Developmental Role of Endocannabinoid Neurotransmission in Reward Learning

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The endocannabinoid system within the brain consists of retrograde messengers and their receptors; this system suppresses both excitatory and inhibitory transmission, thereby acting as a regulator of synaptic transmission and plasticity. Endocannabinoid signaling within the brain mediates a variety of behaviours ranging from social reward to reward and fear learning to decision-making. Research conducted in our laboratory will revolve around understanding the neurobiological sequelae of endocannabinoid modulation as it relates to reward learning in mammals, especially in the context of ontogenetic fluctuation in endocannabinoid signalling. Fundamental research into how developmental fluctuations in endocannabinoid signalling interact with exogenous modulation (e.g., due to genetic variation, stress etc.,) to impact behavior and learning is important to further our understanding of the basal role of these systems, and how they help to integrate environmental exposures. The long-term objective of this research program is to understand the long-lasting behavioural and brain circuit activity sequelae of both endogenous (e.g., genetic variation in receptor or enzyme function) and exogenous (e.g., stress, social rejection, cannabinoid exposure) endocannabinoid modulation during critical developmental periods, and the causal neural underpinnings of these consequences. For the upcoming 5-year period, my trainees and I will pharmacologically manipulate endocannabinoid signaling during adolescence, which is a critical period for endocannabinoid fluctuations, to study the behavioural and brain circuit changes arising from these manipulations. We hypothesize that manipulation of endocannabinoid signaling during adolescence will produce long-term changes in reward learning through altering corticolimbic circuitry. In objective 1, we will test the effects of selective pharmacological agonism or inverse agonism of either CB1Rs or CB2Rs during different phases of adolescence on instrumental and Pavlovian conditioning with food reward in adulthood. In objective 2, we will test the effects of pharmacological inhibition of the metabolizing enzymes FAAH and MAGL during adolescence on instrumental and Pavlovian conditioning in adulthood. In objective 3, in vivo electrophysiological recordings from brain reward circuitry will be performed in adulthood after adolescent endocannbinoid manipulation, and potential correlations with behavioural changes (in instrumental and Pavlovian learning) will be assessed. The research program proposed here is timely, innovative, and likely to increase our understanding of the fundamental role endocannabinoid signaling plays in our brain's response to genetic and environmental factors during development. In addition, this research will provide a vehicle for much needed training in behavioural neuropharmacology and electrophysiology to the highly qualified personnel, enriching Canada's workforce and improving scientific literacy.