2-Arachidonoylglycerol signaling in anxiety, depression, and stress adaptation

Stress is a major risk factor for the development of mood and anxiety disorders and the causative agent in posttraumatic stress disorder (PTSD). Development of stress-related psychopathology is variable among individuals and involves complex interactions between susceptibility mechanisms favoring development of psychopathology and resiliency mechanisms protecting against the development of mental illness in the face of adversity. Understanding the molecular, cellular, and circuit-level mechanisms by which stress exposure is translated into affective pathology could have broad implications for understanding the pathophysiology of stress-related psychiatric disorders and for the development of novel treatment approaches. We propose to test the overarching hypothesis that the endogenous cannabinoid 2-Arachidonoylglycerol (2-AG) is a critical regulator of stress adaptation and propose to elucidate the synaptic and cellular mechanisms by which 2-AG signaling serves to mitigate pathological responses to stress exposure. We will first test the hypothesis that 2-AG signaling inhibits bi-directional excitatory coupling between the amygdala and ventral hippocampus, a neural circuit critical for mediating innate danger avoidance and generalization of learned fear responses. We will test the hypothesis that stress causes a functional collapse of 2-AG signaling within this circuit leading to synaptic strengthening, the generation of increased avoidance, and fear generalization. We will also test the hypothesis that stress exposure leads to increases in 2-AG release within distinct amygdala circuits in a neural activity-dependent manner using a novel virally encoded GPCR-based endocannabinoid biosensor. These studies will reveal, for the first time, the temporal dynamics and activity-dependent mechanisms mediating stress-induced endocannabinoid mobilization within amygdala circuits. Lastly, we will use in vivo single-cell calcium imaging approaches to test the hypothesis that 2-AG is required for the dynamic changes in neuronal ensemble representations to threat predictive cues that occur during fear learning, expression, generalization, and extinction. Taken together, these data will provide new mechanistic insight into how 2-AG signaling regulates stress-related biobehavioral processes relevant to neuropsychiatric disorders including PTSD and could reveal novel pathophysiological mechanisms contributing to the translation of stress exposure into affective pathology.