Choi, Doo-Sup

Abstract The external globus pallidus (GPe) has traditionally been viewed as a relay nucleus within the basal ganglia (BG), but accumulating evidence indicates a more dynamic role in reinforcement learning (RL). One key characteristic of GPe activity—transient pauses in high-frequency discharge (HFD) neurons—is preserved across species, yet its potential implications in RL remains unclear. Here, we developed a neurophysiologically grounded computational model to investigate the origin and role of GPe pauses in RL. Our model successfully replicated a range of empirical observations, including pause dynamics during learning and cue-related activity modulation. We demonstrated that the GPe-subthalamic nucleus (STN) circuit functions analogously to a denoising autoencoder, modulating baseline excitability in downstream BG circuits and that GPe pauses emerge as circuit-level consequences of strong, convergent inhibition from the GPe to STN. Simulations and in vivo recordings revealed that the activity of GPe-STN projecting neurons increases following sudden environmental changes, promoting adaptive exploration by disrupting action value contrast. Intriguingly, this same configuration impairs performance with extended training, suggesting that habitual behavior may benefit from weakened GPe-to-STN projections. These findings provide a unifying framework for understanding GPe pause dynamics and highlight circuit-level distinctions supporting the balance between flexibility and proficiency in RL.

AbstractBackgroundWorkforce engagement can provide structure, income, feelings of accomplishment, and personal contacts, growing an individual's recovery capital (RC). Employed individuals are also more likely to complete addiction treatment. We sought to investigate whether changes in employment status from alcohol treatment admission to discharge correlated with changes in alcohol use frequency over those time points.MethodsThe Treatment Episode Dataset—Discharges (2017–2021) provided the data. Employment status (full‐time, part‐time, unemployed, and not in labor force) and alcohol use frequency (daily use, some use, and no use in past month) were assessed at treatment admission and discharge. Changes in alcohol use frequency during treatment were recorded as Reduction or No reduction. Logistic regression using reduced alcohol use frequency as the dependent variable included employment status at admission and discharge separately. A second analysis included employment status at both admission and discharge and their interaction term. An adjusted model included all covariates (race, ethnicity, age, education, and referral source), with its results being used to derive the marginal probabilities of reduced alcohol use frequency.ResultsThere were 856,085 alcohol treatment admissions over the 5 years, with 221,724 (25.9%) first admissions. Transitioning from not in the labor force or unemployed to full‐time saw the largest percentage of encounters decreasing alcohol use frequency: 71.9% (95% CI: 70.0–73.7) and 69.3% (95% CI: 68.1–70.5), respectively. Those remaining unemployed had the lowest reduction at 26.7% (95% CI: 26.3–27.1), with a sample reduction of 42.7% (95% CI: 42.5–42.9) overall. Far more people (60.4%) completed treatment within the Reduction group than in the No reduction group (30.2%).ConclusionsFindings suggest that improving employment status may be relevant for reducing alcohol use frequency. This aligns with past work showing overall improved health outcomes with lower unemployment levels. Incorporating vocational training and workforce engagement activities into outpatient treatment may help augment traditional approaches to improve an individual's RC.

Abstract The dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors, while the dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors. In this study, we sought to investigate two pathways, direct medium spiny neuron (dMSN) and indirect medium spiny neuron (iMSN) in the two dorsal striatal subregions (DMS and DLS) in ethanol-seeking and drinking behaviors. Here, we selectively ablated iMSN DMS→GPe and iMSN DLS→GPe and trained mice to exhibit goal-directed and habitual reward-seeking behaviors using random ratio (RR) and random interval (RI) operant conditioning, respectively. We found that partial ablation of iMSN DLS→GPe exhibited increased resilience to bitter-tasting ethanol solution when subjected to quinine adulterated reward in operant conditioning paradigms, suggesting compulsive-like seeking behavior. Consistently, in a separate cohort of mice, we found that the iMSN DLS→GPe ablated mice show higher preference and consumption of quinine adulterated ethanol solution than control mice in two-bottle choice continuous access drinking, with increasing quinine concentration and exhibit more compulsive-like behavior. On the other hand, ablation of iMSN DMS→GPe resulted in insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior but no change in compulsive ethanol-seeking and drinking behavior. Together, our findings demonstrate that DLS iMSN function is essential in inhibiting compulsive-like behavior.

