Citations

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.

Chemotherapy-induced cognitive impairment (CICI) has emerged as a significant medical problem without therapeutic options. Using the platinum-based chemotherapy cisplatin to model CICI, we revealed robust elevations in the adenosine A 2A receptor (A 2A R) and its downstream effectors, cAMP and CREB, by cisplatin in the adult mouse hippocampus, a critical brain structure for learning and memory. Notably, A 2A R inhibition by the Food and Drug Administration–approved A 2A R antagonist KW-6002 prevented cisplatin-induced impairments in neural progenitor proliferation and dendrite morphogenesis of adult-born neurons, while improving memory and anxiety-like behavior, without affecting tumor growth or cisplatin’s antitumor activity. Collectively, our study identifies A 2A R signaling as a key pathway that can be therapeutically targeted to prevent cisplatin-induced cognitive impairments.

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. Several key factors play a crucial role in AD including Aβ accumulation, intracellular neurofibrillary tangles accumulation, and neuronal loss (specifically in the dentate gyrus of the hippocampus). Neurofibrillary tangles have been long associated with the neuronal loss in the dentate gyrus. Of note, Aβ accumulation plays an important role in the impairment of neurogenesis, but recent studies started to shed a light on the role of APP gene expression on the neurogenesis process. In this review, we will discuss the recent approaches to neurogenesis in Alzheimer disease and update the development of therapeutic methods.

Background and Purpose Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. Experimental Approach We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. Key Results Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. Conclusion and Implications These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

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.