Prelimbic 2-arachidonoylglycerol in the regulation of fear memory specificity

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that develops following exposure to a traumatic event. In PTSD, patients may experience generalization of their fear responses even to otherwise safe stimuli leading to the decline in their quality of life. Understanding the mechanisms for pathological fear generation and anxiety may lead to development of better treatments for PTSD. The endocannabinoid (eCB) system is a retrograde neurotransmitter system that has been implicated in regulating fear and anxiety. Particularly, 2-arachidonoylglycerol (2-AG), one of the major centrally active eCB lipids, is thought to mediate resiliency to traumatic experiences as well as aspects of fear learning including expression and extinction. Here we aim to test the hypothesize that 2-AG may be involved in regulating fear generalization. We will utilize a combination of viral, genetic, and single cell in vivo calcium imaging approaches to address 1) whether 2-AG signaling in prelimbic prefontal cortex is required for the specificity of fear memories and 2) how PL neurons encode fear memory specificity and how this process is disrupted when 2-AG signaling is impaired. Our preliminary data indicate that pharmacological inhibition of 2-AG synthesis facilitates cue and contextual fear generalization and that discrete prefrontal cortex neural populations code for conditioned stimulus responses supporting the premise and feasibility of the proposed project. Determining how fear generalization emerges leading to loss of the ability to discriminate between safe and dangerous stimuli and how this process is fine-tuned by 2-AG could pave the way towards novel treatments for PTSD.