Citations

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.

Abstract GLP-1 agonists have become increasingly interesting as a new Parkinson’s disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. “Motivated” behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

Abstract Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane‐bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre‐mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a compartment where PPGL is known to originate. We report that while there is modest expansion of TH + glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondiabetic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH + cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.

AbstractThe corticostriatal circuitry and its glutamate‐γ‐aminobuturic acid (GABA) interactions play an essential role in regulating neuronal excitability during reward‐seeking behavior. However, the contribution of GABAergic interneurons in the corticostriatal circuitry remains unclear. To investigate the role of GABAergic interneurons, we focused on parvalbumin‐expressing fast‐spiking interneurons (Pv‐FSI) in the corticostriatal circuitry using the designer receptors exclusively activated by designer drugs approach in a Pv‐Cre mouse model. We hypothesize that Pv‐FSI activation elicits changes in cortical glutamate levels and reward‐seeking behaviors. To determine molecular and behavioral effects of Pv‐FSI, we performed microdialysis and operant conditioning tasks for sucrose and alcohol rewards. In addition, we also examined how alcohol reward itself affects Pv‐FSI functioning. Interestingly, our microdialysis results demonstrate that alcohol exposure inhibits Pv‐FSI functioning in the medial prefrontal cortex (mPFC) and this consequently can regulate glutamate levels downstream in the nucleus accumbens. For sucrose reward‐seeking behaviors, Pv‐FSI activation in the mPFC increases sucrose self‐administration whereas it does not promote alcohol seeking. For alcohol rewards, however, Pv‐FSI activation in the mPFC results in increased compulsive head entry in operant chambers during devaluation procedures. Overall, our results suggest that not only do Pv‐FSI contribute to changes in the cortical microcircuit and reward‐seeking behaviors but also that alcohol affects Pv‐FSI neurotransmission. Therefore, Pv‐FSI has prompted interest in their role in maintaining a balance in neuronal excitation/inhibition and in regulating reward‐seeking processes such as compulsivity, all of which are important factors for excessive alcohol seeking. image

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).

Abstract Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal‐directed and habitual reward‐seeking behaviours, respectively. Previously, our study shows that the ethanol‐sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol‐drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal‐directed and habitual ethanol‐seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4 days of random interval (RI), mice exhibited habitual seeking for 10S, but goal‐directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E‐seeking behaviour on a fixed ratio (FR) for 6 days and RI for 8 days. On the other hand, during FR and the first 4 days of RI schedules, mice showed goal‐directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4 days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal‐directed reward‐seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward‐seeking behaviours.

Suicide is a major public health concern; nevertheless, its neurobiology remains unknown. An area of interest in suicide research is the dorsolateral prefrontal cortex (DLPFC). We aimed to identify altered proteins and potential biological pathways in the DLPFC of individuals who died by suicide employing mass spectrometry-based untargeted proteomics. Postmortem DLPFC from age-matched male suicide mood disorder cases (n = 5) and non-suicide mood disorder cases (n = 5) were compared. The proteins that differed between groups at false discovery rate (FDR) adjusted p-values (Benjamini–Hochberg–Yekutieli) <0.3 and Log2 fold change (FC) >|0.4| were considered statistically significant and were subjected to pathway analysis by Qiagen Ingenuity software. Thirty-three of the 5162 detected proteins showed significantly altered expression levels in the suicide cases and two of them after adjustment for body mass index. The top differentially expressed protein was potassium voltage-gated channel subfamily Q member 3 (KCNQ3) (Log2FC = −0.481, p = 2.10 × 10−09, FDR = 5.93 × 10−06), which also showed a trend to downregulation in Western blot (p = 0.045, Bonferroni adjusted p = 0.090). The most notably enriched pathway was the GABA receptor signaling pathway (p < 0.001). Here, we report a reduction trend of KCNQ3 levels in the DLPFC of male suicide victims with mood disorders. Further studies with a larger sample size and equal sex representation are needed.

Abstract Eating disorders and substance use disorders frequently co‐occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [ r g ], twin‐based = 0.23‐0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome‐wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance‐use‐related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism‐based genetic correlations between eating disorder‐ and substance‐use‐related phenotypes. Significant positive genetic associations emerged between AUD and AN ( r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN ( r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating ( r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating ( r gs = −0.19 to −0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co‐varying for major depressive disorder loci. The patterns of association between eating disorder‐ and substance‐use‐related phenotypes highlights the potentially complex and substance‐specific relationships among these behaviors.

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.