investigated. Through studying the MCH system and its contributions to the central regulation of ingestive behavior, the principal goal of the proposed 5-year research career development plan is to facilitate the applicant's transition from Research Assistant Professor to Tenure-track Assistant Professor with independent R01 funding. The proposed research will enable the applicant to master several virus-based neuroanatomical and chemogenetic techniques, rodent behavioral paradigms, high- resolution whole brain mapping with functional connectivity analyses. Using these techniques, she will determine the role of MCH to vHP neuronal circuitry in mediating feeding behavior, the relevance of this pathway to obesity, and will identify collateral projections, functional connections, and downstream targets. Specific Aim 1 utilizes dual virus chemogenetic techniques to selectively activate MCH neurons that project to the vHP in order to study the role of vHPà MCH neuronal circuitry in mediating several aspects of feeding behavior. Specific Aim 2 uses viral-based neural tracing, immunohistochemistry and in situ hybridization to further characterize these neurons by their collateral projections and phenotypic gene/protein expression profiles. Aim 3 uses the novel combination of dual virus chemogenetics with whole brain perfusion mapping to determine downstream regions engaged by activating MCH neurons that project to the vHP. Additionally, experiments in Aim 3 will determine how MCH to vHP neuronal circuitry augments regional brain activity during food impulsivity. This novel combination of approaches allows for investigation of the interaction between activating specific nodes of a defined circuit and immediate behavioral effects. Results from these experiments will be generative as pilot data for an R01 submission by the applicant, will provide significant contributions to ingestive behavior research, and will overall provide the applicant with a unique set of skills for her independent research career.