Abstract
The striatum is the input structure of the basal ganglia network that contains heterogeneous neuronal populations, including two populations of projecting neurons called the medium spiny neurons (MSNs), and different types of interneurons. We developed a transgenic mouse model enabling inducible ablation of the striatonigral MSNs constituting the direct pathway by expressing the human diphtheria toxin (DT) receptor under the control of the Slc35d3 gene promoter, a gene enriched in striatonigral MSNs. DT injection into the striatum triggered selective elimination of the majority of striatonigral MSNs. DT-mediated ablation of striatonigral MSNs caused selective loss of cholinergic interneurons in the dorsal striatum but not in the ventral striatum (nucleus accumbens), suggesting a region-specific critical role of the direct pathway in striatal cholinergic neuron homeostasis. Mice with DT injection into the dorsal striatum showed altered basal and cocaine-induced locomotion and dramatic reduction of L-DOPA-induced dyskinesia in the parkinsonian condition. In addition, these mice exhibited reduced anxiety, revealing a role of the dorsal striatum in the modulation of behaviors involving an emotional component, behaviors generally associated with limbic structures. Altogether, these results highlight the implication of the direct striatonigral pathway in the regulation of heterogeneous functions from cell survival to regulation of motor and emotion-associated behaviors.
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Acknowledgements
This work was supported by CNRS, Aix-Marseille Université, Fondation de France, Fédération pour la Recherche sur le Cerveau. D.R. was supported by a grant from the Ministry of Education and Research and France Parkinson. We thank A. de Kerchove d’Exaerde for his help in the BAC transgenesis and single-cell RT-PCR experiments, A. Moqrich for helpful discussion and comments on the manuscript, and A. Reynders for her critical comments on the manuscript. We also thank the animal and imaging facilities of the IBDM.
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Révy, D., Jaouen, F., Salin, P. et al. Cellular and Behavioral Outcomes of Dorsal Striatonigral Neuron Ablation: New Insights into Striatal Functions. Neuropsychopharmacol 39, 2662–2672 (2014). https://doi.org/10.1038/npp.2014.121
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DOI: https://doi.org/10.1038/npp.2014.121
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