AbstractThis critical review summarizes the current state of omics‐based biomarkers in the alcohol research field. We first provide definitions and background information on alcohol and alcohol use disorder (AUD), biomarkers, and “omic” technologies. We next summarize using (1) genetic information as risk/prognostic biomarkers for the onset of alcohol‐related problems and the progression from regular drinking to problematic drinking (including AUD), (2) epigenetic information as diagnostic biomarkers for AUD and risk biomarkers for alcohol consumption, (3) transcriptomic information as diagnostic biomarkers for AUD, risk biomarkers for alcohol consumption, and (4) metabolomic information as diagnostic biomarkers for AUD, risk biomarkers for alcohol consumption, and predictive biomarkers for response to acamprosate in subjects with AUD. In the final section, the clinical implications of the findings are discussed, and recommendations are made for future research.

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Most GABAergic neurons synthesize GABA from glutamate and release it in the synaptic cleft in the CNS. However, astrocytes can also synthesize and release GABA, activating GABA receptors in the neighboring neurons in physiological and pathological conditions. As the primary homeostatic glial cells in the brain, astrocytes play a crucial role in regulating GABA homeostasis and synaptic neurotransmission. Accumulating evidence demonstrates that astrocytic GABA dysregulation is implicated in psychiatric disorders, including alcohol use disorder (AUD) and major depressive disorder (MDD), the most prevalent co-occurring psychiatric disorders. Several current medications and emerging pharmacological agents targeting GABA levels are in clinical trials for treating AUD and MDD. This review offers a concise summary of the role of astrocytic GABA regulation in AUD and MDD. We also provide an overview of the current understanding and areas of debate regarding the mechanisms by which astrocytes regulate GABA in the CNS and their potential significance in the molecular basis of AUD and MDD, paving the way toward future research directions and potential therapeutic target areas within this field.

An imbalance in goal-directed and habitual behavioral control is a hallmark of decision-making–related disorders, including addiction. Although external globus pallidus (GPe) is critical for action selection, which harbors enriched astrocytes, the role of GPe astrocytes involved in action-selection strategies remained unknown. Using in vivo calcium signaling with fiber photometry, we found substantially attenuated GPe astrocytic activity during habitual learning compared to goal-directed learning. The support vector machine analysis predicted the behavioral outcomes. Chemogenetic activation of the astrocytes or inhibition of GPe pan-neuronal activities facilitates the transition from habit to goal-directed reward-seeking behavior. Next, we found increased astrocyte-specific GABA (γ-aminobutyric acid) transporter type 3 (GAT3) messenger RNA expression during habit learning. Notably, the pharmacological inhibition of GAT3 occluded astrocyte activation–induced transition from habitual to goal-directed behavior. On the other hand, attentional stimuli shifted the habit to goal-directed behaviors. Our findings suggest that the GPe astrocytes regulate the action selection strategy and behavioral flexibility.

Abstract The external globus pallidus (GPe) guides action selection. However, it remains elusive how diverse GPe cells engage in routine formation while learning action sequences in repetitive reward-seeking conditioning. Here, we investigated the Ca2+ signals of GPe cells during routine formation. We found that the dynamics of astrocytes and prototypic neurons’ activities are associated with the refinement of the action sequence, which enables cost-effective reward-seeking.

Abstract The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual reward-seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant reward-seeking. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe◊DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation reduced habitual seeking-behaviors, which was blocked by systemic D1R agonism. Our findings reveal a novel role of this arkyGPe◊DLS circuit in constraining habitual reward-seeking, which is relevant to addictive behaviors and other compulsive disorders.

Abstract The external globus pallidus (GPe) is an integrative hub and gateway for behavioral flexibility in reward-related behaviors. However, it remains unknown whether enriched astrocytes in the GPe guide behavioral flexibility. Here, we trained mice to exhibit goal-directed and habitual reward-seeking behaviors using the behavior tasks with effort- and time-based reward delivery, respectively. Then, we examined the temporal dynamics of GPe astrocytes during goal-directed and habitual learning. Overall, GPe astrocytes were substantially silenced during habitual learning compared to goal-directed learning. In the timescale of action events, GPe astrocyte activities were increased immediately after termination of reward-taking behavior before the following action. However, during habitual learning, the increase of astrocyte activity was not evident. Moreover, support vector machine (SVM) analysis demonstrated that GPe astrocytes dynamics predicted whether mice perform goal-directed or habitual behaviors. Interestingly, chemogenetic activation of GPe astrocytes, which dampened GPe neuronal firings and habitual behaviors, exhibting goal-directed behaviors. Strikingly, brief and repeated attentional stimulations recapitulated the effect of chemogenetic activation of GPe in intervening the habitual reward-seeking behaviors with increased GPe astrocyte activities. Our findings reveal a novel insight that increasing GPe astrocytic activities attenuates habitual behavior and improves behavioral flexibility, which may provide a potential therapeutic target for decision-making-related disorders, such as obsessive-compulsive disorder and addiction.