Citations

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.

Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. A major risk factor for this condition is increased serum low-density lipoprotein cholesterol (LDL-C) levels for which statins have been successful in reducing serum LDL-C to healthy concentrations. However, patients who are statin intolerant or those who do not achieve their treatment goals while on high-intensity statin therapy, such as those with familial hypercholesterolemia, remain at risk. With the discovery of PCSK9 inhibitors, the ability to provide more aggressive treatment for patients with homozygous and heterozygous familial hypercholesterolemia has increased. Ezetimibe reduces LDL-C by 15%-20% when combined with statin. 2 , 3 Protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been found to achieve profound reductions in LDL-C (54%-74%) when added to statins. They have shown dramatic effects at lowering major adverse cardiovascular events (MACE) in high-risk patients 4 with LDL-C levels ≥70 mg/dL and can be used in populations that are statin intolerant or not at goal levels with maximally tolerated statin therapy. PCSK9 inhibitors also produce minimal side effects. Myopathy, a common side effect for patients on statins, has been rare in patients on PCSK9 inhibitors. Randomized trials have shown that reduction in LDL-C has translated to clinical benefits even in patients who have not achieved their LDL-C target.

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.

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 .

Habitual reward‐seeking behavior is a hallmark of addictive behaviors. Although habitual behavior could be reversed to goal‐directed behavior, this shifting is not well studied. Here, we identify a role of astrocyte activation in the dorsomedial striatum (DMS) on transition from habitual to goal‐directed reward‐seeking behavior. Utilizing the Inscopix endomicroscopy/fiber photometry in vivo calcium imaging and the cell‐type specific activation of designer receptors exclusively activated by designer drugs (DREADDs), we confirmed that GFAP‐driven activation of hM3Dq DREADDs increases intensity and frequency of calcium signaling in the DMS astrocytes of ALDH1L1‐GCaMP6s expressing mice. We found that this chemogenetic activation of the DMS astrocytes increase and decrease neuronal excitability of direct pathway Medium Spiny Neurons (dMSNs) and indirect pathway Medium Spiny Neurons (iMSNs), respectively. Specifically, it reduced the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in the dMSNs, whereas it increased the amplitude of the sEPSCs and decreased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the iMSNs. The changes in synaptic events induced by astrocytic activation were significantly inhibited by either of the pretreatments of DPCPX (Adenosine A1R antagonist, 1 μM), PSB12379 (Inhibitor of ectonucleotidase, CD73, 10 μM), NBTI [Inhibitor of the astrocytic adenosine transporter, equilibrative nucleoside transporter 1 (ENT1, slc29a1), 10 μM], and genetic deletion of ENT1. These data suggest that astrocytic activation‐induced synaptic activities are, in part, adenosine‐dependent. In the evaluation tests of goal‐directed and habitual reward‐seeking, the chemogenetic activation of the DMS astrocytes shifted the habitual behavior to goal‐directed action in sucrose reward‐seeking for WT, but not ENT1 KO mice. The astrocytic activation‐induced shifting was rescued when ENT1 expression was normalized in the DMS astrocytes of the ENT1 KO mice. On the other hand, when mice were trained to have goal‐directed behavior, the astrocytic activation in the DMS did not change the reward‐seeking behavioral pattern. Together, our results indicate that astrocyte‐regulated adenosine signaling in the DMS determines goal‐directed and habitual behaviors by selectively regulating synapses in the MSNs. The interaction between astrocytes and neurons via adenosine signaling could be a potential therapeutic target for maladaptive reward‐seeking behaviors. Support or Funding Information This work was supported by the Samuel C. Johnson for Genomics of Addiction Program at Mayo Clinic, the Ulm Foundation, and National Institute on Alcohol Abuse and Alcoholism (K01 AA027773 to SK, R01 AA018779 to DSC).

