Biology subjects

George, B. E.

Publications and source records attributed to George, B. E..

6 recordsLinked to original sources

bioRxiv2026

Chronic Intermittent Ethanol Exposure Produces Physiological Tolerance and Distinct Behavioral Alterations Across Abstinence in Female Mice

Chronic ethanol consumption produces long-lasting effects on the brain that contribute to persistent behavioral changes. This has been modeled in animals using the chronic intermittent ethanol (CIE) paradigm, which induces escalation of consumption and alterations in affective and cognitive behavior. While this model has been well characterized in male subjects, the effects of CIE in females and long-term effects that persist beyond the acute withdrawal remain relatively underexplored. Here, female C57BL/6J mice were exposed to four weeks of chronic intermittent ethanol (CIE) vapor to induce dependence. Following CIE, mice were evaluated for physiological tolerance to ethanol and alterations in anxiety-like behaviors and memory processing. Using the ethanol responsivity battery (ERB) assay to assess physiological tolerance, we found blunted responsiveness to the intoxicating effects of ethanol in the CIE-exposed females, indicating heightened ethanol tolerance that persists beyond the acute withdrawal phase. A cohort underwent behavioral testing following CIE to characterize changes in anxiety-like behavior, exploration, and memory across abstinence. In early abstinence (<5 days post-CIE), CIE-exposed females showed increased exploratory behavior compared with Air controls. After one week of abstinence, CIE-exposed females displayed impaired object recognition memory. CIE-exposed females also showed increased anxiety-like behavior at protracted abstinence time points, exhibiting hyponeophagia in the novelty-suppressed feeding test at 2 weeks post-CIE. In addition, following cued fear conditioning, we found reduced extinction recall at 4 weeks post-CIE. Together, this work indicates that chronic alcohol exposure leads to increased alcohol tolerance and distinct, persistent alterations in memory and anxiety-like behavior in female mice.

neuroscience↗

bioRxiv2026

ABEL: an active-learning behavior estimation and labeling platform

Detailed behavior analysis is essential for thorough characterization of ethologically relevant behaviors in model organisms, yet manual annotation of the full behavioral repertoire remains subjective, time intensive, and susceptible to observer error. Advances in machine learning have enabled high-throughput pose estimation on recorded video, but tools for behavior classification from pose and video data are still developing. Instead of hand-scoring every frame of video, experimenters can instead label a small subset of video frames and software trained through machine learning makes predictions on the rest. Here, we present an Active-learning Behavior Estimation and Labeling (ABEL) platform that uses clip-level active learning (i.e., human labeling of short video snippets) with multimodal features (pose, video, context/ROI) to train robust behavior classifiers. We rigorously validated ABEL-derived behavior predictions against expert human observers and field-standard automated software, across diverse rodent behavioral assays. Across eight assays and 45 behaviors, model training required 19.5 hours of human annotation in total, with the reviewer scoring ~8% of available video. Models trained in ABEL achieved a mean precision-recall area under the curve (PR-AUC - a 0-1 score of how well a model balances missed detections against false alarms, with 1 being perfect) of 0.90 (SD 0.09, range 0.60-0.99), with no association between performance and behavior prevalence (r = 0.20). This was aided by custom tools, Essence Extractor and UMAP Interactive Selection, for targeted discovery of high probability clips which reduce the clip review needed to find a rare behavior 6-fold relative to random sampling and 10-fold relative to labeling whole videos. As a biological validation, we assessed how ABEL-derived behaviors relate to underlying neuronal calcium dynamics. Behavior labels were tightly synced with neuronal signatures distinct from ambiguous behavior and randomly chosen, behavior-unrelated time windows (shuffle control). Together, these data indicate that ABEL provides an efficient platform for frame-precise classification of distinct ethologically relevant behaviors.

neuroscience↗

bioRxiv2026

Chronic oral fentanyl consumption produces dynamic behavioral adaptations during abstinence in female mice

