Biology subjects

Abrahao, K. P.

Publications and source records attributed to Abrahao, K. P..

8 recordsLinked to original sources

bioRxiv2026

External Globus Pallidus Arkypallidal Circuit Dynamics Gate Risk-Taking Behavior

Exploration allows animals to gather information and adapt to changing conditions. Yet, it also exposes them to potential threats, requiring neural systems that weigh uncertainty and regulate behavioral transitions between cautious and exploratory states. These computations are distributed across cortical and subcortical networks, including the basal ganglia, which integrate sensory, motivational, and contextual information to shape action-selection behaviors. Within this circuitry, the globus pallidus externa (GPe) occupies a central but underappreciated role. Once viewed as a relay between striatum and downstream nuclei, the GPe is gaining recognition as a dynamic regulator that integrates diverse inputs and exerts bidirectional control over motor and cognitive processes. Here, we examine arkypallidal NPAS1-expressing GPe (GPeNPAS1) neurons, which form preferential inhibitory projections to the striatal matrix. Chemogenetic manipulations and in vivo calcium measurement reveal that GPeNPAS1 activity modulates and encodes risk-taking behavior sequences, identifying a circuit mechanism by which the GPe can regulate adaptive decision-making in risky contexts.

neuroscience↗

bioRxiv2026

Chronic neuropathic pain alters reversal learning without generally impacting sucrose self-administration in mice

Chronic pain is associated with neuropsychiatric comorbidities characterized by impairments in cognitive and behavioral flexibility, yet the direct impact of chronic pain on reward-guided behavior remains poorly understood. Here, we investigated how chronic neuropathic pain altered sucrose-reinforced behavior across multiple behavioral assays with distinct cognitive-behavioral demands in male and female mice. Mice underwent spared nerve injury (SNI) or sham surgery and were tested in operant sucrose self-administration, reversal learning, and extinction training. The impact of acute painful stimulation on sucrose seeking was also assessed. SNI produced stable mechanical hypersensitivity without affecting acquisition or extinction of sucrose self-administration, indicating intact baseline acquisition and sucrose seeking. In contrast, chronic neuropathic pain selectively altered behavioral flexibility: SNI females exhibited faster acquisition of reversal learning, while SNI mice as a group showed impaired inhibition of responding on the previously reinforced lever during early reversal. Acute painful stimulation suppressed sucrose seeking in males, but not in females, independent of chronic pain status. At the neural level, painful mechanical stimulation differentially modulated medial prefrontal cortex (mPFC) activity, increasing infralimbic c-Fos expression in SNI mice while decreasing it in sham controls relative to non-stimulated animals. There was no evidence of chronic mPFC hyperactivity as indexed by {Delta}FosB expression. Together, these findings demonstrate that chronic neuropathic pain did not globally disrupt sucrose reward-related behavior, but instead selectively altered behavioral flexibility and pain-reward interactions in a sex-dependent manner, with accompanying alterations in mPFC engagement following aversive stimulation.

animal behavior and cognition↗

bioRxiv2026

Alcohol or stress exposure during late adolescence impairs risk assessment later in life, disrupting the ethological structure of behavior in mice

BackgroundDecision-making is a key component of adaptive behavior and relies on risk assessment as a critical process that enables organisms to evaluate threats before exploring potentially dangerous areas. During adolescence, this process is particularly vulnerable to disruption by external factors such as stress and substance use, potentially leading to changes in the structure of defensive and exploratory behaviors, potentially leading to riskier choices. MethodsWe investigated whether repeated ethanol intoxication or pharmacological stress during late adolescence (7-8 weeks of age) alters overall behavioral structure, focusing on risk assessment behaviors, in adulthood. Male and female C57BL/6 mice received four intermittent injections of saline, ethanol (4.0 g/kg), or the 2-adrenergic antagonist yohimbine (2.0 mg/kg). In early adulthood (9th week), animals were tested in the Light-Dark Box and Elevated Plus Maze. In addition to traditional anxiety-like behavior and exploratory measures, risk assessment behaviors (stretches and head outs) were classified as NoGo (risk evaluation without entering the aversive area) or Go (risk evaluation followed by exploration), and behavioral organization was examined using first-order Markov chain analyses. ResultsBoth ethanol and yohimbine exposure produced persistent reductions in NoGo risk assessment behaviors in adulthood, in both sexes, with minimal effects on classical anxiety-like measures. Correlation and transition probability analyses revealed a reorganization of behavioral structure, characterized by reduced transitions toward risk assessment events and a bias toward risk-taking actions. ConclusionsThese findings indicate that repeated late adolescent alcohol intoxication and stress exposure induce long-lasting alterations in risk assessment and decision-making strategies.

animal behavior and cognition↗

bioRxiv2025

The Role of Insular Anterior Parvalbumin GABAergic Interneurons in Impulsivity-Related and Alcohol-Seeking Behaviors

