Role of 2-AG and stress in PFC output circuits gating appetitive behavior

Stress is a key risk factor that underlies the pathophysiology of several psychiatric disorders such as post- traumatic stress disorder (PTSD) and Major depressive disorder (MDD). Altered evaluation of reward/appetitive stimuli is a pivotal behavioral deficit that alters quality of life in patients suffering from stress-related disorders. The prefrontal cortex (PFC) is a neuroanatomical hub involved in the computation of reward cues and goal directed behavior. Projections from the prelimbic area (PL) of PFC to periaqueductal grey (PAG), Ventral tegmental area (VTa) and Nucleus Accumbens (NAc) form an important output triad influencing various aspects of approach and consumption of reward. 2-Arachidonoylglycerol (2-AG), a widely circulating endocannabinoid (eCB) is strongly implicated in stress induced alteration in the activity of PFC neuronal sub-populations in a circuit specific manner. We will utilize a combination of ethologically relevant quantitative behavioral approaches, in-vivo single cell calcium imaging in freely behaving animals and pharmacology to ask 1) Does 2-AG modulation differentially influence the projection-specific PFC neuronal activity implicated in reward evaluation and approach. 2), how does an acute exposure to stressful stimuli alter foraging behavior and the activity of these distinct projection-specific PFC ensembles 3) Can stress induced deficits in reward evaluation and procurement be reversed by selectively modulating 2-AG levels? Our preliminary data demonstrates that pharmacological 2-AG augmentation increases approach and consumption of reward in a neutral environmental setting. Additionally, in-vivo single cell calcium imaging shows that PAG projecting neurons in the PL selectively represent food approach and consumption and that 2-AG augmentation leads to suppression in the activity of this neuronal sub-set. Together these observations underline the importance and feasibility of the proposed study. Understanding how 2-AG drives stress induced pathological alterations of reward circuits may lead to the development of better therapeutic strategies to treat stress-related psychiatric disorders.