Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions

Abstract

The dorsal striatum 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, but contribution of D 2 Rstriatopallidal and D 1 R-striatonigral neurons in the dorsomedial (DMS, associative) and dorsolateral (DLS, sensorimotor) striatum to distinct functions remains elusive. To delineate cell type-specific motor functions of the DMS or the DLS, we selectively ablated D 2 R-and D 1 Rexpressing striatal neurons with spatial resolution. We found that associative striatum exerts a population-selective control over locomotion and reactivity to novelty, striatopallidal and striatonigral neurons inhibiting and stimulating exploration, respectively. Further, DMS-striatopallidal neurons are involved only in early motor learning whereas gradual motor skill acquisition depends on striatonigral neurons in the sensorimotor striatum. Finally, associative striatum D 2 R neurons are required for the cataleptic effect of the typical neuroleptic drug haloperidol and for amphetamine motor response sensitization. Altogether, these data provide direct experimental evidence for cell-specific topographic functional organization of the dorsal striatum.

Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions

“…Our behavioral data showing reduced locomotion in DT-injected DTR þ mice confirm the BG model of the direct pathway promoting movement and are consistent with recent studies reporting that optogenetic activation or specific ablation of striatonigral MSNs enhances and reduces locomotion, respectively (Durieux et al, 2012;Kravitz et al, 2010). The increase in GAD 67 mRNA level in the SNr of DT-injected mice further supports the view that hypolocomotion results from overactive BG outflow subsequent to removal of the inhibitory influence exerted by striatonigral MSNs.…”

“…Knowing that transgene expression level is highly dependent on the promoter used to drive its expression, we can assume that DTR level is quite different in the two models. This might also explain the difference in the efficient DT dose between the two studies (0.5 ng/ml vs 0.1 ng/ml in Durieux et al, 2012); indeed 0.1 ng/ml did not produce significant ablation in our model (not shown). Level of DTR expression might impact the degenerative process, as for instance the kinetics of striatonigral MSNs death and glial reactivity, and differently affect cholinergic interneurons.…”

“…We performed a series of experiments suggesting that the cholinergic loss, which occurred specifically in the dorsal but not in the ventral striatum, is the consequence of striatonigral MSNs' ablation. Another study, in which ablation of striatonigral MSNs is also obtained by DTR activation, reported no change in the number of striatal cholinergic interneurons after DT injection (Durieux et al, 2012). In this study, DTR expression in striatonigral MSNs is achieved by crossing iDTR mice (in which DTR expression is under the control of the ubiquitous Rosa26 promoter but is prevented by a loxPflanked STOP cassette) with D 1 -Cre mice.…”

“…Recent advances in cell-type-specific technologies have provided a wealth of data allowing a more comprehensive understanding of MSNs roles in drug addiction (Durieux et al, 2009;Durieux et al, 2012;Ferguson et al, 2011;Lobo et al, 2010), cognitive functions (Hikida et al, 2010;Hikida et al, 2013;Nishizawa et al, 2012;Tai et al, 2012;Yawata et al, 2012), and parkinsonian physiopathology (Kravitz et al, 2010). Here, we developed a new inducible model of diphtheria toxin (DT) receptor-mediated ablation to further explore the functional implications of striatonigral MSNs of the dorsal striatum.…”

“…For behavioral characterization, we first focused on motor function linked to disturbed striatal dopamine tone, cocaine-induced locomotion, and L-DOPA-induced dyskinesia (LID), which are associated with selective and robust molecular changes in striatonigral MSNs, including ERK signaling (BertranGonzalez et al, 2008;Santini et al, 2009). Acute response to psychostimulant has been investigated using amphetamine in a model of striatonigral MSNs ablation restricted to subterritories of the dorsal striatum (Durieux et al, 2012), and direct demonstration of dorsal striatonigral MSNs involvement in LID, a major complication of the most common pharmacotherapy of PD, is still lacking. We next moved to non-motor function as accumulating evidence suggests that, in addition to sensorimotor information processing, the dorsal striatum might also mediate emotional/motivational functions classically ascribed to the ventral striatum (Balleine et al, 2007).…”