Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and human, exposure to calorie-dense food has been associated with increased astrocyte reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the cognitive defect in flexible behaviors induced by obesity, while manipulation of astrocyte in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control

The Addiction-Susceptibility TaqIA/Ankk1 Controls Reward and Metabolism Through D2 Receptor-Expressing Neurons

Background: A large body of evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the TaqIA polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the ankyrin repeat and kinase domain containing 1 kinase (Ankk1) near the dopamine D2 receptor (D2R) gene. Homozygous expression of the A1 allele correlates with a 30% to 40% reduction of striatal D2R, a typical feature of addiction, overeating, and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior are unknown. Methods: Here, we used transgenic and viral-mediated strategies to reveal the role of Ankk1 in the regulation of activity and functions of the striatum. Results: We found that Ankk1 is preferentially enriched in striatal D2R-expressing neurons and that Ankk1 loss of function in the dorsal and ventral striatum leads to alteration in learning, impulsivity, and flexibility resembling endophenotypes described in A1 carriers. We also observed an unsuspected role of Ankk1 in striatal D2R-expressing neurons of the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with or without the A1 allele. Conclusions: Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for Ankk1 in the regulation of body metabolism.Altérations du système de récompense dans l'anorexie mentaleRole du biostatus en acides gras polyinsaturés dans les troubles de contrôle exécuti

Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs

Implication de la transmission dopaminergique mésocorticolimbique dans la flexibilité comportementale : rôle des hétéromères de récepteurs dopaminergiques et glutamatergiques NMDA