Alcohol use is a major global health concern, particularly during adolescence, a developmental period characterized by heightened impulsivity, a known risk factor for alcohol misuse. The insular cortex is critically involved in interoceptive processing and impulsivity regulation, and its activity is powerfully shaped by parvalbumin (PV)-expressing GABAergic interneurons. We hypothesized that developmental differences in PV interneuron activity within the insular cortex contribute to impulsivity-related behaviors and alcohol consumption. To investigate this, male C57BL/6 mice were assessed at two developmental stages: adolescence (postnatal day 28) and young adulthood (postnatal day 64). Impulsivity was measured using the Omission-Contingency Learning (OCL) task, while alcohol intake and preference were evaluated using a two-bottle choice paradigm. Adolescent mice displayed higher impulsivity and greater alcohol consumption than adults. Double immunofluorescence labeling (Fos+/NeuN+ and Fos+/PV+) showed that increased impulsivity was associated with reduced activation of PV interneurons in the insular cortex. Chemogenetic activation of PV interneurons in adult PV-Cre mice reduced impulsivity in the OCL task and decreased alcohol intake. These findings indicate that insular PV interneurons play a modulatory role in impulsive behavior and alcohol consumption, suggesting a potential therapeutic target for impulse-control and alcohol-use disorders.

neuroscience↗

bioRxiv2025

Impact of Repeated Heavy Ethanol Intoxication During Early Adolescence on Adult Anxiety-Like, Exploratory, Risk Assessment, and Drinking Behaviors in Mice

Exceeding binge-level drinking is common among adolescents and is associated with both short- and long-term adverse outcomes. This study evaluated the effects of repeated ethanol-induced intoxication during early adolescence on behavioral outcomes in early adulthood. Male and female C57BL/6J mice (5 weeks old) received intraperitoneal (i.p.) injections of either saline (control) or 3.2 g/kg ethanol (intoxicated). A subset of intoxicated mice had blood collected on days 1 and 4, confirming heavy intoxication ([~]289 mg/dL). At 9 weeks of age, animals were tested in the Light-Dark Box (LDB) and Elevated Plus Maze (EPM) immediately after receiving either saline or 1.2 g/kg ethanol. In the LDB, early adolescence intoxication did not affect anxiety-like behaviors but reduced risk assessment behaviors in males, indicating riskier decision-making. No pretest ethanol effect was observed. In the EPM, pretest ethanol produced an anxiolytic effect, accompanied by increased exploration and a reduction in risk-assessment behaviors, while adolescence intoxication did not yield significant effects. To better characterize behavioral organization beyond discrete measures, we applied Markov chain models to quantify first-order transition probabilities to and from risk-assessment states. This analysis revealed that pretest ethanol markedly reduced the complexity of behavioral structure, especially in the EPM, while adolescent intoxication had no detectable ethological effect. Finally, a separate cohort of controls and intoxicated mice underwent a two-bottle choice Intermittent Overnight Drinking protocol in adulthood. Adolescent ethanol intoxication increased voluntary ethanol intake in females but not in males. These findings highlight long-lasting and sex-specific consequences of early adolescent intoxication on risk-related behaviors and alcohol consumption.

animal behavior and cognition↗

bioRxiv2022

Distinct mechanisms of CB1 and GABAB receptor presynaptic modulation of striatal indirect pathway projections to mouse Globus Pallidus

Presynaptic modulation is a fundamental process regulating synaptic transmission. Striatal indirect pathway projections originate from A2A- expressing spiny projection neurons (iSPNs), targeting the globus pallidus external segment (GPe) and control the firing of the tonically active GPe neurons via GABA release. It is unclear if and how the presynaptic GPCRs, GABAB and CB1 receptors, modulate iSPN-GPe projections. Here we used an optogenetic platform to study presynaptic Ca2+ and GABAergic transmission at iSPN projections, using a genetic strategy to express the calcium sensor GCaMP6f or the excitatory channelrhodopsin (hChR2) on iSPNs. We found that P/Q-type calcium channels are the primary VGCC-subtype controlling presynaptic calcium and GABA release at iSPN-GPe projections. N-type and L-type VGCCs contribute to GABA release at iSPN-GPe synapses. GABAB receptor activation resulted in a reversible inhibition of presynaptic Ca2+ transients (PreCaTs) and an inhibition of GABAergic transmission at iSPN-GPe synapses. CB1 receptor activation did not inhibit PreCaTs while inhibiting GABAergic transmission at iSPN-GPe projections. CB1 effects on GABAergic transmission persisted in experiments where NaV and KV1 were blocked, indicating a VGCC- and KV1 independent presynaptic mechanism of action of CB1 receptors. Taken together, presynaptic modulation of iSPN-GPe projections by CB1 and GABAB receptors is mediated by distinct mechanisms. Key PointsP/Q-type are the predominant VGCC controlling presynaptic Ca2+ and GABA release on the striatal indirect pathway projections GABAB receptor modulate of iSPN-GPe projections via a VGCC- dependent mechanism CB1 receptors modulate iSPN-GPe projections via a VGCC- independent mechanism

neuroscience↗

bioRxiv2021

Sex-dependent changes in murine striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence

Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is known to be affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors, e.g., irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during withdrawal in a mouse chronic cannabis exposure model. Using a THC treatment regimen known to produce tolerance we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance inducing THC treatment. Sex differences were observed in nearly all metrics. Altered striatal DA release, sleep and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. To our knowledge these findings provide the first model of directly translatable non-precipitated cannabis withdrawal symptoms, in particular, sleep disruption.

neuroscience↗

bioRxiv2019

Alcohol Effects on Globus Pallidus Connectivity: Role of Impulsivity and Binge Drinking

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe - frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.

neuroscience↗