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Séminaire - Alban de KerchoveThe role of the two efferent neuronal populations of the striatum in addiction and motor control: 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 cortex) and the dorsomedial striatum (DMS) (innervated by prefrontal and other associative cortices), 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 nucleus accumbens (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 combining BAC transgenesis, Cre/lox recombination and toxin receptor cell 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 control over locomotion 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 complete 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 protocol.

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.