Throughout their life, nearly one in three people will be affected by a psychiatric disorder. However, conventional pharmacological treatments remain relatively ineffective, and are often accompanied by significant side effects due to their lack of selectivity. Therefore, a consensus is emerging on the need to identify mechanisms underlying symptomatic dimensions common to several psychiatric pathologies (transnosographic approach); in order to develop personalized medicine in psychiatry. In this context, executive function disorders - the cognitive processes that enable an individual to adapt to a constantly changing environment - are a common symptom of many psychiatric pathologies. Such symptoms are correlated with impaired dopaminergic transmission within the medial prefrontal cortex (mPFC) forming the mesocortical pathway, and subcortical areas such as the ventral striatum or nucleus accumbens (NAc) forming the mesolimbic pathway. However, the mechanisms by which this mesocorticolimbic dopaminergic transmission enables an individual to flexibly adapt his or her behavior remain unclear. Moreover, in both structures, the activity of dopaminoceptive neurons is strongly regulated by the convergence of glutamatergic and dopaminergic afferents. However, how neurons integrate these signals is still poorly characterized. My preclinical thesis project therefore aims at unraveling how mesocorticolimbic dopaminergic projections modulates behavioral flexibility, and more specifically to establish the role of the physical interaction - or heteromerization - between D1 dopaminergic receptors (D1R) or D2 (D2R) and N-methyl-d-aspartate glutamatergic receptors (NMDA) within the mPFC and NAc. We show that this dopaminergic pathway is crucial for the animal's ability to adapt to changes in the consequences of its actions. From a mechanistic point of view, we demonstrate that D1/NMDA and D2/NMDA receptor heteromers in the mPFC and NAc constitute a central mechanism for mediating the effects of dopamine on executive functions. Indeed, our results show that inhibiting mesocorticolimbic dopaminergic transmission through chemogenetic manipulation, or blocking the ability of dopaminergic and NMDA receptors to form heteromers in NAc or mPFC through the use of interfering peptides, specifically disrupts the ability of animals to update associations between lever pressing and reward, in tasks assessing behavioral flexibility. These results suggest that mesocorticolimbic dopaminergic transmission is selectively involved in updating associations between an action and its outcomes, and that such effects are largely mediated by dopaminergic and NMDA receptor heteromers. Since these heteromers have distinct effects from their individual receptors, these data suggest that they could be prime targets for the development of more specific therapeutic treatments: their specific manipulation could allow avoiding the side effects associated with conventional pharmacological treatments that target the cognate receptors. Using a calcium sensor coupled with fiber photometry, we characterized i) the neural signature of mPFC dopaminoceptive neurons expressing D1R or D2R during Pavlovian and operant conditioning, especially during the update of associations, and ii) the effect of heteromer blockade on these activities. We were able to demonstrate calcium activity at the time of reinforced lever pressing and of cues predicting the reward delivery, as well as a decrease in activity during reward consumption. The blockade of D1/NMDA and D2/NMDA altered discrete components of this activity pattern. This mechanism provides a better understanding of how behavioral adaptation processes are set in motion, and thus constitutes an innovative therapeutic target. It could lead to the development of personalized treatments targeting executive function disorders and, more specifically, alterations in behavioral flexibility.Près d’une personne sur trois est affectée par une pathologie psychiatrique au cours de sa vie. Pour autant les traitements pharmacologiques classiques restent relativement peu efficaces et s’accompagnent souvent d’effets secondaires importants, du fait de leur manque de sélectivité. Un consensus émerge ainsi sur la nécessité d’identifier des mécanismes sous-jacents à des dimensions symptomatiques communes (approche transnosographique) afin de développer une médecine personnalisée en psychiatrie. Dans ce contexte, des troubles des fonctions exécutives – processus cognitifs permettant à un individu de s’adapter à un environnement en constante évolution - sont un symptôme commun à de nombreuses pathologies psychiatriques. Ils sont corrélés à une altération de la transmission dopaminergique au sein du cortex préfrontal médian (mPFC) formant la voie mésocorticale et d’aires sous-corticales telles que le striatum ventral ou noyau accumbens (NAc) constituant la voie mésolimbique. Pourtant, les mécanismes par lesquels cette transmission dopaminergique dite mésocorticolimbique permet à un individu d’adapter son comportement de façon flexible restent à éclaircir. Par ailleurs, dans ces deux structures, l’activité des neurones dopaminoceptifs est fortement régulée par la convergence d’afférences glutamatergiques et dopaminergiques. Cependant, la façon dont les neurones intègrent ces signaux est encore peu caractérisée. Mon projet de thèse préclinique vise ainsi à comprendre comment la transmission dopaminergique mésocorticolimbique module la flexibilité comportementale, et plus particulièrement l’interaction physique – ou hétéromérisation - entre les récepteurs dopaminergiques de type D1 (D1R) ou D2 (D2R) et les récepteurs glutamatergiques de type N-méthyl-d-aspartate (NMDA) au sein du mPFC et du NAc. Nos résultats montrent qu’inhiber la transmission dopaminergique mésocorticolimbique par manipulation chémogénétique, ou bloquer la capacité de récepteurs dopaminergiques et NMDA à former des hétéromères dans le NAc ou le mPFC par utilisation de peptides interférents, perturbe spécifiquement la capacité des animaux à réactualiser les associations entre appui levier et récompense, dans des tâches permettant d’évaluer la flexibilité comportementale. Ces résultats suggèrent que la transmission dopaminergique mésocorticolimbique est sélectivement impliquée dans la mise à jour d’associations entre une action et ses conséquences et que de tels effets sont largement médiés par les hétéromères de récepteurs D1/NMDA et D2/NMDA du mPFC et du NAc. Ces hétéromères ayant des effets distincts des récepteurs individuels, ces données suggèrent qu’ils pourraient être des cibles de choix pour le développement de traitements thérapeutiques plus spécifiques : leur manipulation pourrait permettre de s’affranchir des effets secondaires liés aux traitements pharmacologiques classiques qui ciblent directement ces récepteurs. En utilisant une approche de senseurs calciques couplée à de la photométrie de fibre, nous avons caractérisé i) la signature neuronale des neurones dopaminoceptifs exprimant D1R ou D2R du mPFC lors d’un conditionnement pavlovien puis opérant et notamment au cours de la réactualisation des associations et ii) l’effet du blocage des hétéromères sur ces activités. Nous avons pu mettre en évidence une réponse calcique au moment de l’appui sur le levier renforcé et des indices prédicteurs de la récompense, ainsi qu’une diminution d’activité lors de la consommation de la récompense. Nous montrons que le blocage des hétéromères D1/NMDA et D2/NMDA module certaines de ces composantes d’activité. Ce mécanisme nous permet ainsi de mieux comprendre la mise en place de processus d’adaptation comportementale et constitue donc une cible thérapeutique innovante. Il pourrait permettre d’envisager des traitements personnalisés visant à cibler les troubles de fonctions exécutives et plus particulièrement les altérations de la flexibilité comportementale

