External globus pallidus input to the dorsal striatum regulates habitual seeking behavior in male mice.

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 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 conditioning. 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 globally reduced seeking behaviors, which was blocked by systemic D1R agonism. Our findings reveal a role of this arkyGPe→DLS circuit in constraining habitual seeking in male mice, which is relevant to addictive behaviors and other compulsive disorders.

Astrocyte activities in the external globus pallidus regulate action-selection strategies in reward-seeking behaviors.

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.

A novel monobactam lacking antimicrobial activity, MC-100093, reduces sex-specific ethanol preference and depressive-like behaviors in mice.

Several ß-lactam derivatives upregulate astrocytic glutamate transporter type 1expression and are known to improve measures in models of mood and alcohol use disorders (AUD) through normalizing glutamatergic states. However, long-term, and high doses of ß-lactams may cause adverse side effects for treating mood disorders and AUD. Studies suggest that MC-100093, a novel ß-lactam lacking antimicrobial activity, rescues GLT1 expression. Thus, we sought to investigate whether MC-100093 improves affective behaviors and reduces voluntary ethanol drinking. We intraperitoneally administered MC-100093 (50 mg/kg) or vehicle once per day to C57BL/6J male and female mice (8-10 weeks old) over 6 days. We employed the open field test and the elevated plus maze to examine the effect of MC-100093 on anxiety-like behaviors. We assayed MC-100093's effects on depressive-like behaviors using the tail suspension and forced swim tests. Next, utilizing a separate cohort of male and female C57BL6 mice, we assessed the effects MC100093 treatment on voluntary ethanol drinking utilizing the 2-bottle choice continuous access drinking paradigm. After screening and selecting high-drinking mice, we systematically administered MC-100093 (50 mg/kg) or vehicle to the high-drinking mice over 6 days. Overall, we found that MC-100093 treatment resulted in sex-specific pharmacological effects with female mice displaying reduced innate depressive-like behaviors during the tail suspension and force swim testing juxtaposed with male treated mice who displayed no changes in tail suspension and a paradoxical increased depressive-like behavior during the forced swim testing. Additionally, we found that MC100093 treatment reduced female preference for 10% EtOH during the 2-bottle choice continuous access drinking with no effects of MC100093 treatment detected in male mice. Overall, this data suggests sex-specific regulation of innate depressive-like behavior and voluntary EtOH drinking by MC100093 treatment. Western blot analysis of the medial prefrontal cortex and hippocampus revealed no changes in male or female GLT1 protein abundance relative to GAPDH.

Adenosine receptors: Emerging non-opioids targets for pain medications.

Physical and emotional pain deteriorates the quality of well-being. Also, numerous non-invasive and invasive treatments for diagnosed diseases such as cancer medications and surgical procedures cause various types of pain. Despite the multidisciplinary approaches available to manage pain, the unmet needs for medication with minimal side effects are substantial. Especially with the surge of opioid crisis during the last decades, non-opioid analgesics may reduce life-threatening overdosing and addictive liability. Although many clinical trials supported the potential potency of cannabis and cannabidiol (CBD) in pain management or treatment, the long-term benefits of cannabis or CBD are still not evident. At the same time, growing evidence shows the risk of overusing cannabis and CBD. Therefore, it is urgent to develop novel analgesic medications that minimize side effects. All four well-identified adenosine receptors, A1, A2A, A2B, and A3, are implicated in pain. Recently, a report demonstrated that an adenosine A1R-specific positive allosteric modulator (PAM) is a potent analgesic without noticeable side effects. Also, several A3R agonists are being considered as promising analgesic agent. However, the importance of adenosine in pain is relatively underestimated. To help readers understand, first, we will summarize the historical perspective of the adenosine system in preclinical and clinical studies. Then, we will discuss possible interactions of adenosine and opioids or the cannabis system focusing on pain. Overall, this review will provide the potential role of adenosine and adenosine receptors in pain treatment.

N6-substituated adenosine analog J4 attenuates anxiety-like behaviors in mice.

