The role of cerebellar endocannabinoids in the reconsolidation and extinction of fear memory

One debilitating mental health problem among veterans is post-traumatic stress disorder (PTSD), which is an anxiety disorder and develops following the experience of life-threatening psychological trauma. A central feature of PTSD is a persistent, pervasive fear response after the threat is no longer present. This is caused by a failure to extinguish the fear memory, a process that involves learning that the stimulus is no longer associated with the aversive events. This is a form of inhibitory learning and produces a lasting decrease in the conditioned fear response (“extinction memory”). Extensive research has been conducted on the amygdala and medial prefrontal cortex (mPFC) . The knowledge gained from these studies has enabled the development of psychotherapeutic interventions that aim to attenuate fear memory by enhancing extinction. However nearly half of the patients do not respond to exposure therapy. This failure highlights the need to move beyond a traditional amygdala- and mPFC-focused investigation of extinction. The second approach is to disrupt the reconsolidation process. Consolidated memory can become transiently labile following reactivation trials and undergoes a reconsolidation process that re-stabilizes the fear memory. During this short window, memory can be disrupted. This offers a window of opportunity for reduce the original fear memory with amnestic agents as a treatment for PTSD. The cerebellum regulates emotional behavior and forms extensive reciprocal connections with cortical regions, including PFC. It is critically involved in both the consolidation and reconsolidation of fear memory. Our preliminary results show that inhibition of cerebellar Purkinje cell activity impaired extinction memory. We will test the hypotheses that reactivation reduces endocannabinoid signaling in the cerebellum to restabilize memory in Aim 1. Aim 2 will test whether extinction increases endocannabinoid signaling in the cerebellum and this is required for extinction memory. We will determine whether inhibition of a transcription factor that regulates an endocannabinoid degrading enzyme disrupts the reconsolidation of fear memory and facilitates extinction memory. Because the proposed study investigates a new mechanism underlying the regulation of endocannabinoid metabolism by reactivation and extinction, it could suggest a novel treatment strategy for PTSD and a new therapeutic target.