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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.

The objective of this study was to evaluate whether juvenile fluoxetine (FLX) exposure induces long-term changes in baseline responses to anxiety-inducing environments, and if so, whether its re-exposure in adulthood would ameliorate this anxiety-like phenotype. An additional goal was to assess the impact of adolescent FLX pretreatment, and its re-exposure in adulthood, on serotonin transporters (5-HTT) and brain-derived-neurotrophic-factor (BDNF)-related signaling markers (TrkB-ERK1/2-CREB-proBDNF-mBDNF) within the hippocampus and prefrontal cortex. To do this, female C57BL/6 mice were exposed to FLX in drinking water during postnatal-days (PD) 35–49. After a 21-day washout-period (PD70), mice were either euthanized (tissue collection) or evaluated on anxiety-related tests (open field, light/dark box, elevated plus-maze). Juvenile FLX history resulted in a persistent avoidance-like profile, along with decreases in BDNF-signaling markers, but not 5-HTTs or TrkB receptors, within both brain regions. Interestingly, FLX re-exposure in adulthood reversed the enduring FLX-induced anxiety-related responses across all behavioral tasks, while restoring ERK2-CREB-proBDNF markers to control levels and increasing mBDNF within the prefrontal cortex, but not the hippocampus. Collectively, these results indicate that adolescent FLX history mediates neurobehavioral adaptations that endure into adulthood, which are indicative of a generalized anxiety-like phenotype, and that this persistent effect is ameliorated by later-life FLX re-exposure, in a prefrontal cortex-specific manner.

Background Anxiety disorders are the most common neuropathologies worldwide, but the precise neuronal mechanisms that underlie these disorders remain unknown. The hippocampus plays a role in mediating anxiety-related responses, which can be modeled in rodents using behavioral assays, such as the elevated plus maze. Yet, the molecular markers that underlie affect-related behavior on the elevated plus maze are not well understood. Methods We used herpes simplex virus vector delivery to overexpress extracellular signal-regulated kinase-2, a signaling molecule known to be involved in depression and anxiety, within the dorsal hippocampus of adult Sprague-Dawley male rats. Three days post virus delivery, we assessed anxiety-like responses on the elevated plus maze or general locomotor activity on the open field test. Results When compared to controls, rats overexpressing extracellular signal-regulated kinase-2 in the dorsal hippocampus displayed an anxiolytic-like phenotype, per increases in time spent in the open arms, and less time in the closed arms, of the elevated plus maze. Furthermore, no changes in locomotor activity as a function of virus infusion were observed on the open field test between the experimental groups. Conclusion This investigation demonstrates that virus-mediated increases of extracellular signal-regulated kinase-2 signaling, within the hippocampus, plays a critical role in decreasing anxiogenic responses on the rat elevated plus maze. As such, our data provide construct validity, at least in part, to the molecular mechanisms that mediate anxiolytic-like behavior in rodent models for the study of anxiety.

Ketamine has shown promising antidepressant efficacy for adolescent treatment-resistant depression. However, the potential enduring consequences of ketamine exposure have not been thoroughly evaluated. Thus, we examined if juvenile ketamine treatment results in long-lasting changes for the rewarding properties of sucrose and cocaine in adulthood, across three separate experiments. In Experiment 1, adolescent male and female C57BL/6 mice received ketamine (20 mg/kg) for 15 consecutive days (Postnatal Day [PD] 35–49). Twenty-one days later (PD70; adulthood) we examined their behavioral responsivity to sucrose (1%) on a two-bottle choice design, or cocaine (0, 5, 10 mg/kg) using the conditioned place preference (CPP) test. We found that juvenile ketamine-pretreatment increased preference for sucrose and environments paired with cocaine in male, but not female, adult mice. This long-term outcome was not observed when male and female mice received ketamine as adults (PD70-84) and tested for sucrose and cocaine preference 21-days later (Experiment 2). Similarly, in Experiment 3, no long-lasting differences in these measures were observed when adolescent male mice were exposed to concomitant ketamine and social stressors (PD35-44), namely the social defeat or vicarious defeat stress paradigms—procedures that mediated a depression-related phenotype (along with a ketamine antidepressant-like response). Collectively, we demonstrate that in the absence of physical or psychological stress, adolescent ketamine exposure increases later life preference for the rewarding properties of sucrose and cocaine in a sex- and age-specific manner. As such, this preclinical work provides awareness for the potential long-term behavioral consequences associated with juvenile ketamine exposure.

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.

