Choi, Doo‐Sup

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.

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.

Alcohol use disorder (AUD) represents an extensive global issue for disease and premature death. One facet of AUD is impulsivity, which is defined as a predisposition toward rapid, unplanned reactions to internal or external stimuli with decreased regard to the negative consequences of these reactions. Due to the potentially harmful consequences associated with impulsive decision making, impulsivity is considered an endophenotype for developing addictive behaviors. Interestingly, the dorsal hippocampus (dHip) has been revealed as an area of interest in addictive behaviors. The dHip is an important brain region involved in regulating behavioral adaptability and learning. Aberrant dHip function has been shown to contribute to impulsive and addictive behaviors. Differential reinforcement of low rates of behavior (DRL) schedules have demonstrated that the hippocampus is implicated in reward acquisition and impulsivity in humans and rodent models. Reward‐seeking induced impulsivity is thought to be driven via contextual recollection of drug‐induced euphoria to environmental cues, a process known to be regulated by the dHip. Our lab has previously demonstrated that adenosine A 2A receptor and ERK‐driven impulsive behavior potentiates hippocampal neuroblast proliferation. However, the fate of these precursor cells and the precise role of ERK signaling in conjunction with impulsive reward‐seeking remain unknown. Here, we demonstrate that DRL‐mediated impulsive reward‐seeking with the 2‐choice reaction time task (2‐CSRTT) increase the number of BrdU labeled cells in the dHip dentate gyrus. Our results also show a significant increase in colocalization of BrdU + and the neuronal marker NeuN + in impulsive animals compared to untrained controls. These results suggest that increased impulsivity may drive neuronal differentiation indicating potential regulation of the neurogenic process. Support or Funding Information This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, the Golby Foundation, the Sands Family, David Lehr Research Award from American Society for Pharmacology and Experimental Therapeutics, and National Institute on Alcohol Abuse and Alcoholism (AA018799). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Aging and other cardiovascular risk factors are associated with increased incidence of Alzheimer's disease (AD). A common feature of cardiovascular risk factors is decreased endothelial nitric oxide (NO). We studied the effect of a loss of endothelial NO on amyloid precursor protein (APP) related phenotype in aged (14–15 month) endothelial nitric oxide synthase deficient (eNOS −/− ) mice. APP, β‐site APP cleaving enzyme 1, and amyloid beta (Aβ) levels were significantly higher in the brains of aged eNOS −/− mice as compared to aged wild type mice. APP and Aβ 1–40 were increased in hippocampal tissue of eNOS −/− mice as compared to wild type mice. Aged eNOS −/− mice displayed an increased inflammatory phenotype as compared to aged wild type mice. Importantly, aged eNOS −/− mice performed worse in a radial arm maze test of spatial learning and memory as compared to aged wild type mice. These data suggest that chronic loss of endothelial NO may be an important contributor to both Aβ related pathology and cognitive decline. Research was supported by NIH grants HL‐111062 and HL‐91867, the Mayo Alzheimer's Disease Research Center (Z.S.K.), AHA scientist development grant (0835436N, A.V.S.), AHA postdoctoral fellowship 12POST8550003 (S.A.A.), Clinical Pharmacology Training Grant (T32 GM08685) (Trainee S.A.A.), the Samuel Johnson Foundation for Genomics of Addiction Program at Mayo Clinic (D.‐S.C.) and the Mayo Foundation.