Sex Differences in Serotonin (5-HT) Activity During Safety Learning

Abstract

Patients with posttraumatic stress disorder (PTSD) often show impaired ability to discriminate between “danger” and “safety” cues. Women are more than twice as likely to be diagnosed with PTSD as compared to men; however, translational research has largely relied on the use of male subjects despite evidence of sex differences in fear-motivated behaviors. Serotonergic activity, originating in the dorsal raphe nucleus (DRN) of the central nervous system (CNS), has been found to modulate fear discrimination in males and may contribute to sex differences observed in a Pavlovian fear discrimination paradigm. In this study, male and intact female Sprague-Dawley rats were exposed to fear conditioning with (CS+/CS-) or without (CS+) a safe conditioned stimulus, then subsequently sacrificed for immunohistochemical analysis of serotonergic activity via quantification of tryptophan hydroxylase (TPH) and Fos in the DRN. Females exhibited more rapid and robust discrimination between the CS+ danger cue and CS- safety cue as compared to males. Regardless of condition, females had more double-labeled TPH+Fos cells compared to males, but males had larger variation in TPH+Fos expression compared to females. A parabolic function for TPH+Fos counts predicted fear discrimination in males, but not females, reinforcing the view that serotonin is a modulator of safety-related behavior in males.