The Effects of Chronic Manipulation of Proopiomelanocortin Neurons in Animal Models

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Project Summary This proposal seeks to train a dual degree, DVM-PhD, student to prepare her for success in a career as an independent clinician-scientist. The applicant will earn a PhD in Biomedical Sciences while simultaneously earning a DVM. The proposed research seeks to determine whether proopiomelanocortin (POMC) neurons in the hypothalamus are a viable target for potential therapies for disorders of energy balance regulation, including obesity and eating disorders. Given that 35-40% of people in the US are obese and 2-5% suffer from eating disorders, it is critically important that we better understand how the brain regulates energy homeostasis. The long-term objective of this proposal is to determine whether chronic manipulation of hypothalamic POMC neurons will correct disturbances in food intake and bodyweight in animal models of energy balance disorders. The following specific aims will be addressed: 1) Determine the impact of chronically stimulating POMC neurons in an animal model of obesity. 2) Determine the impact of chronically inhibiting POMC neurons in an animal model of anorexia. Chronic stimulation of POMC neurons in mice fed an obesogenic diet (Aim 1) and chronic inhibition of POMC neurons in mice undergoing the activity-based anorexia behavioral assay (Aim 2) will be achieved using chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) technology. Adeno-associated virus technology will be used to deliver either stimulatory hM3Dq (Aim 1) or inhibitory hM4Di (Aim 2) DREADDs specifically to POMC neurons in the hypothalamus. Clozapine-n-oxide, an inert ligand that only activates DREADDs, will be administered to mice in discrete boluses via implantable, programmable microinfusion pumps. In addition to monitoring physiological endpoints such as bodyweight and food intake, RNAscope will be used to determine the degree of POMC neuron activation or inhibition. Immunohistochemistry will be used to verify adequate DREADD expression in POMC neurons. Altogether, this research proposal will determine whether chronic manipulation of POMC neurons will correct the food intake and bodyweight disturbances observed in rodent models of obesity and anorexia. In addition, the results of this proposal will be of value for future studies aimed at developing therapies for energy balance disorders.