Abstract There has been a disproportionate increase in fluoxetine (FLX) prescription rates within the juvenile population. Thus, we evaluated how adolescent FLX exposure alters expression/phosphorylation of proteins from the extracellular signal-regulated kinase (ERK)-1/2 cascade within the adult prefrontal cortex (PFC). Male Sprague-Dawley rats were exposed to FLX (20 mg/kg) for 15 consecutive days [postnatal day (PD) 35–49]. At PD70 (adulthood), we examined protein markers for ERK1/2, ribosomal S6 kinase (RSK) and mammalian target of rapamycin (mTOR). FLX-pretreatment decreased body weight, while increasing PFC phosphorylation of ERK1/2 and RSK, as well as total mTOR protein expression in adulthood. We provide first-line evidence that juvenile FLX pretreatment induces long-term decreases in body weight gain, along with neurobiological changes in the adult PFC—highlighting that early life antidepressant exposure increases ERK-related signaling markers in later life.

Anxiety-related illnesses constitute one of the leading causes of disability across the globe. Consequently, the need for validated preclinical models to uncover the etiology of anxiety phenotypes remains essential. Given the link between social stress experience and the manifestation of anxiogenic-like outcomes, we evaluated whether social defeat stress (SDS) reduces open-space exploratory behavior in prairie voles (Microtus ochrogaster). Thus, we exposed adult sexually-naïve male voles to 10 consecutive days of SDS episodes and evaluated responses to the anxiogenic environment of the light/dark box test or the elevated plus-maze, 24 hours later. We found that, when compared to non-stressed controls, SDS-exposed voles displayed longer latency to enter the light compartment of the light/dark box. Similarly, on the elevated plus-maze, SDS-exposed voles displayed decreases in the number of entries into the open arms, while spending more time in the closed arms of the maze. No differences in locomotor activity were noted between the experimental groups. Collectively, these data indicate that chronic SDS exposure induces anxiety-like responses in adult male prairie voles, thus, providing a preclinical model for the study of social stress-induced anxiogenic phenotypes.

Rationale Ontogenetic differences in the behavioral responsiveness to cocaine have often been attributed to the maturation of dopaminergic elements (e.g., dopamine transporters, D2 High receptors, receptor coupling, etc.). Objective The purpose of this study was to determine whether ontogenetic changes in cocaine pharmacokinetics might contribute to age-dependent differences in behavioral responsiveness. Methods Male and female neonatal (PD 5), preweanling (PD 10 and PD 20), and adult (PD 70) rats were injected (IP) with cocaine or saline and various behaviors (e.g., locomotor activity, forelimb paddle, vertical activity, head-down sniffing, etc.) were measured for 90 min. In a separate experiment, the dorsal striata of young and adult rats were removed at 10 time points (0–210 min) after IP cocaine administration. Peak cocaine values, cocaine half-life, and dopamine levels were determined using HPLC. Results When converted to percent of saline controls, PD 5 and PD 10 rats were generally more sensitive to cocaine than older rats, but this effect varied according to the behavior being assessed. Peak cocaine values did not differ according to age or sex, but cocaine half-life in brain was approximately 2 times longer in PD 5 and PD 10 rats than adults. Cocaine pharmacokinetics did not differ between PD 20 and PD 70 rats. Conclusions Differences in the cocaine-induced behavioral responsiveness of very young rats (PD 5 and PD 10) and adults may be attributable, at least in part, to pharmacokinetic factors; whereas, age-dependent behavioral differences between the late preweanling period and adulthood cannot readily be ascribed to cocaine pharmacokinetics.

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<0.05). 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.

Stress-induced illnesses, like major depression, are among the leading causes of disability across the world. Consequently, there is a dire need for the validation of translationally-suited animal models incorporating social stress to uncover the etiology of depression. Prairie voles (Microtus ochrogaster) are more translationally relevant than many other rodent models as they display monogamous social and parental behaviors and more primate-like neuroanatomy. Therefore, we evaluated whether a novel social defeat stress (SDS) model in male prairie voles induces depression-relevant behavioral outcomes. Adult sexually-naïve male prairie voles experienced SDS bouts from a conspecific pair-bonded male aggressor, 10 min per day for 10 consecutive days. Non-stressed controls (same-sex siblings) were housed in similar conditions but never experienced physical stress. Twenty-four hr later, voles were evaluated in social interaction, sucrose preference, and Morris water maze tests – behavioral endpoints validated to assess social withdrawal, anhedonia-related behavior, and spatial memory performance, respectively. SDS-exposed voles displayed lower sociability and body weight, decreased preference for a sucrose solution, and impairment of spatial memory retrieval. Importantly, no differences in general locomotor activity were observed as a function of SDS exposure. This study does not include female voles in the experimental design. We found that repeated SDS exposure, in male prairie voles, results in a depression-relevant phenotype resembling an anhedonia-like outcome (per reductions in sucrose preference) along with social withdrawal and spatial memory impairment – highlighting that the prairie vole is a valuable model with potential to study the neurobiology of social stress-induced depression-related outcomes.