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Bender, B. N.

Publications and source records attributed to Bender, B. N..

6 recordsLinked to original sources

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↗

Stress-coping behavior during predator odor exposure is associated with differences in decision making

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are chronic psychiatric disorders that have overlapping symptomology and risk factors, including altered motivation and impulsive behavior. Inescapable exposure to a predator odor stressor (2,3,5-Trimethyl-3-Thiazoline (TMT)) produces PTSD-like symptomology in rats. Individual differences in stress-coping behaviors such as freezing and defensive digging during TMT exposure can predict long-term differences in alcohol-related behaviors and altered neurobiology. Here, we sought to evaluate the relationship between stress coping behavior during TMT exposure and different aspects of decision making. In Experiment 1, male and female rats were trained on an adjusting-amounts delay discounting task, and delay discounting curves were established before and >2 weeks after TMT exposure. In Experiment 2, female rats were trained to self-administer alcohol and sucrose in a concurrent choice procedure. Lever responses and preference for alcohol over sucrose were evaluated before and >2 weeks after TMT exposure, and then motivation for competing reinforcers was evaluated using progressive ratios. Active coping (digging) during TMT exposure was correlated with increased post-TMT impulsive choice (Experiment 1), reduced sucrose lever responses both before and after TMT exposure (Experiment 2), and reduced sucrose lever breakpoint (Experiment 2). Additionally, TMT-exposed rats had increased motivation for both alcohol and sucrose self-administration when available concurrently (Experiment 2). Overall, these findings suggest that behavior prior to and during a stressful experience can predict susceptibility to negative effects on decision making, which may help future studies identify the neurobiology underlying risk for aberrant reward-related behaviors after a traumatic event.

neuroscience↗

Xylazine potentiates the interoceptive effects of fentanyl in male and female rats

RationaleXylazine, a sedative typically used in veterinary medicine, has been increasingly detected as an adulterant in the unregulated opioid supply and present in opioid overdose deaths. Therefore, xylazine-adulterated fentanyl is a growing public health concern. People who use drugs have reported that xylazine changes and prolongs the effects of fentanyl ObjectivesWe used standard operant drug discrimination procedures to better understand how xylazine impacts the discriminative stimulus/interoceptive effects of fentanyl. MethodsMale and female Long-Evans rats (n=23) were trained to discriminate fentanyl (0.032 mg/kg intraperitoneal) such that one lever was reinforced with sucrose on days when fentanyl was administered, and the other lever was reinforced when vehicle was administered. Once rats met testing criteria, we tested a dose range of fentanyl to confirm discriminative stimulus control, then we tested if xylazine alone produced fentanyl-like effects and if the addition of xylazine to fentanyl impacted fentanyl interoceptive effects. ResultsStimulus control was confirmed, as rats showed increased percent responses on the fentanyl-appropriate lever as well as decreased response rates for increasing doses of fentanyl. Xylazine alone did not substitute for the stimulus effects of fentanyl but produced similar response rate reductions as fentanyl alone. Xylazine co-administered with fentanyl potentiated the stimulus effects of lower doses of fentanyl in both males and females and potentiated response rate reductions. ConclusionsThese results indicate that xylazine enhances the interoceptive effects of fentanyl, which may inform clinical research about xylazine-adulterated fentanyl.

neuroscience↗

The persistent effects of predator odor stressor enhance interoceptive sensitivity to alcohol through GABA-A receptor adaptations in the prelimbic cortex in male, but not female rats

BackgroundTraumatic stress is associated with high rates of problematic alcohol use, but how the persistent effects of trauma impact sensitivity to alcohol remain unknown. This study examined the persistent effects of traumatic stress exposure on sensitivity to alcohol and underlying neurobiological mechanisms in rats. MethodsMale (N=98) and female (N=98) Long-Evans rats were exposed to the predator odor TMT, and two weeks later, molecular, neuronal, and behavioral sensitivity to alcohol were assessed. Next, rats were trained to discriminate alcohol from water (male N=70; female N=56), and the impact of TMT on interoceptive sensitivity to alcohol and the alcohol-like effects of systemic GABAA receptor activation were evaluated. Lastly, functional involvement of GABAA and NMDA receptors in the prelimbic cortex (PrL) and the anterior insular cortex (aIC) was investigated. ResultsTMT exposure sex-dependently altered PrL Gabra1, and elevated aIC Grin2b and Grin2c in males. TMT increased PrL c-Fos in males, which was attenuated by alcohol administration. Alcohol-induced locomotor and startle response effects were attenuated in the TMT group in both sexes. TMT exposure potentiated interoceptive sensitivity to alcohol in males but not in females, and this effect was driven by GABAA receptors in the PrL. Greater stress reactivity during TMT exposure was associated with higher interoceptive sensitivity to alcohol, and alcohol exposure history was linked to a heightened stress response to TMT in males. ConclusionsTraumatic stress increased interoceptive sensitivity to alcohol in males, but not females, through PrL GABAA receptor adaptations, potentially enhancing the stimulatory, and by extension the rewarding, effects of alcohol.

neuroscience↗

Changes in dorsomedial striatum activity mediate expression of goal-directed vs. habit-like cue-induced cocaine seeking

A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking when drug seeking is goal-directed but not habitual. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habitual cue-induced cocaine seeking and how it is impacted by cue extinction. Rats trained to self-administer cocaine paired with an audiovisual cue on schedules of reinforcement that promote goal-directed or habitual cocaine seeking had different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium and dopamine responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habitual behavior and the DLS are unaffected.

neuroscience↗

Intermittent cocaine self-administration has sex-specific effects on addiction-like behaviors in rats

Intermittent access (IntA) models of cocaine self-administration were developed to better model in rodents how cocaine is used by human drug users. Compared to traditional continuous access (ContA) models, IntA has been shown to enhance several pharmacological and behavioral effects of cocaine, but few studies have examined sex differences in IntA. Moreover, no one has examined the efficacy of cue extinction to reduce cocaine seeking in the IntA model, which has previously shown to be ineffective in other models that promote habit-like cocaine seeking. Therefore, rats were implanted with jugular vein catheters and dorsolateral striatum (DLS) cannulae and trained to self-administer cocaine paired with an audiovisual cue with ContA or IntA. In subsets of rats, we evaluated: the ability of Pavlovian cue extinction to reduce cue-induced drug seeking; motivation for cocaine using a progressive ratio procedure; compulsive cocaine taking by pairing cocaine infusions with footshocks; and dependence of drug-seeking on DLS dopamine (a measure of habit-like behavior) with the dopamine antagonist cis-flupenthixol. Overall, cue extinction reduced cue-induced drug seeking after ContA or IntA. Compared to ContA, IntA resulted in increased motivation for cocaine exclusively in females, but IntA facilitated more compulsive cocaine taking exclusively in males. After 10 days of IntA training, but not fewer, drug-seeking was dependent on DLS dopamine most notably in males. Our results suggest that IntA may be valuable for identifying sex differences in the early stages of drug use and provide a foundation for the investigation of the mechanisms involved. Highlights- IntA promotes increased motivation for cocaine in females - IntA augments compulsive cocaine self-administration in males - IntA promotes DLS dopamine-dependent cocaine seeking, most notably in males - Cue extinction overall reduces cue-induced drug seeking after ContA or IntA - Under IntA, females self-administer more cocaine when in estrous

neuroscience↗