RationaleThe opioid epidemic continues to be driven by synthetic opioids, particularly fentanyl, yet the long-term behavioral manifestations of withdrawal remain poorly characterized. Women exhibit unique vulnerabilities to opioid use disorder, including greater susceptibility to withdrawal-related symptoms and relapse, suggesting that defining the behavioral adaptations that emerge during prolonged fentanyl abstinence may identify mechanisms underlying female-specific relapse vulnerability. Thus, we used an oral fentanyl drinking model to longitudinally examine nociceptive, affective, and exploratory behaviors across chronic exposure and abstinence in female mice. MethodsAdult female C57BL/6J mice underwent a modified 5-week Drinking-in-the-Dark paradigm with 4-hour daily access to fentanyl (30 {micro}g/mL) or water. Somatic withdrawal was assessed following naloxone-precipitated withdrawal. Thermal and mechanical nociception, sucrose preference, exploratory behavior, acoustic startle, nest building, and locomotor activity were evaluated during fentanyl exposure and throughout one month of abstinence. ResultsFemale mice exhibited robust naloxone-precipitated somatic withdrawal, confirming physiological effects of opioid drinking. Chronic fentanyl exposure produced transient thermal hyperalgesia during weeks 2-4 of drinking that resolved by the final week, but re-emerged after 30 days of abstinence. After 30 days of abstinence, we also found increased mechanical sensitivity. During early abstinence, fentanyl-exposed mice exhibited increased sucrose consumption and greater exploration of anxiogenic environments without alterations in general locomotion. Increased exploratory behavior persisted into prolonged abstinence and was partially rescued in mice who previously received naloxone. Additionally, fDID mice exhibited impaired nesting behavior, while prior naloxone-precipitated withdrawal improved nest-building performance. ConclusionsWe demonstrate that chronic opioid exposure, precipitated withdrawal trials, and duration of abstinence interact to shape protracted withdrawal phenotypes in female mice that extend well beyond drug exposure. These results provide insight into persistent withdrawal symptoms that may shape relapse vulnerability using a novel translationally relevant framework.

neuroscience↗

bioRxiv2026

Divergent ethanol drinking phenotypes are linked to region-specific dysregulation of serotonin systems in the mouse brain

Excessive alcohol drinking is a leading cause of preventable death in the United States. High alcohol consumption and persistent drinking despite adverse events, also known as compulsive drinking, are key criteria that contribute to the development and progression of alcohol use disorder (AUD). There is a clear need to better understand the mechanisms that support these related but distinct behaviors. The serotonin (5-HT) system has been associated with alcohol consumption and risk of alcohol dependence, however given the complexity of this system, there remains much to discover regarding specific alcohol related phenotypes. The current study uses a combination of volitional home-cage drinking and operant conditioning to phenotype mice based on ethanol intake and persistence of alcohol drinking following quinine adulteration, a model to study compulsive drinking. Brain tissue of 10 regions known to be implicated in regulating executive function, reward, and stress was collected, and gene expression of serotonergic receptors, transporters, and enzymes was quantified. Three opioid receptors were included given their well-established roles in alcohol-related behaviors and interactions with the 5HT system. Region-specific gene expression patterns emerged, with serotonergic and opioid receptor expression differentially associated with alcohol drinking phenotype. 5-HT and opioid receptors displayed opposing directionality across regions, consistent with functional heterogeneity within the system. These findings identify region-specific molecular alterations following chronic alcohol that may contribute to individual differences in alcohol drinking phenotypes, highlighting candidate targets for biomarkers of increased alcohol use disorder susceptibility or as interventions aimed at preventing the progression of AUD.

neuroscience↗

bioRxiv2025

Selective dysregulation of serotonin dynamics in the anterior cingulate cortex and central amygdala following binge alcohol consumption

Serotonin (5HT) is a critical modulator of brain function and behavior that is dysregulated in alcohol use disorder (AUD). The anterior cingulate cortex (ACC) and central nucleus of the amygdala (CeA) play distinct roles in AUD and undergo functional changes in 5HT signaling following binge drinking, but our understanding of real-time 5HT dynamics in these structures is lacking. We hypothesized that binge drinking would elicit brain-region specific dysfunction in 5HT dynamics during appetitive and aversive stimuli processing. Using fiber photometry with the GRAB5HT sensor, we identified distinct reward and aversion 5HT signaling motifs in the ACC and CeA. Consumption of alcohol and other tastants elicited a suppression of GRAB5HT signal in the ACC and an increase in 5HT signal in the CeA. In contrast, aversive stimuli similarly increased 5HT in both structures. The effect of binge drinking on 5HT function was surprisingly non-uniform, producing brain-region, sex-, and stimulus-specific dysfunction in 5HT signaling that dramatically shifted across weeks of alcohol experience. This suggests that adaptations in 5HT signaling are specific to neural circuits underlying discrete functions. Optogenetically stimulating 5HT terminals in the ACC and CeA increased avoidance behavior without being overtly rewarding or aversive, and stimulating 5HT release in the ACC blunted alcohol drinking. Together, these data identify distinct 5HT reward and aversion signaling motifs in the ACC and CeA and highlight early binge drinking as a critical stage of 5HT adaptation and a potential window for therapeutic intervention.

neuroscience↗

bioRxiv2022

Heroin Self-Administration Induces Altered Dopamine Terminal Dynamics in the Nucleus Accumbens

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-hrs, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. After one day of withdrawal, male rats exhibited lower basal extracellular levels of dopamine as well as reduced dopaminergic responses to a heroin challenge (0.1 mg/kg/inf, IV). Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats have reduced stimulated dopamine release during tonic-like, single-pulse stimulations but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor activity was increased following heroin self-administration. These results reveal a marked low dopamine state following heroin-exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.

neuroscience↗