Implication of mesocorticolimbic dopamine transmission in behavioral flexibility : a role for dopamine and glutamate NMDA receptor heteromers

Près d’une personne sur trois est affectée par une pathologie psychiatrique au cours de sa vie. Pour autant les traitements pharmacologiques classiques restent relativement peu efficaces et s’accompagnent souvent d’effets secondaires importants, du fait de leur manque de sélectivité. Un consensus émerge ainsi sur la nécessité d’identifier des mécanismes sous-jacents à des dimensions symptomatiques communes (approche transnosographique) afin de développer une médecine personnalisée en psychiatrie. Dans ce contexte, des troubles des fonctions exécutives – processus cognitifs permettant à un individu de s’adapter à un environnement en constante évolution - sont un symptôme commun à de nombreuses pathologies psychiatriques. Ils sont corrélés à une altération de la transmission dopaminergique au sein du cortex préfrontal médian (mPFC) formant la voie mésocorticale et d’aires sous-corticales telles que le striatum ventral ou noyau accumbens (NAc) constituant la voie mésolimbique. Pourtant, les mécanismes par lesquels cette transmission dopaminergique dite mésocorticolimbique permet à un individu d’adapter son comportement de façon flexible restent à éclaircir. Par ailleurs, dans ces deux structures, l’activité des neurones dopaminoceptifs est fortement régulée par la convergence d’afférences glutamatergiques et dopaminergiques. Cependant, la façon dont les neurones intègrent ces signaux est encore peu caractérisée. Mon projet de thèse préclinique vise ainsi à comprendre comment la transmission dopaminergique mésocorticolimbique module la flexibilité comportementale, et plus particulièrement l’interaction physique – ou hétéromérisation - entre les récepteurs dopaminergiques de type D1 (D1R) ou D2 (D2R) et les récepteurs glutamatergiques de type N-méthyl-d-aspartate (NMDA) au sein du mPFC et du NAc. Nos résultats montrent qu’inhiber la transmission dopaminergique mésocorticolimbique par manipulation chémogénétique, ou bloquer la capacité de récepteurs dopaminergiques et NMDA à former des hétéromères dans le NAc ou le mPFC par utilisation de peptides interférents, perturbe spécifiquement la capacité des animaux à réactualiser les associations entre appui levier et récompense, dans des tâches permettant d’évaluer la flexibilité comportementale. Ces résultats suggèrent que la transmission dopaminergique mésocorticolimbique est sélectivement impliquée dans la mise à jour d’associations entre une action et ses conséquences et que de tels effets sont largement médiés par les hétéromères de récepteurs D1/NMDA et D2/NMDA du mPFC et du NAc. Ces hétéromères ayant des effets distincts des récepteurs individuels, ces données suggèrent qu’ils pourraient être des cibles de choix pour le développement de traitements thérapeutiques plus spécifiques : leur manipulation pourrait permettre de s’affranchir des effets secondaires liés aux traitements pharmacologiques classiques qui ciblent directement ces récepteurs. En utilisant une approche de senseurs calciques couplée à de la photométrie de fibre, nous avons caractérisé i) la signature neuronale des neurones dopaminoceptifs exprimant D1R ou D2R du mPFC lors d’un conditionnement pavlovien puis opérant et notamment au cours de la réactualisation des associations et ii) l’effet du blocage des hétéromères sur ces activités. Nous avons pu mettre en évidence une réponse calcique au moment de l’appui sur le levier renforcé et des indices prédicteurs de la récompense, ainsi qu’une diminution d’activité lors de la consommation de la récompense. Nous montrons que le blocage des hétéromères D1/NMDA et D2/NMDA module certaines de ces composantes d’activité. Ce mécanisme nous permet ainsi de mieux comprendre la mise en place de processus d’adaptation comportementale et constitue donc une cible thérapeutique innovante. Il pourrait permettre d’envisager des traitements personnalisés visant à cibler les troubles de