Stress is a prevailing risk factor for mood-related illnesses, wherein women represent the majority of those affected by major depression. Despite the growing literature suggesting that affective ...disorders can arise after a traumatic event is vicariously experienced, this relationship remains understudied in female subjects at the preclinical level. Thus, the objective of the current investigation was to examine whether exposure to emotional and/or psychological stress (ES) mediates depression-related outcomes in female mice.
Female C57BL/6 mice (8 weeks old, null parity) vicariously experienced the defeat bout of a male conspecific, by a male CD1 aggressor, for 10 consecutive days. Twenty-four hours after the last stress exposure, female mice were tested in the social interaction, sucrose preference, tail suspension, or elevated plus maze tests. Furthermore, we examined whether ketamine and chlordiazepoxide, pharmacological agents used to treat mood-related disorders in the clinical population, would reverse the ES-induced social dysfunction.
When compared with control mice, female mice exposed to ES displayed decreased social behavior and preference for sucrose, along with increased immobility in the tail suspension test. Also, they displayed higher levels of blood serum corticosterone, as well as decreased body weight. Lastly, the ES-induced avoidance-like phenotype was ameliorated by both ketamine and chlordiazepoxide.
Our data indicate that female mice exposed to ES display a behavioral and physiologic profile that mimics symptoms of depression in the clinical population. As such, this experimental model may be adopted to examine vicarious stress-induced mood-related disorders, as well as pharmacological antidepressant response, in a sex-specific manner.
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.
The hippocampus mediates responses to affect-related behavior in preclinical models of pharmacological antidepressant efficacy, such as the forced swim test. However, the molecular mechanisms that ...regulate escape-directed behavior in this preclinical model of despair are not well understood. Here, using viral-mediated gene transfer, we assessed how overexpression of extracellular signal-regulated protein kinase (ERK)-2 within the dorsal hippocampus influenced behavioral reactivity to inescapable swimming stress in adult male Sprague-Dawley rats. When compared to controls, rats overexpressing hippocampal ERK-2 displayed increases in the time to initially adopt a posture of immobility, along with decreases in total time spent immobile, without influencing general locomotor activity. Collectively, the results indicate that hippocampal upregulation of ERK-2 increases escape-directed behavior in the rat forced swim test, thus providing insight into the neurobiological mechanisms that mediate antidepressant efficacy.
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.
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 bi-parental behaviors. 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 h 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.
•Social defeat stress decreases social behavior in adult male prairie voles•Social defeat stress decreases sucrose preference in adult male prairie voles•Social defeat stress impairs spatial memory in adult male prairie voles•Vole social defeat stress displays strong face validity as a model for the study of depression-related phenotypes
•Oral self-administration of the methamphetamine is possible with rats.•Both early and late adolescent nicotine exposure alter methamphetamine responding.•Female adolescent rats respond at higher ...rates for access to methamphetamine.
Adolescent nicotine exposure increases methamphetamine (MA) intake in adult male rats; however, little is known about how nicotine affects MA self-administration during the adolescent period. Therefore, we assessed whether exposing rats to nicotine during early or late adolescence affects oral MA self-administration.
146 male and female rats were treated with saline or nicotine (0.16 or 0.64 mg/kg) from postnatal day (PD) 25-PD 34 (the early exposure phase) and/or PD 35-PD 55 (the late exposure phase). Rats began an oral MA self-administration procedure on PD 35.
Only the sex variable, but not nicotine, affected sucrose and MA acquisition, as female rats had more nose pokes than males during training. On the test sessions, female rats exposed to nicotine (0.64 mg/kg) in the early exposure phase had more active nose pokes than saline-treated female rats or nicotine-treated male rats. Rats exposed to nicotine (0.16 mg/kg) in the late exposure phase had fewer active nose pokes during testing than rats exposed to saline. Nose poke responding during extinction was not altered by nicotine exposure, but administering nicotine (0.16 or 0.64 mg/kg) to male rats in the early exposure phase did decrease nose pokes during the drug-primed reinstatement session.
Our results show that adolescent female rats are more sensitive to the reinforcing effects of oral sucrose and MA than adolescent males, and that preadolescent nicotine exposure enhances oral MA self-administration in female rats. These findings suggest that preteen nicotine use may increase vulnerability to later MA abuse in teenage girls.
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.
•Adolescent fluoxetine history impairs spatial memory in adult male mice.•Adolescent exposure to fluoxetine does not influence spatial memory in adult female mice.•Adolescent exposure to fluoxetine ...does not impact episodic memory in adulthood.
Epidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance.
We exposed separate groups of adolescent (postnatal day PD 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM).
We found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 h after training. Conversely, 48 h post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX.
A limitation of this study is that normal adolescent mice (i.e., non-stressed) were evaluated for memory-related behavior three weeks after antidepressant exposure. Thus, it is possible that FLX pre-exposure in combination with animal models for the study of depression may yield different results.
Together, these results demonstrate enduring spatial memory-related deficiencies after pre-exposure to FLX during adolescence in male, but not female, C57BL/6 mice.
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