Cortical pyramidal tract neurons constrain pathological dopaminergic motor responses

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.