Objective: Assess the correlates of movement vigor in Substantia Nigra dopaminergic neurons

Background: Current basal ganglia models have focused on the role of dopamine in movement initiation. This contrasts with what is observed in Parkinson’s Disease (PD) where chronic dopamine depletion leads not only to loss of movements (akinesia) but also to reduction in their speed and amplitude (bradykinesia).

Methods: Inspired by the repetitive finger tapping manoeuvre used to assess PD patients we developed a new self-paced operant task, in which mice learn to perform a sequence of fast actions using only one forepaw at a time. We collected data on speed, acceleration and spatial position of the lever and mouse paw. A miniature epifluorescence microscope (~1.9g) was used to image GCaMP6f fluorescence (a calcium indicator) in dopaminergic Substantia Nigra pars compacta (SNpc) cells while TH-cre mice performed the task. After animals learned the task, partial dopamine depletion is induced by unilateral intrastriatal 6-Hydroxydopamine (6-OHDA) injection.

Results: Healthy mice learned the task, with a progressive improvement in performance and a reduction in variability. During task performance, we identified distinct populations of SNpc neurons specifically modulated by reward consumption or movement sequence initiation. Phasic activity of a subpopulation of movement-modulated SNpc neurons preceded the start of a learned lever-press sequence and was related to the upcoming sequence vigor (higher activity related with faster movements and/or longer sequences). Unilateral SNpc depletion with 6-OHDA lead to a side specific loss of movement vigor (with slower movement and shorter sequences).

Conclusions: We developed a clinically-relevant task for skilled movements assessment in mice, and identified SNpc correlates of movement vigor. Dopamine depletion caused slower movement speeds and shorter movement sequences. Ongoing analysis will allow us to clarify the role of SNpc dopaminergic neurons in healthy and chronic dopamine depleted conditions. This will increase our understanding of basal ganglia dysfunction in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dopaminergic-neurons-in-substantia-nigra-pars-compacta-code-the-vigor-of-movement-sequences/