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Le Touquet – Paris-Plage, France

Girault J.-A.,Institute du Fer a Moulin | Girault J.-A.,French Institute of Health and Medical Research | Girault J.-A.,University Pierre and Marie Curie
Progress in Molecular Biology and Translational Science | Year: 2012

The striatum is a deep region of the forebrain involved in action selection, control of movement, and motivation. It receives a convergent excitatory glutamate input from the cerebral cortex and the thalamus, controlled by dopamine (DA) released in response to unexpected rewards and other salient stimuli. Striatal function and its dysfunction in drug addiction or Parkinson's disease depend on the interplay between these neurotransmitters. Signaling cascades in striatal medium-sized spiny neurons (MSNs) involve multiple kinases, phosphatases, and phosphoproteins, some of which are highly enriched in these neurons. They control the properties of ion channels and the plasticity of MSNs, in part through their effects on gene transcription. This chapter summarizes signaling in MSNs and focuses on the regulation of multiple protein phosphatases through DA and glutamate receptors and the role of ERK. It is hypothesized that these pathways are particularly adapted to the specific computing properties of MSNs and the function of the basal ganglia circuits in which they participate. © 2012 Elsevier Inc. Source

Meye F.J.,Institute du Fer a Moulin | Meye F.J.,French Institute of Health and Medical Research | Meye F.J.,University Pierre and Marie Curie | Ramakers G.M.J.,University Utrecht | Adan R.A.H.,University Utrecht
Translational Psychiatry | Year: 2014

The midbrain dopamine system has an important role in processing rewards and the stimuli associated with them, and is implicated in various psychiatric disorders. This system is tightly regulated by various G protein-coupled receptors (GPCRs). It is becoming increasingly clear that these receptors are not only activated by (endogenous) agonists but that they also exhibit agonist-independent intrinsic constitutive activity. In this review we highlight the evidence for the physiological role of such constitutive GPCR activity (in particular for cannabinoid 1, serotonin 2C and mu-opioid receptors) in the ventral tegmental area and in its output regions like the nucleus accumbens. We also address the behavioral relevance of constitutive GPCR signaling and discuss the repercussions of its abolition in dopamine-related psychiatric diseases. © 2014 the American College of Gastroenterology All rights reserved. Source

Meye F.J.,Institute du Fer a Moulin | Meye F.J.,French Institute of Health and Medical Research | Meye F.J.,University Pierre and Marie Curie | Adan R.A.H.,University Utrecht
Trends in Pharmacological Sciences | Year: 2014

Overconsumption of high caloric food plays an important role in the etiology of obesity. Several factors drive such hedonic feeding. High caloric food is often palatable. In addition, when an individual is sated, stress and food-related cues can serve as potent feeding triggers. A better understanding of the neurobiological underpinnings of food palatability and environmentally triggered overconsumption would aid the development of new treatment strategies. In the current review we address the pivotal role of the mesolimbic dopamine reward system in the drive towards high caloric palatable food and its relation to stress- and cue-induced feeding. We also discuss how this system may be affected by both established and potential anti-obesity drug targets. © 2013 Elsevier Ltd. All rights reserved. Source

Herve D.,French Institute of Health and Medical Research | Herve D.,University Pierre and Marie Curie | Herve D.,Institute du Fer a Moulin
Frontiers in Neuroanatomy | Year: 2011

In the principal neurons of striatum (medium spiny neurons, MSNs), cAMP pathway is primarily activated through the stimulation of dopamine D1 and adenosine A 2A receptors, these receptors being mainly expressed in striatonigral and striatopallidal MSNs, respectively. Since cAMP signaling pathway could be altered in various physiological and pathological circumstances, including drug addiction and Parkinson's disease, it is of crucial importance to identify the molecular components involved in the activation of this pathway. In MSNs, cAMP pathway activation is not dependent on the classical Gs GTP-binding protein but requires a specific G protein subunit heterotrimer containing Gαolf/β2/γ7 in particular association with adenylyl cyclase type 5. This assembly forms an authentic functional signaling unit since loss of one of its members leads to defects of cAMP pathway activation in response to D1 or A 2A receptor stimulation, inducing dramatic impairments of behavioral responses dependent on these receptors. Interestingly, D1 receptor (D1R)-dependent cAMP signaling is modulated by the neuronal levels of Gαolf, indicating that Gαolf represents the rate-limiting step in this signaling cascade and could constitute a critical element for regulation of D1R responses. In both Parkinsonian patients and several animal models of Parkinson's disease, the lesion of dopamine neurons produces a prolonged elevation of Gαolf levels. This observation gives an explanation for the cAMP pathway hypersensitivity to D1R stimulation, occurring despite an unaltered D1R density. In conclusion, alterations in the highly specialized assembly of Gαolf/β2/γ7 subunits can happen in pathological conditions, such as Parkinson's disease, and it could have important functional consequences in relation to changes in D1R signaling in the striatum. © 2011 Hervé. Source

Gaspar P.,French Institute of Health and Medical Research | Gaspar P.,University Pierre and Marie Curie | Gaspar P.,Institute du Fer a Moulin | Lillesaar C.,French National Center for Scientific Research
Philosophical Transactions of the Royal Society B: Biological Sciences | Year: 2012

The serotonin (5-HT) system is generally considered as a single modulatory system, with broad and diffuse projections. However, accumulating evidence points to the existence of distinct cell groups in the raphe. Here, we review prior evidence for raphe cell heterogeneity, considering different properties of 5-HT neurons, from metabolism to anatomy, and neurochemistry to physiology. We then summarize more recent data in mice and zebrafish that support a genetic diversity of 5-HT neurons, based on differential transcription factor requirements for the acquisition of the 5-HT identity. In both species, PET1 plays a major role in the acquisition and maintenance of 5-HT identity in the hindbrain, although some 5-HT neurons do not require PET1 for their differentiation, indicating the existence of several transcriptional routes to become serotoninergic. In mice, both PET1- dependent and -independent 5-HT neurons are located in the raphe, but have distinct anatomical features, such as the morphology of axon terminals and projection patterns. In zebrafish, all raphe neurons express pet1, but Pet1-independent 5-HT cell groups are present in the forebrain. Overall, these observations support the view that there are a number of distinct 5-HT subsystems, including within the raphe nuclei, with unique genetic programming and functions. © 2012 The Royal Society. Source

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