Biology subjects

Schuh, K. M.

Publications and source records attributed to Schuh, K. M..

4 recordsLinked to original sources

bioRxiv2026

Region-specific regulation of glucocorticoid and mineralocorticoid receptor signaling in a mouse model of oral contraceptive exposure

Combined oral contraceptives (OCs), containing synthetic estrogen and a progestin such as levonorgestrel (LVNG), are widely used, and up to 10% of users experience adverse mood states and increased depression risk. It is well-established that OCs modulate the hypothalamic-pituitary-adrenal (HPA) axis and blunt the cortisol responses to acute stress. This interaction with stress regulatory pathways is one mechanism by which OCs might impact mood. Here, we used a mouse model of OC exposure (ethinyl estradiol (EE) + LVNG) to investigate how OCs affect regulation of the diurnal CORT cycle and stress-related signaling in the dorsal and ventral hippocampus and paraventricular nucleus of the hypothalamus (PVN). We found that EE+LVNG did not alter basal corticosterone (CORT) levels, but impaired glucocorticoid receptor (GR) - mediated negative feedback in the dexamethasone suppression test. Molecular analyses revealed distinct, region-specific effects. In the dorsal hippocampus, EE+LVNG enhanced glucocorticoid receptor (GR)-dependent gene signaling and prolonged Fkbp5 induction. In the ventral hippocampus, EE+LVNG enhanced mineralocorticoid receptor (MR)-dependent signaling and reduced stress-induced corticotropin-releasing factor expression. In the PVN, EE+LVNG reduced MR expression and modulated MR-dependent signaling. Together, these findings demonstrate that chronic OC exposure disrupts GR- and MR-dependent regulation across stress-related brain regions and impairs glucocorticoid feedback, providing potential mechanisms by which OCs blunt stress responsivity, modify long-term HPA-axis function, and increase susceptibility or resilience to stress and depression.

neuroscience↗

bioRxiv2023

A mouse model of hormonal contraceptive exposure: depression, motivation, and the stress response

Hormonal contraceptives, including oral contraceptives (OCs), regulate hormonal cycles and broadly affect physiological processes, including stress responsivity. Whereas many users describe overall improved mood, up to 10% of OC users experience adverse effects, including depression and anxiety. Given the link between regulation of hypothalamic-pituitary-adrenal (HPA) axis, stress exposure, and risk for depression, it is likely that OC-effects on stress mediate increased risk or increased resilience to these disorders. In this study, we developed and characterized a tractable mouse model of OC exposure with which to identify the mechanisms underlying OC modulation of brain, behavior, and mood. Specifically, we aimed to determine whether translationally relevant doses of OC-hormones in mice mimic changes in stress responsivity observed in humans taking OCs and describe behavioral changes during OC exposure. Young adult female C57Bl/6N mice received daily ethinyl estradiol (EE) and levonorgestrel (LVNG) in 10% sucrose, EE and drospirenone (DRSP) in 10% sucrose, or 10% sucrose alone. Translationally relevant doses of EE+LVNG-exposure, but not EE+DRSP, suppressed the acute stress response, consistent with effects observed in human OC users. EE+LVNG caused a specific anhedonia-like effect, without broad changes in stress-coping behavior, other depression-like behaviors, or anxiety-like behaviors. The suppression of regular estrous cycling, together with the blunting of the corticosterone response to acute stress, demonstrate the utility of this model for future studies to identify the mechanisms underlying OC interactions with stress, motivation, and risk for depression.

neuroscience↗

bioRxiv2023

Sex, but not early life stress, effects on two-bottle choice alcohol drinking behaviors in mice

AbstractO_ST_ABSBackgroundC_ST_ABSIn humans, early life stress (ELS) is associated with an increased risk for developing both alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). We previously used an infant footshock model that produces stress-enhanced fear learning (SEFL) in rats and mice and increases aversion-resistant alcohol drinking in rats to explore this shared predisposition. The goal of the current study was to extend this model of comorbid PTSD and AUD to male and female C57BL/6J mice. MethodsAcute ELS was induced using 15 footshocks on postnatal day (PND) 17. In adulthood, alcohol drinking behavior was tested in one of three two-bottle choice drinking paradigms. In continuous access, mice were given 24 h access to 5% or 10% ethanol and water for five consecutive drinking sessions each. In limited access drinking in the dark, mice were given 2 h of access to 15% ethanol and water across 15 sessions 3 h into the dark cycle. In intermittent access, mice were presented with 20% ethanol and water Monday, Wednesday, and Friday, for four consecutive weeks. In a fifth week of intermittent access drinking, increasing concentrations of quinine (10 mg/L, 100 mg/L, and 200 mg/L) were added to the ethanol to test aversion-resistant drinking. Intermittent access drinking was tested with and without a period of adolescent drinking (PND 35). ResultsInfant footshock did not alter drinking in the continuous or limited access tasks. Adult consumption and preference were lower in the intermittent access task when adolescent drinking was included and there were ELS-induced differences in consumption of quinine-adulterated ethanol in females. ConclusionsOur results demonstrate that infant footshock followed by a period of adolescent drinking is a viable model of comorbid PTSD and AUD in rats and mice.

neuroscience↗

bioRxiv2022

Greater resistance to footshock punishment in female C57BL/6J mice responding for ethanol

BackgroundOne characteristic of alcohol use disorder (AUD) is compulsive drinking, or drinking despite negative consequences. When quinine is used to model such aversion-resistant drinking, female rodents typically are more resistant to punishment than males. Using an operant response task where C57BL/6J responded for ethanol (EtOH) mixed with quinine, we previously demonstrated that female mice tolerate higher concentrations of quinine in EtOH than males. Here, we aimed to determine if this female vulnerability to aversion-resistant drinking behavior is similarly observed when footshock punishment is used. MethodsMale and female C57BL/6J mice were trained to respond for 10% EtOH in an operant task on a fixed ratio 3 schedule. After consistent responding, mice were tested in a punishment session using either a 0.25 mA or 0.35 mA footshock. To assess footshock sensitivity, a subset of mice underwent a flinch, jump, vocalize test in which behavioral responses to increasing amplitudes of footshock (0.05 - 0.95 mA) were assessed. In a separate cohort of mice, males and females were trained to respond for 2.5% sucrose and responses were punished using a 0.25 mA footshock. ResultsMales and females continued to respond for 10% EtOH when paired with a 0.25 mA footshock. Females alone continued to respond for EtOH when a 0.35 mA footshock was delivered. Both males and females reduced responding for 2.5% sucrose when punished with a 0.25 mA footshock. Finally, footshock sensitivity in the flinch, jump, vocalize test did not differ by sex. ConclusionsFemales continue to respond for 10% EtOH despite a 0.35 mA footshock and this behavior is not due to differences in footshock sensitivity between males and females. These results suggest that female C57BL/6J mice are generally more resistant to punishment in an operant self-administration paradigm. These results add to the literature characterizing aversion-resistant alcohol drinking behaviors in females.

neuroscience↗