5-HT2C receptors in the BNST modulate contextual fear conditioning without affecting acute ELS-enhanced fear learning in adult rats

Abstract

Abstract: Background/Objectives: Rodents provide a useful translational model of fear- and anxiety-related behaviors. Previously stressed animals exhibit physiological and behavioral stress responses that parallel those observed in anxious humans. Patients diagnosed with posttraumatic stress disorder (PTSD) present with a spectrum of debilitating anxiety symptoms that result from exposure to one or more traumatic events, with women having increased vulnerability for diagnosis; however, the mechanisms of this increased vulnerability remain unknown. PTSD involves a complex network of highly interconnected brain regions, including the bed nucleus of the stria terminalis (BNST). The precise circumstances that engage the BNST and the neural mechanisms that mediate its involvement in PTSD are not fully known. Serotonin (5-HT) release into the BNST yields increased expression of both fear and anxiety, specifically through 5-HT2C receptor signaling. Methods: Here, we investigated whether BNST 5-HT2C receptor signaling is necessary for the stress-enhancement of adult contextual fear learning that is observed in animals previously exposed to acute early life stress. Rats received 0 or 15 footshocks on postnatal day 17, an established model of stress-enhanced fear learning (i.e., SEFL). In adulthood, rats received bilateral infusions of vehicle, a 5-HT2C receptor antagonist (RS-102221), or a 5-HT2C receptor agonist (MK-212) into the BNST 15 minutes prior to 1-footshock contextual fear conditioning in a novel context. The next day, rats were returned to the fear conditioning context to assess their fear memory (freezing). Results: BNST infusions of RS-102221 reduced contextual fear conditioning, independent of aELS condition and sex. Infusions of MK-212 had no effect. Conclusions: Taken together, these data suggest that serotonergic signaling through 5-HT2C receptors in the BNST contribute to contextual fear conditioning, but not SEFL.