fonctions exécutives et plus particulièrement les altérations de la flexibilité comportementale.Throughout their life, nearly one in three people will be affected by a psychiatric disorder. However, conventional pharmacological treatments remain relatively ineffective, and are often accompanied by significant side effects due to their lack of selectivity. Therefore, a consensus is emerging on the need to identify mechanisms underlying symptomatic dimensions common to several psychiatric pathologies (transnosographic approach); in order to develop personalized medicine in psychiatry. In this context, executive function disorders - the cognitive processes that enable an individual to adapt to a constantly changing environment - are a common symptom of many psychiatric pathologies. Such symptoms are correlated with impaired dopaminergic transmission within the medial prefrontal cortex (mPFC) forming the mesocortical pathway, and subcortical areas such as the ventral striatum or nucleus accumbens (NAc) forming the mesolimbic pathway. However, the mechanisms by which this mesocorticolimbic dopaminergic transmission enables an individual to flexibly adapt his or her behavior remain unclear. Moreover, in both structures, the activity of dopaminoceptive neurons is strongly regulated by the convergence of glutamatergic and dopaminergic afferents. However, how neurons integrate these signals is still poorly characterized. My preclinical thesis project therefore aims at unraveling how mesocorticolimbic dopaminergic projections modulates behavioral flexibility, and more specifically to establish the role of the physical interaction - or heteromerization - between D1 dopaminergic receptors (D1R) or D2 (D2R) and N-methyl-d-aspartate glutamatergic receptors (NMDA) within the mPFC and NAc. We show that this dopaminergic pathway is crucial for the animal's ability to adapt to changes in the consequences of its actions. From a mechanistic point of view, we demonstrate that D1/NMDA and D2/NMDA receptor heteromers in the mPFC and NAc constitute a central mechanism for mediating the effects of dopamine on executive functions. Indeed, our results show that inhibiting mesocorticolimbic dopaminergic transmission through chemogenetic manipulation, or blocking the ability of dopaminergic and NMDA receptors to form heteromers in NAc or mPFC through the use of interfering peptides, specifically disrupts the ability of animals to update associations between lever pressing and reward, in tasks assessing behavioral flexibility. These results suggest that mesocorticolimbic dopaminergic transmission is selectively involved in updating associations between an action and its outcomes, and that such effects are largely mediated by dopaminergic and NMDA receptor heteromers. Since these heteromers have distinct effects from their individual receptors, these data suggest that they could be prime targets for the development of more specific therapeutic treatments: their specific manipulation could allow avoiding the side effects associated with conventional pharmacological treatments that target the cognate receptors. Using a calcium sensor coupled with fiber photometry, we characterized i) the neural signature of mPFC dopaminoceptive neurons expressing D1R or D2R during Pavlovian and operant conditioning, especially during the update of associations, and ii) the effect of heteromer blockade on these activities. We were able to demonstrate calcium activity at the time of reinforced lever pressing and of cues predicting the reward delivery, as well as a decrease in activity during reward consumption. The blockade of D1/NMDA and D2/NMDA altered discrete components of this activity pattern. This mechanism provides a better understanding of how behavioral adaptation processes are set in motion, and thus constitutes an innovative therapeutic target. It could lead to the development of personalized treatments targeting executive function disorders and, more specifically, alterations in behavioral flexibility

