Thesis advisor: John P. Christianson / 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. / Thesis (BS) — Boston College, 2018. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Arts and Sciences Honors Program. / Discipline: Biology.

<p>Persistent and maladaptive fear in the absence of a threat can be disruptive because it decreases an organism’s opportunity to seek life-sustaining substances. Learned safety signaling can suppress fear and encourage reward-seeking behavior, thus freeing the organism from fear induced immobilization. The infralimbic (IL) region of the prefrontal cortex is important for recalling fear extinction memories and for suppressing fear via learned safety signals. Neurons in the IL show an excitatory response to an extinguished fear cue. We thus hypothesized that neurons in the IL would encode safety by showing an excitatory response during active fear suppression to a learned safety signal. </p> <p>To assess global changes in IL activity, we monitored IL multi-unit activity to different cues while training animals in a fear-reward-safety discrimination task (Sangha, Chadick, & Janak, 2013). During the discrimination task, male rats learned that the reward cue predicted liquid sucrose, the fear cue predicted footshock and the joint presentation of both the fear and safety cues resulted in no footshock. We also counterbalanced the modality of fear and safety cues (auditory vs visual) with two separate groups of animals to control for potential sensory modality effects. Male rats showed high levels of freezing to the fear cue, and significantly reduced levels of freezing to the combined fear+safety cue. Male rats also showed high levels of port activity to the reward cue. There was no significant difference in the learning rate between the two counterbalanced conditions. </p> <p>Our multi-unit-data showed an increase in IL neuronal firing to the fear+safety cue across training sessions. This effect was consistent between the two counterbalanced conditions. We also examined single-unit activity from all animals that received light as the safety cue (n=8). This allowed us to examine the population response profile with a subset of the total animals. Although not statistically significant, our preliminary single-unit data demonstrated a decrease in the percentage of neurons that showed an inhibitory response to the fear+safety cue, but no change in the percentage of neurons that showed an excitatory response to the fear+safety cue. There was also no change in the magnitude of averaged firing rate in fear+safety excitatory or inhibitory neurons across training. Taken together, the decreased inhibition of single-unit activity in the IL may drive the increased excitation in multi-unit activity in the IL during behavioral fear suppression to a safety signal. </p>