Endocannabinoid Regulation of Homeostatic Feeding

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To maintain optimal biological conditions for survival, energy balance within an organism is a tightly regulated homeostatic process where deprivation of food, or loss of energy stores, will promote food intake to ensure that appropriate energy reservoirs are present. This homeostatic regulation of feeding is heavily dependent upon discrete cell populations within the hypothalamus that respond to changes in metabolic hormones and nutritional status to promote food-seeking behaviour and ingestion. That being said, the mechanisms subserving how dynamic changes in energy status modulate neural activity within these hypothalamic cell networks are not entirely understood. One candidate system that has gained increasing interest with respect to its ability to link these processes is the endocannabinoid (eCB) system. The eCB system was first identified as the biological target through which THC, the psychoactive constituent of cannabis, exerted its effects on brain function and behaviour. Given the appetite stimulating effects of THC, it is not surprising that eCB signaling itself has proven to be an important regulator of feeding behaviour. Converging evidence in the field demonstrates the importance of eCB signaling in the regulation of feeding, but the "how" and the "where" by which eCB signaling influences homeostatic feeding is not well established. This Discovery grant will test the hypothesis that dynamic changes in eCB signaling, within discrete hypothalamic nuclei and cell types, in response to changes in nutritional status are mediated by peripheral metabolic hormones and drive homeostatic shifts in food consumption. The approach taken by my lab is creative and unique, and utilizes a combination of sophisticated pharmacological, viral and biochemical approaches. Through the objectives proposed in this grant we will determine the cell types and nuclei within the hypothalamus through which eCB signaling modulates homeostatic feeding. More so, we will also determine the specific mechanism by which peripheral hormonal signals, which convey information regarding energy reserves and nutritional status to the brain, alter eCB signaling to govern ingestive behaviour. The diversity of the methodologies employed within this research program functions as an ideal avenue for the training of highly qualified personnel, from undergraduate to postdoctoral. Importantly, this work will fill knowledge gaps in our understanding of the neurobiology of feeding behaviour and help consolidate our understanding of how eCB signaling contributes to the homeostatic control of feeding.