Cell-Type-Specific Adaptions in Striatal Medium-Sized Spiny Neurons and Their Roles in Behavioral Responses to Drugs of Abuse

International audienceDrug addiction is defined as a compulsive pattern of drug-seeking- and taking- behavior, with recurrent episodes of abstinence and relapse, and a loss of control despite negative consequences. Addictive drugs promote reinforcement by increasing dopamine in the mesocorticolimbic system, which alters excitatory glutamate transmission within the reward circuitry, thereby hijacking reward processing. Within the reward circuitry, the striatum is a key target structure of drugs of abuse since it is at the crossroad of converging glutamate inputs from limbic, thalamic and cortical regions, encoding components of drug-associated stimuli and environment, and dopamine that mediates reward prediction error and incentive values. These signals are integrated by medium-sized spiny neurons (MSN), which receive glutamate and dopamine axons converging onto their dendritic spines. MSN primarily form two mostly distinct populations based on the expression of either DA-D1 (D1R) or DA-D2 (D2R) receptors. While a classical view is that the two MSN populations act in parallel, playing antagonistic functional roles, the picture seems much more complex. Herein, we review recent studies, based on the use of cell-type-specific manipulations, demonstrating that dopamine differentially modulates dendritic spine density and synapse formation, as well as glutamate transmission, at specific inputs projecting onto D1R-MSN and D2R-MSN to shape persistent pathological behavioral in response to drugs of abuse. We also discuss the identification of distinct molecular events underlying the detrimental interplay between dopamine and glutamate signaling in D1R-MSN and D2R-MSN and highlight the relevance of such cell-type-specific molecular studies for the development of innovative strategies with potential therapeutic value for addiction. Because drug addiction is highly prevalent in patients with other psychiatric disorders when compared to the general population, we last discuss the hypothesis that shared cellular and molecular adaptations within common circuits could explain the co-occurrence of addiction and depression. We will therefore conclude this review by examining how the nucleus accumbens (NAc) could constitute a key interface between addiction and depression

Respective roles of the distinct populations of Medium Spiny Neurons of the Nucleus Accumbens in reward processing

National audienceThe nucleus accumbens (NAc) is a major structure that plays a key role in action selection and execution as well as reward processing and reward-dependent learning. It is largely composed of GABAergic Medium Spiny Neurons (MSN) that are divided into two distinct subpopulations, those expressing the dopamine D1 receptor (D1R; dMSNs), and those expressing the D2 receptor (D2R; iMSNs). Based on the model of the dorsal striatum, it has been proposed that dMSNs and iMSNs of the NAc play antagonistic effects on reward processing, but their respective roles are still largely debated (Carvalho Poyraz et al. 2016; Soares-Cunha et al. 2016). Herein, we aimed at deeper exploring the implication of these two populations of MSNs of the NAc core on various components of reward processing. Using operant conditioning tasks and pharmacogenetic approaches we show that activation of iMSNs decreases motivation to obtain a food reward but increases food consumption, while inhibition had the opposite effect, with no impact on hedonic reactivity. Interestingly, in vivo electrophysiology experiments in anesthetized animals revealed that the increased iMSN excitability boosts the activity of dopaminergic VTA neurons. Surprisingly, we observed that both inhibition and activation of dMSNs led to a decrease in performance in motivational tasks, likely related to a strong modulation of consummatory processes. Our data shed light on the complex function of dMSNs and iMSNs of the NAc core in reward processing and highlight differential effects on consummatory vs. motivational processes

Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine’s rewarding effects but preserves natural reward processing

International audienc

Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs.SCOPUS: ar.jinfo:eu-repo/semantics/publishe