Chemogenetic Restoration of Autonomous Subthalamic Nucleus Activity Ameliorates Parkinsonian Motor Dysfunction

McIver, Eileen L.; Chu, Hong-Yuan; Atherton, Jeremy F.; Cosgrove, Kathleen E.; Kondapalli, Jyothisri; Wokosin, David L.; Surmeier, D. James; Bevan, Mark D.

doi:10.2139/ssrn.3257347

Cited by 1 publication

(1 citation statement)

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“…The dSPN-GPe innervation is selectively strengthened in a chronic PD model Both circuit model and experimental data converge on the idea that an increased striatopallidal input contributes to the aberrant activity in the GPe in PD (Albin et al, 1989;Wichmann and DeLong, 2003;Walters et al, 2007;Ballion et al, 2009;Kita and Kita, 2011a, b;Lemos et al, 2016;Ryan et al, 2018;McIver et al, 2019). Our previous study demonstrated that total striatal input in unidentified GPe neurons increased following chronic 6-OHDA lesion (Cui et al, 2016).…”

Section: Dms and Dls Inputs Share A Similar Organizationmentioning

confidence: 76%

Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Cui¹,

Chang³

et al. 2020

Preprint

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The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

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