Increased mGlu5 mRNA expression in BLA glutamate neurons facilitates resilience to the long- term effects of a single predator scent stress exposure.

Abstract

Post-traumatic stress disorder (PTSD) develops in a subset of individuals exposed to a trauma with core features being increased anxiety, and impaired fear extinction. To model the heterogeneity of PSTD behavioral responses, we exposed Sprague-Dawley rats to predator scent stress (TMT) once for 10 minutes and then tested for anxiety-like behavior 7 days later using the elevated plus-maze and acoustic startle response. Rats displaying anxiety-like behavior in both tasks were classified as stress-Susceptible, and rats exhibiting behavior no different from unstressed Controls were classified as stress-Resilient. Our previous findings revealed increased mRNA expression of mGlu5 in the amygdala and PFC and CB1R mRNA in the amygdala of Resilient rats. Here, we performed fluorescent in situ hybridization (FISH) to determine the subregion and cell-type-specific expression of these genes in Resilient rats. We found higher mRNA expression of mGlu5 in the BLA, IL, and PL, and CB1R in the BLA of Resilient rats relative to Controls. Using dual-labeled FISH we determined that mGlu5 and CB1R mRNA increases were limited to vGlut+ cells. To test the necessity of mGlu5 receptor activity for attenuating contextual fear, intra-BLA infusions of the mGlu5 negative allosteric modulator MTEP were administered prior to context re-exposure. MTEP increased contextual fear on the day of administration, which extinguished over the course of two additional un-drugged sessions. These results suggest that an enhanced mGlu5 expression within BLA glutamate neurons contributes to the behavioral flexibility observed in stress-Resilient animals by facilitating a capacity for extinguishing contextual fear associations.