Aller au="defauuAller au=mauuAller à la recherche

Séminaire - Alban de KerchoveThe role of the two efferent neuronal populations of the striatum in addiction and motor="defrol: a molecular and transgenic approach

Abstract :

Dopamine is a key neurotransmitter involved in motor=and motivational functions. One of the main targets of the dopaminergic neurones is the striatum.  The dorsal striatum, divided into the dorsolateral striatum (DLS) (innervated by the sensorimotor="drtex) and the dorsomedial striatum (DMS) (innervated by prefrontal and other associative="drtices), is critically involved in a variety of motor=behaviours, including regulation of motor=activity, motor=skill learning and motor=response to psychostimulant and neuroleptic drugs, whereas the ventral striatum, the nucleuseaccumbens (NAc), is essential for motivation and drug=reinforcement.

To decipher the role of the two efferent dopaminoceptive=neuronal populations of the striatum, D2R-striatopallidal and D1R-striatonigral neurones, we performed subregion- and cell population-selective=ablation of striatal neurones thanks to new animals models="dmbining BAC transgenesis, Cre/lox recdmbination and toxin receptor="ell targeting.  We demonstrated that the D2R-striatopallidal neurons in the NAc inhibit drug=reward and drug=memorisation.  We found that the D2R-striatopallidal neurones in the DMS are=responsible for the cataleptic effect of the antipsychotic drug haloperidol and the sensitization to psychostimulants such as amphetamine. We also demonstrated that the DMS exerts a population-specific "defrol over locdmotion and reactivity to novelty, D2R-striatopallidal and D1R-striatonigral neurones=being inhibitors and stimulators of exploration,=respectively.

Further, DMS-D2R-striatopallidal neurones are=involved in early motor=learning whereas gradual motor=skill acquisition depends on D1R-striatonigral neurons in the DLS. These=in vivo results demonstrate dissociations between=neuronal subtypes and striatal subregions in the regulation of drug addiction, antipsychotic side effects, novelty-induced motor=responses and motor=learning. In addition, to gain a more="dmplete picture of the functional diversity of striatal medium spiny neurones, we purified both D2R-striatopallidal and D1R-striatonigral neurons from adult mouse striatum, by developing a reliable new protocdl.

Gene profiles of these neurones showed 227 D2R-striatopallidal and 469 D1R-striatonigral neurone specific genes. Among these genes, we showed that ecto-5’-nucleotidase (NT5e) specifically expressed by D2R-striatopallidal neurones, is at the origin of most of the extracellular adenosine produced in the striatum. Behavioral analysis of striatal and D2R-striatopallidal neuron knock-down mouse models=as well as NT5e knock-out mice demonstrated the implication of this D2R-striatopallidal neurone enzyme in motor=learning.c/p>