Sex differences in long-term fear and anxiety-like responses to deep brain stimulation in a preclinical model of PTSD

Abstract

Deep brain stimulation (DBS) is currently being investigated in patients and preclinical models of posttraumatic stress disorder (PTSD), but differences in behaviour according to sex remain elusive. We exposed female and male rats to fear conditioning and extinction. Thereafter, animals were treated with ventromedial prefrontal cortex DBS, followed by a battery of tests to measure fear and anxiety-like behaviour. As in our prior work, animals with high freezing scores during extinction (weak extinction; WE) were segregated from those with lower freezing scores (non-weak extinction; nWE), since the former population was previously shown to develop prolonged fear and anxiety-like responses. Vaginal lavages were collected after fear extinction to study the estrous cycle. After the experiments, brains were processed for the measurement of estrogen (ER) and progesterone receptors (PR) in the hypothalamus and hippocampus. We found that DBS-treated males had a more pronounced reduction in freezing than females during all recall sessions. In females, DBS induced an anxiolytic-like effect in the open field, while a reduction in the latency to feed during novelty suppressed feeding was noticed in both sexes. Noteworthy, a reduction in freezing during recall and anxiolytic-like responses following DBS were observed in males of all phenotypes, but only in nWE females. While no effect of the estrous cycle was noticed on fear memory, DBS-treated females in metestrus/diestrus during extinction had a more prominent response in the elevated plus maze. A similar expression of ERα, ERβ and PRβ in the hypothalamus and hippocampus was found in DBS-treated females and controls.