Kynurenic acid (KYNA), a glial-derived metabolite of tryptophan metabolism, is an antagonist of the alpha 7 nicotinic acetylcholine receptor and the glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. Kynurenic acid levels are increased in both the brain and cerebrospinal fluid of several psychiatric disorders including bipolar disorder, schizophrenia, and Alzheimer disease. In addition, pro-inflammatory cytokines have been found to be elevated in the blood of schizophrenic patients suggesting inflammation may play a role in psychiatric illness. As both pro-inflammatory cytokines and KYNA can be elevated in the brain by peripheral lipopolysaccharide (LPS) injection, we therefore sought to characterize the role of neuroinflammation on learning and memory using a well-described dual-LPS injection model. Mice were injected with an initial injection (0.25 mg/kg LPS, 0.50 mg/kg, or saline) of LPS and then administrated a second injection 16 hours later. Our results indicate both 0.25 and 0.50 mg/kg dual-LPS treatment increased l-kynurenine and KYNA levels in the medial pre-frontal cortex (mPFC). Mice exhibited impaired acquisition of CS+ (conditioned stimulus) Pavlovian conditioning. Notably, mice showed impairment in reference memory while working memory was normal in an 8-arm maze. Taken together, our findings suggest that neuroinflammation induced by peripheral LPS administration contributes to cognitive dysfunction.

AbstractDisruptions in circadian rhythms are risk factors for excessive alcohol drinking. The ethanol‐sensitive adenosine equilibrative nucleoside transporter type 1 (ENT1, slc29a1) regulates ethanol‐related behaviors, sleep, and entrainment of circadian rhythms. However, the mechanism underlying the increased ethanol consumption in ENT1 knockout (KO) mice in constant light (LL) and whether there are sex differences in ethanol consumption in ENT1 mice are less studied. Here, we investigated the effects of loss of ENT1, LL, and sex on ethanol drinking using two‐bottle choice. In addition, we monitored the locomotor activity rhythms. We found that LL increased ethanol drinking and reduced accumbal ENT1 expression and adenosine levels in male but not female mice, compared with control mice. Interestingly, only LL‐exposed male, not female, ENT1 KO mice exhibited higher ethanol drinking and a longer circadian period with a higher amplitude compared with wild‐type (WT) mice. Furthermore, viral‐mediated rescue of ENT1 expression in the NAc of ENT1 KO mice reduced ethanol drinking, demonstrating a possible causal link between ENT1 expression and ethanol drinking in males. Together, our findings indicate that deficiency of ENT1 expression contributes to excessive ethanol drinking in a sex‐dependent manner.

BackgroundImpairment of monocarboxylate transporter (MCT)‐dependent astrocyte‐neuron lactate transfer disrupts long‐term memory and erases drug‐associated memories in mice. However, few studies have examined how drugs of abuse alter astrocyte‐neuron lactate transfer in neurocircuits related to addiction. This is particularly pertinent for ethanol (EtOH), which has been demonstrated to impair central nervious system (CNS) glucose uptake and significantly alter peripheral levels of glucose, lactate, acetate, and ketones.MethodsWe subjected C57BL/6J mice to a chronic intermittent EtOH (CIE) exposure paradigm to investigate how chronic EtOH exposure alters the concentration of glucose and lactate within the serum and CNS during withdrawal. Next, we determine how chronic injections of lactate (1 g/kg, twice daily for 2 weeks) influence central and peripheral glucose and lactate concentrations. Finally, we determine how CIE and chronic lactate injection affect astrocyte‐neuron lactate transfer by analyzing the expression of MCTs.ResultsOur results show that CIE induces lasting changes in CNS glucose and lactate concentrations, accompanied by increased expression of MCTs. Interestingly, although chronic lactate injection mimics the effect of EtOH on CNS metabolites, chronic lactate injection is not associated with increased expression of MCTs.ConclusionCIE increases CNS concentrations of glucose and lactate and augments the expression of MCTs. Although we found that chronic lactate injection mimics EtOH‐induced increases in CNS lactate and glucose, lactate failed to alter the expression of MCTs. This suggests that although lactate may influence the homeostasis of bioenergetic molecules in the CNS, EtOH‐associated increases in lactate are not responsible for increased MCT expression.

Abstract Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge‐like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5‐choice serial reaction time task (5‐CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5‐CSRTT sessions. We further characterized our ethanol‐induced impulsive mice using Open Field, y‐maze, two‐bottle choice, and an action‐outcome task. Our results indicate that continuous binge‐like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol‐induced impulsive mice exhibited anxiety‐like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol‐treated mice were less motivated for a sucrose reward compared with air‐exposed control mice, while also demonstrating reduced responding during action‐outcome testing. Overall, ethanol‐treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice.