Indiana University-Purdue University Indianapolis (IUPUI) / Drinking despite aversive consequences, or compulsive drinking, is a criterion of alcohol use disorder and can be modeled in rodents by adding bitter quinine into alcohol. Previous studies have shown the development of quinine-resistant ethanol (EtOH) drinking following a drinking history, but used animals that achieved relatively low blood alcohol levels. Selectively bred crossed High Alcohol Preferring (cHAP) mice average over 250 mg/dl during a two-bottle choice procedure. Compulsive drinking is hypothesized to be D1-receptor mediated via the dorsolateral striatum (DLS). We hypothesized that 2 weeks of free-choice EtOH would lead to quinine resistance and intra-DLS infusion of a D1-antagonist, SCH23390, would attenuate quinine-resistant alcohol drinking with no effect on non-conflicted EtOH drinking. Infusion of SCH23390 into the DMS would not affect quinine-resistant drinking. cHAP mice had guide cannulae placed in the DLS or DMS and had either two weeks (2W) of EtOH and water two-bottle choice or were EtOH naïve (0W). Mice were infused with either SCH23390 or saline immediately prior to one 10% EtOH and water test day and SCH23390 did not disturb alcohol drinking. The following day, we adulterated the EtOH with 0.32-g/L quinine (0.89 mM), and mice received the same microinjection. For animals cannulated in the DLS, 2W history group infused with saline drank more quinine-adulterated EtOH than the 0W saline mice. While SCH23390 infused 0W animals looked no different from saline treated mice, it attenuated quinine + EtOH intake in the 2W animals to the level of 0W animals. Interestingly, DMS-cannulated mice demonstrated similar behavior, with SCH23390 reducing EtOH + quinine consumption, while leaving EtOH consumption undisturbed. Quinine resistance following 2 weeks of free-choice EtOH consumption is attenuated by acute administration of a D1-antagonist in the DLS, suggesting that an alcohol history induces compulsivity and that dopamine contributes to this behavior. This is unique to compulsive drinking, as non-conflicted EtOH drinking was unaffected.

Indiana University-Purdue University Indianapolis (IUPUI) / Background Compulsive alcohol drinking is a defining characteristic of alcohol use disorder and the dorsolateral striatum (DLS) is implicated in regulating this inflexible behavior. AMPA receptors have been implicated in both goal-directed (dorsomedial striatal dependent) and DLS dependent inflexible behaviors with antagonism in the DLS and general DLS inhibition altering inflexible behavior including habit and compulsion. Discrepancies exist in the preclinical models used to investigate compulsive-like alcohol. The purpose of these experiments was to establish a robust model of compulsive-like quinine adulterated alcohol (QuA) drinking in C57BL/6J male and female mice, assess associated AMPA receptor protein expression in the dorsal striatum, and to antagonize DLS AMPA receptors during compulsive-like QuA drinking using a model of binge-like alcohol drinking, Drinking-in-the-Dark (DID). Methods In aim 1, C57BL/6J mice were allowed free access to 20% (v/v) alcohol (alcohol history), or water (water history) for two hours each day beginning three hours into the dark cycle for 23 days. On days 15 and 22 mice were given QuA to test for compulsive-like QuA drinking. 24-hours following the last DID session brain slices were taking for DLS and DMS AMPA receptor western blot. In aim 2, C57BL/6J mice were given a total of 21 days alcohol history, to establish a compulsive-like phenotype, or water history, prior to infusion. On days 22 and 24 mice were given a bilateral infusion of one of three concentrations of NBQX, an AMPA receptor antagonist, into the DLS, immediately prior to DID where the DID solution was either alcohol or QuA. Results We found that three weeks, not two, is sufficient to produce robust compulsive-like QuA drinking in C57BL/6J mice. We failed to replicate our compulsive-like DID model in aim 2 and found that infusion of NBQX reduced 2-hour alcohol drinking and reduced 2-hour QuA drinking when QuA was the second solution presented on infusion days in male water history mice only. We also found that NBQX reduced 20-minute front-loading in female alcohol history mice on alcohol intake and trended toward QuA intake. Overall locomotor activity was affected by drug infusions. Conclusions Together, these data suggest that compulsive-like alcohol drinking can be achieved following three-weeks DID and DLS infusion of NBQX reduces both alcohol and QuA drinking in a sex and drinking history dependent way, and these effects may be reliant on an initial single QuA or alcohol exposure.

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Indiana University-Purdue University Indianapolis (IUPUI) / The striatum is a key brain region involved in regulating motor output and integration. The dorsal and ventral subdivisions of the striatum work in concert to mediate the reinforcing and motor behavioral outputs of the striatum. Moreover, dysfunction of these striatal regions is involved in various diseases including Parkinson’s disease and drug addiction. Therefore, understanding and characterizing biochemical and molecular changes within the striatum associated with these diseases is key in devolving novel therapeutics to treat these disease states. The main output neurons of the striatum are GABAergic, medium-spiny neurons (MSNs), and striatal functionality is mediated by neuroplastic changes in MSN activity. Within MSNs, dopaminergic receptor activation triggers a cascade of reversable phosphorylation, which is facilitated by the activation of specific protein kinases and inhibition of specific protein phosphatases. In comparison to the 350 serine/threonine protein kinases expressed within the striatum, there are only 40 major serine/threonine protein phosphatases. However, serine/threonine protein phosphatases, such as protein phosphatase 1 (PP1), gain their target specificity by interacting with phosphatase-targeting proteins. Within the striatum, the neurabins, termed neurabin and spinophilin, are the most abundant PP1 targeting proteins in dendritic spines. Spinophilin’s expression in the striatum has been strongly characterized, and spinophilin has been shown to regulate striatal-dependent motor-skill learning and amphetamine-induced locomotor sensitization. In contrast to spinophilin, neurabin’s expression within the striatum and its involvement in these striatal-dependent behaviors has not been fully probed. I found that neurabin expression in the striatum is not sex-dependent but is age-dependent. In addition to these data, I also present validation of new global, constitutive and conditional neurabin knock-out mouse lines. Finally, I present data that, unlike previous studies in spinophilin knockout mice, neurabin knockout mice have enhanced striatal-dependent motor-skill learning, but do not impact amphetamine-induced locomotor sensitization. Further characterization of neurabin’s expression in the striatum, and its role in these key striatal behaviors could provide a druggable target for therapeutics designed to address striatal dysfunction.

Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals.

Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals.

Le striatum, tout particulièrement sa région sensorimotrice, est connu pour jouer un rôle crucial dans l’expression de routines motrices qui nécessitent la réalisation d’une suite de mouvements. Dans ce travail, nous avons étudié la contribution respective des neurones efférents et des interneurones cholinergiques du striatum dans les processus qui sous - tendent l’expression de séquences motrices automatisées, en enregistrant l’activité unitaire de ces deux populations neuronales chez des singes entraînés à effectuer des mouvements d’atteinte manuelle de cibles. Par cette approche, nous avons examiné les modifications d’activité de ces neurones lors d’un changement des conditions de performance durant la réalisation de la séquence de mouvements. Ainsi en manipulant l’ordre habituel ou la structure temporelle de la séquence, nous avons montré, au sein du striatum sensorimoteur, que les neurones efférents et les interneurones cholinergiques participent au traitement des informations spatiales et temporelles qui caractérisent une séquence motrice automatisée. Par ailleurs, nous avons montré que ces deux populations neuronales sont différentiellement activées lorsque l’ordre de la séquence est visuellement spécifié ou déterminé sur la base d’informations mémorisées. Ces résultats apportent des informations essentielles pour mieux comprendre les mécanismes neuronaux impliqués, au niveau du striatum sensorimoteur, dans le contrôle des séquences motrices automatisées. / It is well known that the striatum, especially its sensorimotor part, is involved in the expression of motor skills which require the production of a sequence of movements. In this study, we addressed the respective contribution of efferent neurons and cholinergic interneurons of the striatum in the processes underlying the expression of motor sequences, by recording single unit activity of these two neuronal populations in monkeys performing sequential arm reaching movements. By this experimental approach, we examined activity modulations of these neurons during a change in the conditions of performance of the motor sequence. Thus, by changing the habitual order or the temporal structure of the sequence, we underlined that within sensorimotor striatum, efferent neurons and cholinergic interneurons are involved in the processing of spatial and temporal information which characterize an automatic motor sequence. In addition, we reported differential activations of these two neuronal populations depending on whether the serial order of the sequence of movements is visually cued or based on internally stored information. Taken together, these results provide essential information in order to better understand the neuronal mechanisms involved, within the sensorimotor part of striatum, in the control of the automatic motor sequences.

La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire, incurable.Elle est due à une mutation dans le gène HD codant l'huntingtine (htt). Cette mutation setraduit dans la protéine par une augmentation de l'expansion polyglutamine (polyGln) qui larend toxique. Bien que la htt soit ubiquitaire dans le système nerveux central, ladégénérescence touche préférentiellement le striatum. Un patron d'expression de gènesspécifiques du striatum pourrait expliquer cette vulnérabilité préférentielle. Nous avons étudiéles effets "modificateurs" de 5 gènes préférentiellement exprimés dans le striatum vis-à-visde la toxicité de la htt mutée par une approche lentivirale chez la souris. Nous avonscaractérisé les effets de ces marqueurs striataux sur la toxicité induite par la htt mutée pardifférentes approches histologiques. Les "modificateurs" de la MH ont été étudiés plus endétail. Nous avons examiné leur localisation et les mécanismes sous-jacents à leurs effetsneuroprotecteurs. Outre une meilleure compréhension du striatum, cette étude a permis ladécouverte de candidat neuroprotecteur qui pourrait permettre de développer de nouvellesthérapies. / Huntington's disease (HD) is an incurable inherited neurodegenerative disease. HD iscaused by a mutation in the HD gene coding huntingtin (htt). This mutation leads to anexpanded polyglutamine tract (polyQ) in the protein which is toxic to neurons. Although thehtt is ubiquitously expressed in the central nervous system, the first area which degeneratesis the striatum. A pattern of genes selectively expressed into the striatum may confer itsvulnerability to mutated htt. We have studied the modifying effects of five newly identifiedstriatal markers against the toxicity induced by mutated htt using lentiviral strategy in miceand histological approaches. For one of these markers, Double Cortin Kinase Like 3(DCLK3), we have further determined their cellular localization and the potential mechanismsunderlying their neuroprotector effects. The present work led to a better understanding of thefunction of the newly identified markers in the striatum and their potential roles in thepreferential vulnerability of the striatum in HD.