Prefrontal endocannabinoids, stress controllability and resilience: A hypothesis

Stressor exposure is a predisposing risk factor for many psychiatric conditions such as PTSD and depression. However, stressors do not influence all individuals equally and in response to an identical stressor some individuals may be vulnerable while others are resilient. While various biological and behavioral factors contribute to vulnerability versus resilience, an individual's degree of control over the stressor is among the most potent. Even with only one experience with control over stress, behavioral control has been shown to have acute and long-lasting stress-mitigating effects. This suggests that control both blunts the response to acute stress and prepares the subject to be resilient to future stressors. In this review, we first summarize the evidence which suggests the ventromedial prefrontal cortex (vmPFC) is a critical component of stressor controllability circuits and a locus of neuroplasticity supporting the acute and long-lasting consequences of control. We next review the central endocannabinoid (eCB) system as a possible mediator of short and long-term synaptic transmission in the vmPFC, and offer a hypothesis whereby eCBs regulate vmPFC circuits engaged when a subject has control over stress and may contribute to the encoding of acute stress coping into long lasting stressor resilience. •Control over stress protects against many consequences of the stressor.•Plasticity in prelimbic (PL) cortex underlies stress resilience.•Stress-induced endocannabinoids (eCB) in PL may contribute to resilience.•PL eCBs may select act/outcome circuits for top-down control of stress response.