RATIONALE: Withdrawal from chronic alcohol exposure produces various physical and mental withdrawal symptoms. Activation of adenosine receptors is known to inhibit withdrawal-induced excitation. However, limited studies investigate how adenosine analogs may prove helpful tools to alleviate alcohol withdrawal-related affective behaviors. OBJECTIVES: This study aimed to investigate the effects of J4 compared with saline using the mice vapor or voluntary ethanol drinking model on behavioral endpoints representing ethanol-withdrawal negative emotionality commonly observed during abstinence from chronic alcohol use. METHODS: We subjected C57BL/6 J mice to chronic intermittent ethanol (CIE) exposure schedule to investigate how 72-h withdrawal from alcohol alters affective-like behavior. Next, we determined how treatment with J4, a second-generation adenosine analog, influenced affective behaviors produced by alcohol withdrawal. Finally, we determined how J4 treatment alters voluntary ethanol drinking using the two-bottle-choice drinking paradigm. RESULTS: Our results show that 72-h withdrawal from chronic intermittent ethanol exposure produces limited affective-like disturbances in male C57BL/6 J mice exposed to 4 cycles ethanol vapor. Most importantly, J4 treatment irrespective of ethanol exposure decreases innate anxiety-like behavior in mice. CONCLUSIONS: Withdrawal from chronic intermittent ethanol exposure and subsequent behavioral testing 72 h later produces minimal affective-like behavior. J4 treatment did however reduce marble-burying behavior and increased time spent in open arms of the elevated plus maze, suggesting J4 may be useful as a general anxiolytic.

Implication of Adult Hippocampal Neurogenesis in Alzheimer's Disease and Potential Therapeutic Approaches.

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 Aß 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, Aß 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.

Novel Behavior of the 2019 Novel Coronavirus With Invasion of the Cardiac Conduction System in the Young.

We report the case of a 35-year-old man (an oil engineer) referred as a coronavirus disease-2019 (COVID-19) case with heart block and a four-day history of headache and fever. The patient was hemodynamically stable with normal respiratory effort and oxygen saturation. Three consecutive COVID-19 tests were positive since admission. Comprehensive clinical assessment investigations were performed. Apart from mild acute phase reactants elevation, all results were within reference limits. He had no leukocytosis and normal cardiac enzymes, chest x-ray findings, echocardiography findings, and healthy coronary arteries. The patient had a fever and electrocardiographic evidence of sinus node dysfunction associated with Mobitz type 2 atrioventricular block that progressed to complete heart block. This was a unique presentation of COVID-19 in a young, otherwise healthy man with the sole manifestation confined to the cardiac conduction system and the absence of respiratory involvement, hypoxemia, and acidosis.

Effect of macerate enzymes on the yield, quality, volatile compounds and rheological property of prickly pear juice.

Pectinase and cellulase enzymes were used to investigate efficacy for improving juice yield, stability and quality from prickly pear fruit. Pectinase improved the yield, stable color, color-assayed as release of anthocyanins or carotinoids and clarity of the juice. A significant increase in the effectiveness of pectinase was observed as the concentration was increased from 0.05 to 0.50% v/w. However, at concentration > 0.25% v/w they tended to impart a bitter flavor in the juice. Among three concentrations of pectinase and cellulase, pectinase at 0.50% v/w produced higher yield, a sediment-free clear juice and high-quality juice. The results indicated that depectinated clarified prickly pear juice behaves as a Newtonian fluid. It was found that the activation energy (Ea) for viscous flow was in the range of 5.02 x 10(3)-20.06 x 10(3) kJ/mol depending on the concentrations of pectinase and cellulase enzyme treatment of prickly pear juice, in contrast to 22.15 x 10(3) kJ/mol in untreated juice. Volatile compound concentrations of twelve compounds were not affected by pectinase and cellulase treatment. Overall the quality of prickly pear juice was better in pectinase-treated juice compared with untreated and cellulase-treated juice.