Rôle de la protéine Arc (Activity-regulated cytoskeleton-associated protein) dans les adaptations moléculaires et comportementales induites par la cocaïne

Molecular and cellular adaptations induced by drugs of abuse in the reward system play a key role in long-term behavioral alterations encountered in addiction. This work falls within an approach of understanding the cellular processes rapidly engaged by cocaine that could underlie the persistent alteration of neuronal physiology and behaviors. Arc protein is a major player in neuronal plasticity. Arc is induced in many behavioral paradigms and is essential for long-term synaptic plasticity and memory consolidation. The aim of this study was to characterize the profile and modality of Arc induction within the mouse striatum in response to cocaine administration. Our study shows that Arc expression is rapidly and transiently increased in the striatum after acute cocaine in an ERK-dependent fashion. This work revealed that cocaine-induced Arc protein rapidly and transiently accumulates in the nucleus of striatal neurons. In the nucleus, Arc is preferentially expressed in active transcription regions and localizes at the vicinity of phosphorylated histones H3. In vitro Arc overexpression decreased glutamate-induced Histones H3 phosphorylation showing that Arc interferes with activity-dependent chromatin remodeling. In vivo genetic invalidation of Arc expression in a transgenic mouse model was associated with a decreased chromatin compaction and increased RNA Polymerase II activity suggesting a repressive role of Arc on transcriptional mechanisms. Total Arc loss of expression leads to increased sensitivity to cocaine and promotes long-term behavioral alterations induced by low doses of cocaine.Les adaptations cellulaires et moléculaires induites par les drogues jouent un rôle central dans les altérations comportementales à long terme observées dans l’addiction. Cette étude s’inscrit dans une démarche de compréhension des processus cellulaires rapidement mis en jeu par la cocaïne et susceptibles d’impacter durablement le fonctionnement neuronal et les comportements. La protéine Arc joue un rôle clé dans l’établissement de la plasticité synaptique à long-terme et la consolidation de la mémoire. Cette étude visait à caractériser l’induction de Arc dans le striatum en réponse à la cocaïne et d’analyser son rôle dans les réponses moléculaires et comportementales qu’elle induit. Notre étude a montré que l’expression de Arc est augmentée rapidement et transitoirement dans le striatum après une injection de cocaïne sous la dépendance de l’activation de la voie ERK. Nous montrons que la cocaïne induit une forte accumulation de la protéine Arc dans le noyau des neurones striataux où Arc se localise dans des zones actives de transcription, à proximité des histones H3 phosphorylées. In vitro, la surexpression de Arc diminue la phosphorylation des histones H3 induite par le glutamate indiquant qu’elle altère le remodelage de la chromatine. L’invalidation génétique de la protéine in vivo dans un modèle de souris transgénique conduit à une décompaction de la chromatine associée à une augmentation de l’activité de la RNA Polymerase II démontrant que Arc exerce un effet répresseur sur les mécanismes transcriptionnels. La perte totale d’expression de Arc favorise le développement d’altérations comportementales à long terme chez des animaux exposés à de faibles doses de cocaïne

Role of Arc protein (Activity-regulated cytoskeleton-associated protein) in molecular and behavioral adaptations to cocaine

Les adaptations cellulaires et moléculaires induites par les drogues jouent un rôle central dans les altérations comportementales à long terme observées dans l’addiction. Cette étude s’inscrit dans une démarche de compréhension des processus cellulaires rapidement mis en jeu par la cocaïne et susceptibles d’impacter durablement le fonctionnement neuronal et les comportements. La protéine Arc joue un rôle clé dans l’établissement de la plasticité synaptique à long-terme et la consolidation de la mémoire. Cette étude visait à caractériser l’induction de Arc dans le striatum en réponse à la cocaïne et d’analyser son rôle dans les réponses moléculaires et comportementales qu’elle induit. Notre étude a montré que l’expression de Arc est augmentée rapidement et transitoirement dans le striatum après une injection de cocaïne sous la dépendance de l’activation de la voie ERK. Nous montrons que la cocaïne induit une forte accumulation de la protéine Arc dans le noyau des neurones striataux où Arc se localise dans des zones actives de transcription, à proximité des histones H3 phosphorylées. In vitro, la surexpression de Arc diminue la phosphorylation des histones H3 induite par le glutamate indiquant qu’elle altère le remodelage de la chromatine. L’invalidation génétique de la protéine in vivo dans un modèle de souris transgénique conduit à une décompaction de la chromatine associée à une augmentation de l’activité de la RNA Polymerase II démontrant que Arc exerce un effet répresseur sur les mécanismes transcriptionnels. La perte totale d’expression de Arc favorise le développement d’altérations comportementales à long terme chez des animaux exposés à de faibles doses de cocaïne.Molecular and cellular adaptations induced by drugs of abuse in the reward system play a key role in long-term behavioral alterations encountered in addiction. This work falls within an approach of understanding the cellular processes rapidly engaged by cocaine that could underlie the persistent alteration of neuronal physiology and behaviors. Arc protein is a major player in neuronal plasticity. Arc is induced in many behavioral paradigms and is essential for long-term synaptic plasticity and memory consolidation. The aim of this study was to characterize the profile and modality of Arc induction within the mouse striatum in response to cocaine administration. Our study shows that Arc expression is rapidly and transiently increased in the striatum after acute cocaine in an ERK-dependent fashion. This work revealed that cocaine-induced Arc protein rapidly and transiently accumulates in the nucleus of striatal neurons. In the nucleus, Arc is preferentially expressed in active transcription regions and localizes at the vicinity of phosphorylated histones H3. In vitro Arc overexpression decreased glutamate-induced Histones H3 phosphorylation showing that Arc interferes with activity-dependent chromatin remodeling. In vivo genetic invalidation of Arc expression in a transgenic mouse model was associated with a decreased chromatin compaction and increased RNA Polymerase II activity suggesting a repressive role of Arc on transcriptional mechanisms. Total Arc loss of expression leads to increased sensitivity to cocaine and promotes long-term behavioral alterations induced by low doses of cocaine

From Signaling Molecules to Circuits and Behaviors: Cell-Type-Specific Adaptations to Psychostimulant Exposure in the Striatum

Addiction is characterized by a compulsive pattern of drug seeking and consumption and a high risk of relapse after withdrawal that are thought to result from persistent adaptations within brain reward circuits. Drugs of abuse increase dopamine (DA) concentration in these brain areas, including the striatum, which shapes an abnormal memory trace of drug consumption that virtually highjacks reward processing. Long-term neuronal adaptations of gamma-aminobutyric acidergic striatal projection neurons (SPNs) evoked by drugs of abuse are critical for the development of addiction. These neurons form two mostly segregated populations, depending on the DA receptor they express and their output projections, constituting the so-called direct (D1 receptor) and indirect (D2 receptor) SPN pathways. Both SPN subtypes receive converging glutamate inputs from limbic and cortical regions, encoding contextual and emotional information, together with DA, which mediates reward prediction and incentive values. DA differentially modulates the efficacy of glutamate synapses onto direct and indirect SPN pathways by recruiting distinct striatal signaling pathways, epigenetic and genetic responses likely involved in the transition from casual drug use to addiction. Herein we focus on recent studies that have assessed psychostimulant-induced alterations in a cell-type-specific manner, from remodeling of input projections to the characterization of specific molecular events in each SPN subtype and their impact on long-lasting behavioral adaptations. We discuss recent evidence revealing the complex and concerted action of both SPN populations on drug-induced behavioral responses, as these studies can contribute to the design of future strategies to alleviate specific behavioral components of addiction

A new automated 3D detection of synaptic contacts reveals the formation of cortico-striatal synapses upon cocaine treatment in vivo

International audienceAddiction can be considered as a form of neuronal adaptation within the reward circuitry. Upon psychostimulant administration, long-term behavioral adaptations are associated with synaptic plasticity and morphological changes of medium spiny neurons (MSN) from the striatum. Increased spine density onto MSN in response to chronic cocaine exposure in mice has been described for more than a decade, but no evidence indicates that these newly formed spines establish connections. We developed a method for labeling, automated detection and morphological analysis of synaptic contacts. Individual labeling of neurons in mice that express the Vesicular GLUtamate Transporter-1 fused to Venus allows visualization of both dendritic spines and axonal boutons. Automated three-dimensional segmentation and morphometric analysis retrieve information on thousands of synapses at high resolution. We used this method to demonstrate that new cortico-striatal connections are formed in the striatum upon chronic cocaine. We also show that the cortical input weight is preserved over other cerebral inputs and that the newly formed spines contact pre-existing axonal boutons. Our results pave the way for other studies, since our method can be applied to any other neuronal type as demonstrated herein for glutamatergic connections on pyramidal neurons and Purkinje cells

Rapid synaptogenesis in the Nucleus Accumbens is induced by a single cocaine administration and stabilized by MAP Kinase interacting kinase 1 activity

International audienceBackground: Repeated cocaine exposure produces new spine formation in Striatal Projection Neurons (SPNs) of the Nucleus Accumbens (NAc). However, an acute exposure to cocaine can trigger long-lasting synaptic plasticity in SPN leading to behavioral alterations. This raises the intriguing question as to whether acute cocaine could modify enduringly striatal connectivity.Methods: A 3D morphometric analysis of presynaptic glutamatergic boutons and dendritic spines was performed on SPN one hour and one week after a single cocaine administration. Time-lapse two-photon microscopy in adult slices was used to determine the precise molecular events sequence responsible for the rapid spine formation.Results: A single injection triggered a rapid synaptogenesis and persistent increase in glutamatergic connectivity in SPN from the shell part of the NAc, specifically. Synapse formation occurred through clustered growth of active spines contacting pre-existing axonal boutons. Spine growth required ERK activation, while spine stabilization involved transcription-independent protein synthesis driven by MAP kinase interacting kinase-1 (MNK-1), downstream from ERK. The maintenance of new spines driven by MNK-1 was essential for long-term connectivity changes induced by cocaine in vivo.Conclusions: Our study originally demonstrates that an acute administration of cocaine is able to induce stable synaptic rewiring in the NAc, which will likely influence responses to subsequent drug exposure. It also unravels a new functional role for cocaine-induced ERK pathway independently of nuclear targets. Finally, it reveals that MNK-1 has a pivotal role in cocaine-induced connectivity

Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations

International audienceBACKGROUND: Addiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive. METHODS: Acute cocaine-treated mice were used for quantitative reverse-transcriptase polymerase chain reaction, immunocytochemistry, and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates. RESULTS: Arc messenger RNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an extracellular-signal regulated kinase-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription, where it colocalizes with phosphorylated histone-H3, an important component of nucleosomal response. In vitro, Arc overexpression downregulates phosphorylated histone-H3 without modifying extracellular-signal regulated kinase phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-polymerase II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine. CONCLUSIONS: Cocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction

Activity-Regulated Cytoskeleton-Associated Protein Accumulates in the Nucleus in Response to Cocaine and Acts as a Brake on Chromatin Remodeling and Long-Term Behavioral Alterations

International audienceBackgroundAddiction relies on persistent alterations of neuronal properties, which depends on gene regulation. Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that modulates neuronal plasticity underlying learning and memory. Its role in cocaine-induced neuronal and behavioral adaptations remains elusive.MethodsAcute cocaine-treated mice were used for Q-RT-PCR, immunocytochemistry and confocal imaging from striatum. Live imaging and transfection assays for Arc overexpression were performed from primary cultures. Molecular and behavioral adaptations to cocaine were studied from Arc-deficient mice and their wild-type littermates.ResultsArc mRNA and proteins are rapidly induced in the striatum after acute cocaine administration, via an ERK-dependent de novo protein synthesis. Although detected in dendrites, Arc accumulates in the nucleus in active zones of transcription where it colocalizes with phosphorylated histone-H3 (pH3), an important component of nucleosomal response. In vitro, Arc overexpression down-regulates pH3 without modifying ERK phosphorylation in the nucleus. In vivo, Arc-deficient mice display decreased heterochromatin domains, a high RNA-Pol II activity and enhanced c-Fos expression. These mice presented an exacerbated psychomotor sensitization and conditioned place preference induced by low doses of cocaine.ConclusionsCocaine induces the rapid induction of Arc and its nuclear accumulation in striatal neurons. Locally, it alters the nucleosomal response, and acts as a brake on chromatin remodeling and gene regulation. These original observations posit Arc as a major homeostatic modulator of molecular and behavioral responses to cocaine. Thus, modulating Arc levels may provide promising therapeutic approaches in drug addiction

A campaign to eradicate bovine babesiosis from New Caledonia

In December 2007, Babesia bovis was introduced to New Caledonia through the importation of cattle that had been vaccinated with a live tick fever (babesiosis and anaplasmosis) vaccine. Although the tick Rhipicephalus (Boophilus) microplus is common in New Caledonia, the territory had previously been free of tick-borne diseases of cattle. This paper describes the initial extent of the outbreak, the measures and rationale for disease control, and the progress to date of the eradication campaign. Initially, 22 properties were affected involving approximately 2300 cattle in ‘high risk’ zones and 1600 in adjoining ‘suspect’ zones. Rather than slaughtering infected herds or attempting to eliminate the tick vector, the campaign was based on quarantine of affected properties, and aggressive tick control in conjunction with 3-monthly treatments of the high risk cattle with the antiprotozoal drug imidocarb dipropionate. Subsequent surveillance by ELISA and PCR showed a progressive and dramatic decline in seroprevalence among infected herds and the absence of new infections. All 22 properties were considered to be free of Babesia within 12 months of the start of the disease control program. These results indicate that the strategy was effective in eliminating Babesia from infected herds and feasible as an eradication strategy on a moderately large scale. Unfortunately, early in the campaign, babesiosis spread to a herd of feral cattle on a property in the ‘suspect’ zone, and this reservoir of infection subsequently resulted in the infection (or reinfection) of cattle on several neighbouring commercial farms. The eradication campaign in New Caledonia is currently focussed on destocking the feral cattle – extensive surveillance suggests that this is the only remaining nidus of infection