Biology subjects

Westbrook, S. R.

Publications and source records attributed to Westbrook, S. R..

6 recordsLinked to original sources

bioRxiv2026

Androgen depletion increases sensitivity to effort-related costs and alters mesoaccumbal circuit function in male mice

BackgroundAndrogen deficiency in males is associated with reduced motivation, fatigue, and decreased goal-directed behavior, yet the neural mechanisms underlying these changes remain poorly understood. Dopamine signaling within the nucleus accumbens (NAc) plays a central role in regulating effort-based decision making. Here, we tested the hypothesis that loss of testicular hormones alters mesoaccumbal dopamine function to increase sensitivity to effort-related costs. MethodsMale mice underwent orchiectomy (ORX) either before puberty onset or in adulthood. Effort-based decision making was assessed using a progressive ratio 1 closed economy (PR1-CE) task. Dopamine-related function was assessed using systemic haloperidol administration and high-performance liquid chromatography to measure dopamine and metabolites, while whole-cell recordings were used to assess intrinsic excitability of NAc spiny projection neurons (SPNs). ResultsORX increased sensitivity to effort costs, reflected by a shift toward energy-efficient responding while maintaining overall food intake. These behavioral changes were accompanied by reduced responsiveness to haloperidol. Postpubertal ORX increased dopamine content and reduced metabolite-to-dopamine ratios in the NAc, consistent with reduced dopamine turnover, whereas prepubertal ORX did not affect dopamine measures. Prepubertal ORX selectively reduced excitability of NAc core D1R+ SPNs, while postpubertal ORX increased excitability across both D1R+ and D1R- populations. ConclusionsAndrogen depletion increases effort cost sensitivity and is associated with alterations in mesoaccumbal circuit function. Although behavioral effects were similar following pre- or postpubertal ORX, distinct neurochemical and cellular adaptations were observed, suggesting developmental timing influences neural adaptations to androgen depletion. These findings provide insight into neural mechanisms linking androgen deficiency to motivational deficits.

neuroscience↗

bioRxiv2025

Chronic stress facilitates behavioral engagement and alters lateral habenula activity during flexible decision making in a sex-dependent manner

The ability to integrate feedback and flexibly adjust behavior under shifting environmental demands is required to optimize decision-making strategies. Clinical and preclinical data indicate that individuals with stress-related disorders and rodents exposed to chronic stress exhibit impaired behavioral flexibility. The lateral habenula (LHb) has emerged as a key brain region contributing to the effects of stress on cognitive performance. However, the extent to which the LHb is recruited to fine-tune decision-making strategies, as well as the impacts of chronic stress on LHb recruitment during task performance, remain largely unknown. To this end, we used a three-week model of chronic unpredictable stress (CUS) and performed in vivo fiber photometry to investigate Ca2+ transients in LHb neurons during an attentional set-shifting task in adult male and female Sprague Dawley rats (n=7-12/sex/group). We found that CUS exposure did not significantly impair behavioral flexibility. Rather, CUS-exposed rats made fewer omissions and exhibited shorter response latencies compared to controls, suggesting enhanced task engagement. We also observed sex differences in LHb Ca2+ activity. In control animals, we found that male rats showed stronger LHb signal prior to decision making, and greater activation following trial outcome than females. These differences were normalized by CUS, resulting in similar signaling patterns across sexes. Altogether, these findings reveal that chronic stress alters LHb activity in a sex-dependent manner without overtly impairing behavioral flexibility, thereby underscoring the importance of the LHb in decision making under stressful conditions. HighlightsO_LIChronic stress decreased response latency without impairing behavioral flexibility C_LIO_LIMale rats displayed greater inhibition of LHb activity prior to decision making C_LIO_LIChronic stress abolished sex differences in LHb activity during decision making C_LI

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bioRxiv2024

The effect of corticosterone on the acquisition of Pavlovian conditioned approach behavior is dependent on sex and vendor

Cues in the environment become predictors of biologically relevant stimuli, such as food, through associative learning. These cues can not only act as predictors but can also be attributed with incentive motivational value and gain control over behavior. When a cue is imbued with incentive salience, it attains the ability to elicit maladaptive behaviors characteristic of psychopathology. We can capture the propensity to attribute incentive salience to a reward cue in rats using a Pavlovian conditioned approach paradigm, in which the presentation of a discrete lever-cue is followed by the delivery of a food reward. Upon learning the cue-reward relationship, some rats, termed sign-trackers, develop a conditioned response directed towards the lever-cue; whereas others, termed goal-trackers, approach the food cup upon lever-cue presentation. Here, we assessed the effects of systemic corticosterone (CORT) on the acquisition and expression of sign- and goal-tracking behaviors in male and female rats, while examining the role of the vendor (Charles River or Taconic) from which the rats originated in these effects. Male and female rats from Charles River had a greater tendency to sign-track than those from Taconic. Administration of CORT enhanced the acquisition of sign-tracking behavior in males from Charles River and females from both vendors. Conversely, administration of CORT had no effect on the expression of the conditioned response. These findings demonstrate a role for CORT in cue-reward learning and suggest that inherent tendencies towards sign- or goal-tracking may interact with this physiological mediator of motivated behavior. HighlightsO_LIMale and female rats from Charles River exhibit more sign-tracking relative to those from Taconic. C_LIO_LICorticosterone increases the acquisition of sign-tracking in male rats from Charles River. C_LIO_LICorticosterone increases the acquisition of sign-tracking in female rats, regardless of vendor. C_LIO_LIThere is no effect of corticosterone on the expression of sign-tracking behavior in either male or female rats. C_LI

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bioRxiv2023

Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats

Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized {Delta}9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHC vapor dosing regimen that approximated CANTHC self-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC rats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHC self-administration as opposed to a sex difference in the effects of CANTHC vapor per se.

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bioRxiv2020

Effects of the GluN2B antagonist, Ro 25-6981, on extinction consolidation following adolescent- or adult-onset methamphetamine self-administration in male and female rats

Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing NMDA receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine (METH, 0.1 mg/kg/infusion i.v.) beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by fourteen sessions with long access (6 h). Subsequently, rats underwent four daily 30-min extinction sessions with immediate post-session injections of either a GluN2B antagonist (Ro25-6981; 6 mg/kg, i.p.) or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH priming injection, with females displaying greater reinstatement than males. These results do not support our a priori hypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to excessive METH-taking, while sex confers vulnerability to relapse to METH-seeking.

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bioRxiv2019

Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory deficits in rats

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.

neuroscience↗