The ability to control the onset, offset or intensity of a stressor is one of the most important factors in determining the physiological and psychological consequences of the stressor. Across species, control over stress leads to resilience while uncontrollable stressors predispose one to psychiatric disease. Control over stress operates via a neural circuit that includes the ventromedial prefrontal cortex (vmPFC). In published and pilot studies we have established that control over stress increases the intrinsic excitability of the vmPFC and propose to test here the role of endogenous cannabinoids (eCBs) in this phenomenon. eCBs are known to alter vmPFC excitability by modulation of local inhibitory interneurons. Our working hypothesis that the experience of control over stress triggers eCB release which blunts activity of GABAergic interneurons within the vmPFC leading to stress resilience. This project incorporates a study of sex differences in stress coping mechanisms, which will help fill the massive gap in our understanding of stress and resilience in women. In a set of discovery experiments we seek to quantify eCB levels in the vmPFC after controllable or uncontrollable stress using LC-MS/MS and quantify prefrontal GABAergic inhibitory activity using acute slice electrophysiology and immunuohistochemistry. The prediction is that controllable stress elevates eCBs, reduces GABAergic synaptic transmission and GABAergic neuronal activation. In mechanistic studies we will knock down or elevate vmPFC eCBs by targeting the eCB degredation enzymes using a combination of viral overexpression and pharmacology. By combining these manipulations with exposure to controllable or uncontrollable stress we can determine whether eCBs are necessary and sufficient for stress resilience in later behavioral tests of social anxiety and fear.
The medial prefrontal cortex mediates stress coping, one of most important psychosocial factors in determining resilience to stress. Using a multi-level approach we will test the interaction of sex and a novel mechanism of prefrontal activation during stress coping: endogenous cannabinoids. The results will lay a foundation for development of sex-specific treatments for PTSD and depression.
