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. Elucidating novel mechanisms by which resiliency factors prevent the transition from stress exposure to psychopathology could have broad implications for preventing and treating stress-related neuropsychiatric disorders. Here we will test the global hypothesis that the endogenous cannabinoid 2- arachidonoylglycerol (2-AG) is a stress resiliency factor that serves a homeostatic role buffering against the adverse behavioral consequences of stress exposure. 2-AG is a key mediator of retrograde synaptic suppression at central synapses via activation of type-1 cannabinoid receptors (CB1). Importantly, stress increases 2-AG levels in a key limbic anxiety circuit containing the prefrontal cortex (PFC) and amygdala where 2-AG signaling suppresses glutamate release. Importantly, we and others have recently shown that pharmacological augmentation of 2-AG signaling can prevent some stress-induced behavioral pathology whereas blocking CB1 receptors worsens the behavioral consequences of stress exposure. Although these data suggest a key role of 2-AG in anxiety modulation and stress adaptation, causal evidence supporting 2-AG signaling in anxiety modulation and stress adaptation is critically absent from the literature. To explicitly test the hypothesis that 2-AG is required for physiological anxiety modulation and stress adaptation we have generated constitutive and conditional mutant mice lacking the primary 2-AG synthetic enzyme diacylglycerol lipase ? (DAGL?). We will test for the first time the necessity and sufficiency of 2-AG signaling within the PFC- amygdala circuit in the regulation of stress adaptation using conditional DAGL? floxed mice and circuit-specific viral CRE injection, and a newly generated lentiviral-DAGL? overexpression system. We will test the hypothesis that 2-AG signaling serves to suppress reciprocal glutamatergic signaling within the PFC-amygdala circuit using ex vivo optogenetic electrophysiological approaches and neuronal activity imaging. If successful, these experiments will provide causal evidence for 2-AG signaling in modulation of anxiety and depressive behaviors and stress adaptation, and reveal circuit- and synaptic-level mechanisms by which 2-AG signaling buffers against the adverse behavioral consequences of stress exposure. Completion of pharmacological studies proposed herein will also validate 2-AG augmentation as a viable approach for the treatment of affective disorders including PTSD.
Mood and anxiety disorders are the most prevalent psychiatric illnesses, and exert substantial personal and economic burden worldwide. Existing treatments for affective illnesses are only partially effective. Here we aim to elucidate a role fo endogenous cannabinoid lipids in the regulation of mood, anxiety and stress responsivity with the ultimate goal of validating endogenous cannabinoid augmentation as a new approach to the treatment of mood and anxiety disorders.
