Long-Term Effects Of Juvenile Ketamine And/or Social Stress Exposure On Spatial Memory Performance In C57bl/6 Mice

Ketamine is administered to manage major depressive disorder in adolescent patients. However, the long-term effects of juvenile ketamine exposure on memory-related tasks have not been thoroughly assessed. Thus, we examined whether exposure to ketamine, psychological stress, or both, results in long-lasting alterations in spatial memory in C57BL/6 mice. Furthermore, we evaluated how ketamine and/or psychological stress history influenced hippocampal protein kinase b¬–mammalian target of rapamycin (AKT-mTOR)-related signaling, since this molecular cascade is associated with ketamine’s acute/fast-acting antidepressant properties. Male and female postnatal day (PD)-35 mice underwent 10-days of vicarious defeat stress (VDS), a form of psychological stress, with or without ketamine exposure (20 mg/kg/day; PD35-44). Later in adulthood (PD70) mice were assessed for spatial memory performance by adopting a water maze task or were euthanized for hippocampal tissue collection. Juvenile pre-exposure to ketamine or VDS, individually, increased the latency (sec) to locate the escape platform in adult male, but not female, mice. However, juvenile history of concomitant ketamine and VDS exposure prevented spatial memory impairment in adulthood. Furthermore, individual ketamine or VDS pre-exposure, unlike their combined history, resulted in long-term decreases of AKT-mTOR signaling within the hippocampus of male mice. Conversely, in female mice, ketamine pre-exposure alone increased hippocampal AKT-mTOR signaling. Our preclinical model demonstrates that ketamine, as a prophylactic treatment for adolescent psychological stress-induced sequalae, does not lead to long-term changes in spatial memory. However, juvenile recreational ketamine misuse, like psychological stress history, results in long-term spatial memory deficits, along with alterations of hippocampal AKT-mTOR signaling, in a sex-specific manner

Ketamine Pre-Exposure Does Not Influence Later-Life Responses to Reward-Related Stimuli in Female C57BL/6 Mice

Preclinical work indicates that exposure to traditional antidepressant medications, in adolescent and adult female subjects, alters reward-related behavior later in life. In recent years, the anesthetic ketamine (KET), now used as a fast-acting antidepressant, has shown promising therapeutic efficacy for the management of depression. However, the potential long-term behavioral consequences of KET exposure across development have not been thoroughly assessed. Thus, to address this issue, we examined if KET exposure, during adolescence or early adulthood, results in enduring alterations in responsivity to the rewarding properties of sucrose and cocaine later in life. Specifically, female C57BL/6 mice were randomly assigned to receive repeated intraperitoneal injections of KET (0 [vehicle; VEH] or 20 mg/kg) for 15 consecutive days during the adolescent (postnatal day [PD] 35-49), or early adult (PD70-84) stage of development. Twenty-one days after KET or VEH exposure, female mice (PD70+ or PD105+, respectively) were assessed on their reactivity to a sucrose solution (1%) adopting a two-bottle choice procedure, or cocaine (0, 5, or 10 mg/kg) using the conditioned place preference test, two well-established measures of reward-seeking behavior. We found that 21-days post KET exposure, female mice spent significantly higher time in the cocaine-paired chamber (p\u3c0.05). However, KET pre-exposure, either during adolescence (PD35-49) or early adulthood (PD70-84), did not influence the preference magnitude for sucrose or cocaine 21-days later (PD70+ and PD105+, respectively). Collectively, our data suggest that exposure to KET does not induce long-term changes to reward-related stimuli, in female C57BL/6 mice

Extrahypothalamic oxytocin neurons drive stress-induced social vigilance and avoidance.

Oxytocin increases the salience of both positive and negative social contexts and it is thought that these diverse actions on behavior are mediated in part through circuit-specific action. This hypothesis is based primarily on manipulations of oxytocin receptor function, leaving open the question of whether different populations of oxytocin neurons mediate different effects on behavior. Here we inhibited oxytocin synthesis in a stress-sensitive population of oxytocin neurons specifically within the medioventral bed nucleus of the stria terminalis (BNSTmv). Oxytocin knockdown prevented social stress-induced increases in social vigilance and decreases in social approach. Viral tracing of BNSTmv oxytocin neurons revealed fibers in regions controlling defensive behaviors, including lateral hypothalamus, anterior hypothalamus, and anteromedial BNST (BNSTam). Oxytocin infusion into BNSTam in stress naïve mice increased social vigilance and reduced social approach. These results show that a population of extrahypothalamic oxytocin neurons plays a key role in controlling stress-induced social anxiety behaviors