Biological mechanisms of sleep and appetite through orexin and cannabinoid receptor interactions

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Background Despite decades of research, many questions remain about how sleep and appetite are regulated and connected in the brain. The hypothalamus is a brain region that coordinates these functions between the nervous and endocrine systems. The orexin and cannabinoid systems both modulate the activity of neurons in the hypothalamus. Orexins stimulate wakefulness and appetite via hypothalamic neurons, whereas cannabinoids supress wakefulness and stimulate appetite via hypothalamic and non-hypothalamic mechanisms. The purpose of this proposal is to explore the molecular and behavioural interactions between the overlapping orexin and cannabinoid systems. There are two orexin receptors - OX1 and OX2 - that are activated by the proteins orexin-A and -B to increase wakefulness and appetite. The cannabinoid receptor CB1R is activated by anandamide (AEA) and 2-arachidonoylglycerol (2-AG)andregulates wakefulness and appetite. OX1 and OX2 are present at high levels in the same neurons as CB1R. Because the location of these receptors overlap and receptor interactions alter function, understanding the co-dependency of these systems may lead to a better understanding of sleep and appetite. The functional and physical interactions among CB1R, OX1, and OX2, and the effects these interactions have on sleep and appetite require exploration. The hypothesis of my research is that the orexin and cannabinoid systems oppose each other to regulate wakefulness and co-operate to increase appetite through physical interactions. Objectives and Approach This proposal has 3 components: cell signaling, behaviour, and tissue analysis. Cell signaling-We will characterize interactions between OX1, OX2, and CB1R and receptor-dependent changes in cell signaling using assays already established in our laboratory.Behaviour -We will analyze sleep and appetite patterns in mice treated with drugs targeting the orexin and cannabinoid systems. Tissue analysis-We will determine where OX1, OX2, and CB1R physically interact in the mouse brain, and whether changes in receptor interaction occur following drug treatments.  Impact The research outlined in this proposal will provide critical information on the cross-talk between two receptor systems that regulate sleep and appetite using methods not previously applied to this field. Research into the biology of the endocannabinoid system is essential to understand the potential values, harms reduction considerations, and marketing policies of Cannabis. It is important that the scientific community work to establish the biological mechanisms by which sleep and appetite are regulated. This research will benefit researchers working in multiple disciplines; and be an important science-to-policy program to stakeholders understanding sleep, food consumption, and drug considerations for Cannabis. HQP trained in this program will be highly employable as they conduct research critical to basic science and policy.