Verslag – Rapport – Bericht – Report - GSKE - FMRE

The dorsal striatum is subdivided into the dorsolateral striatum, DLS, corresponding to the primate
putamen, predominantly innervated by the sensorimotor cortex and the dorsomedial striatum, DMS,
homologous to primate caudate nucleus, receiving projections from prefrontal and other association
cortices (Graybiel, 2008). The DMS is more engaged during initial stages of motor skill learning, when the
task is more dependent on attention and susceptible to interference (Luft and Buitrago, 2005) while the
DLS is required for progressive skill automatization and habit learning (Yin et al., 2004, 2009). Elimination
of D 1 R-striatonigral neurons in the DMS induced a reduction in ambulation while, in contrast, DMS
D 2 R-striatopallidal neuron ablated mice displayed hyperlocomotion. This showed that the modulatory
influence on locomotion observed following full ablations was recapitulated in DMS-restricted ablations,
indicating that associative striatum area exerts a MSN population-dependent control over spontaneous
locomotion. (Durieux et al., 2012). In the same line, we also showed that the direct pathway in the
associative cortico-striatal loop (DMS) is necessary for novelty-induced exploration and that in DMS
D 2 R-neuron ablated mice, a continuous translation of sensory stimuli to locomotion lead to a state of
continuous exploration/locomotion.
Evaluation of involvement of DLS and DMS D 1 R striatonigral and D 2 R striatopallidal neurons in motor
skill learning showed that in naive animals, when task performance is more susceptible to interference
and more dependent on attention (Luft and Buitrago, 2005), D 1 R- and D 2 R-MSNs work in concert
to promote acquisition of a new motor skill. Activation of D 1 R-MSNs in the sensorimotor striatum is
required for progressive automaticity of task performance, while activation of D 2 R-MSNs in associative
striatum inhibits competing exploratory activity. During later skill learning stage, attention to action is less
required and DMS D 2 R-MSNs progressively disengage of the process while DLS D 1 R-MSN pathway is
still required for skill automatization.
Treatment of schizophrenia positive symptoms with typical neuroleptic drugs is often associated with
motor side effects such as catalepsy. We evaluated involvement of each neuronal population in motor
responses to neuroleptic drugs and showed that only D 2 R-striatopallidal neuron removal selectively
in the associative striatum completely abolished haloperidol–induced catalepsy, indicating that
D 2 R-antagonism in striatopallidal neurons of the associative striatum (DMS) is critical for the motor
effects of haloperidol (Durieux et al., 2012). In the same line, we also showed that DMS D 2 R-neurons
necessarily contribute to the development of behavioural sensitization to amphetamine (Durieux et al.,
2012), while numerous studies identified the ventral striatum as the main striatal region contributing to
psychostimulants sensitization.
Altogether, our results provide direct in vivo experimental evidence for dissociation between neuronal
subtypes and striatal subregions in the regulation of novelty or drug-induced motor responses and
motor learning.
1.b Specific optogenetic control of D 1 R-striatonigral and D 2 R-striatopallidal MSN
The models described above allow a functional cell-type dissection of different striatal regions with a
high spatial resolution, but are not reversible. We therefore start to develop optogenetics, that is based
on the use of light-activatable proteins (“opto-”) encoded in DNA (“-genetic”) to reversibly modulate
in physiological timescale, in vivo or ex vivo, the activity of genetically targeted neuronal populations
in rodents. We had previously examining the feasibility of the technic ex vivo. Adeno-associated virus
(AAV), in which expression of Channelrhododopsin-2 (ChR2) cation channel, fused with eYFP, is
dependent upon Cre-recombination has been stereotactically injected for transfection into the striatum
of A 2A R-Cre mice (see above and Durieux et al., 2009,2012). Experiments combining perforated patch
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Verslag – Rapport – Report 2012