Sex differences in fear expression and persistence in an animal model of Post-Traumatic Stress Disorder.

Post-Traumatic Stress Disorder (PTSD) is a complex psychiatric condition arising from traumatic experiences, marked by abnormal fear memories. Despite women are twice as likely as men to develop PTSD, the biological mechanisms underlying this disparity remain inadequately explored, particularly in preclinical studies involving female subjects. Previous research shows that female rats exhibit active fear responses, while males display passive behaviors. Additionally, sex differences in ultrasonic vocalizations (USVs) during fear conditioning have been observed, indicating varying emotional responses. Here, we validated a traumatic stress model consisting of footshock exposure paired with social isolation - originally developed in male rats - on females for the first time, focusing on sex differences in fear memory expression, retention and extinction. Our findings reveal that only during trauma exposure, males predominantly exhibited passive responses, whereas females demonstrated more active responses, despite both sexes emitting similar numbers of alarm USVs. Females also showed lower levels of freezing and USV emissions throughout extinction sessions and displayed a higher extinction rate compared to males. Notably, only males displayed a conditioned fear response when triggered by a single mild stressor. These findings highlight sex differences in trauma responses and fear memory processes. The study emphasizes the importance of incorporating 22-kHz USV evaluations along with other behavioral metrics for a comprehensive understanding of fear memory. This research contributes to the existing literature on traumatic stress models as well as underscores the necessity of including female subjects in preclinical studies to better inform treatment and prevention strategies tailored to both sexes.

Sex-dependent Effects of the Drugs of Abuse Amphetamine and the Smart Drug 3,4-Methylenedioxypyrovalerone on Fear Memory Generalization in Rats.

In recent years there has been an increase in the development of new synthetic drugs, among which the "bath salt" 3,4-methylenedioxypyrovalerone (MDPV), a psychostimulant with a mechanism of action similar to those of cocaine and amphetamine, stands out. Drugs of abuse have been consistently shown to affect memory function in male rodents. We have recently shown that amphetamine and MDPV induce generalization of fear memory in an inhibitory avoidance discrimination task in male rats. Although abuse of illicit drugs is more prevalent in men than in women, several studies have demonstrated that females are more vulnerable to the effects of drugs of abuse than males and the effects caused by substance dependence on memory in females are still under-investigated. Thus, we examined the effects of subchronic amphetamine or MDPV administrations on memory in a contextual fear conditioning/generalization paradigm in adult male and female rats. Animals were given daily subchronic injections of the drugs, starting 6 days prior to the beginning of the behavioral procedures until the end of the paradigm. On day 1 of the experimental protocol, all rats were exposed to a safe context and, the day after, to a slightly different chamber where they received an unsignaled footshock. Twenty-four and forty-eight hours later, freezing behavior and emission of 22 kHz-ultrasonic vocalizations (USVs) were measured in the two different contexts to assess fear memory retention and generalization. Our results indicate that MDPV treatment altered freezing in both sexes, USVs were affected by amphetamine in males while by MDPV in females.

Sex-divergent long-term effects of single prolonged stress in adult rats.

Single prolonged stress (SPS) is an experimental model that recapitulates in rodents some of the core symptoms of post-traumatic stress disorder (PTSD). Although women have a two-fold greater risk to develop PTSD, most preclinical studies have been carried out in males. Furthermore, the long-term effects of behavioral alterations induced by SPS have been rarely investigated. Here, we evaluated the long-term effects of SPS on PTSD-relevant behavioral domains in rats and whether these effects were sex-dependent. To this aim, separate cohorts of male and female adult rats were subjected to SPS and, 30 days later, long-term effects were assessed. We found that SPS exposure reduced locomotor activity in both sexes in an open field task. Males only showed increased anxiety-like behavior in the elevated plus maze and marble burying tests, enhanced acoustic startle response and impaired spatial memory retention while females were unaffected. SPS exposure did not alter auditory fear memory dynamics in males, but it did alter extinction retrieval in females. We provide the first evidence that SPS reproduces long-term emotional alterations in male, but not in female, rats which were observed 30 days following trauma exposure, thus resembling some of the hallmark symptoms of PTSD. Furthermore, our results show for the first time a long-term SPS-induced alteration of cued fear extinction in females. Our findings are relevant to future research on trauma-related disorders and may help develop sex-specific interventions to treat PTSD.