Cortical pyramidal tract neurons constrain pathological dopaminergic motor responses
- 1Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital
Abstract
Pyramidal tract (PT) neurons constitute a major cortical output pathway to subcortical structures, yet their contribution to parkinsonian and dyskinetic motor states remains unclear. Here, we show that chemogenetic activation of motor cortical PT neurons selectively confines pathological dopaminergic motor responses. Unilateral PT chemogenetic activation suppressed spontaneous locomotion in healthy mice but did not improve motor deficits following an ipsilateral 6-hydroxydopamine lesion. Instead, it attenuated contraversive rotations provoked by pharmacological D1-receptor stimulation and selectively reduced axial levodopa-induced dyskinesia. Mechanistically, PT stimulation reduced acute D1-mediated c-Fos induction in the dopamine-depleted striatum, without affecting chronic {Delta}FosB accumulation induced by repeated levodopa exposure. These findings identify a functional interaction between cortical PT output and striatal D1-receptor signalling that limits maladaptive motor responses to dopaminergic stimulation. Our results uncover a previously unrecognised cortical mechanism regulating pathological motor behaviour and suggest PT neurons as a potential substrate for circuit-based therapies in Parkinson's disease.
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BibTeX
@misc{atudorei2026cortical,
title = {{Cortical pyramidal tract neurons constrain pathological dopaminergic motor responses}},
author = {M. Atudorei and G. E. D. Olsson and C. del Agua Villa and C. Corcea and U. Gether and M. A. Cenci and H. Siebner and M. Rickhag},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.758468},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.758468v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Cortical pyramidal tract neurons constrain pathological dopaminergic motor responses
AU - M. Atudorei
AU - G. E. D. Olsson
AU - C. del Agua Villa
AU - C. Corcea
AU - U. Gether
AU - M. A. Cenci
AU - H. Siebner
AU - M. Rickhag
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.758468
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.758468v1
AB - Pyramidal tract (PT) neurons constitute a major cortical output pathway to subcortical structures, yet their contribution to parkinsonian and dyskinetic motor states remains unclear. Here, we show that chemogenetic activation of motor cortical PT neurons selectively confines pathological dopaminergic motor responses. Unilateral PT chemogenetic activation suppressed spontaneous locomotion in healthy mice but did not improve motor deficits following an ipsilateral 6-hydroxydopamine lesion. Instead, it attenuated contraversive rotations provoked by pharmacological D1-receptor stimulation and selectively reduced axial levodopa-induced dyskinesia. Mechanistically, PT stimulation reduced acute D1-mediated c-Fos induction in the dopamine-depleted striatum, without affecting chronic {Delta}FosB accumulation induced by repeated levodopa exposure. These findings identify a functional interaction between cortical PT output and striatal D1-receptor signalling that limits maladaptive motor responses to dopaminergic stimulation. Our results uncover a previously unrecognised cortical mechanism regulating pathological motor behaviour and suggest PT neurons as a potential substrate for circuit-based therapies in Parkinson's disease.
ER -