A permissive role for dopamine in the production of vigorous movements

Abstract

Dopamine is essential for the production of vigorous movements, but how dopamine modifies the gain of motor commands remains unclear. Here, we developed a dexterous motor task in which head-restrained mice self-initiate fast and large-amplitude lever pushes with their left forelimb to earn rewards. We show that this task is goal-directed and depends on cortico-striatal circuits in the hemisphere contralateral to the limb used to push the lever. We find that unilateral loss of midbrain dopamine neurons reduces the speed and amplitude of lever pushes, and that levodopa treatment rapidly restores motor vigor, consistent with parkinsonian bradykinesia. Photometry recordings of striatal dopamine levels indicate that the therapeutic efficacy of levodopa does not require phasic dopamine release. In dopamine-intact mice, optogenetic stimulation of midbrain dopamine neurons calibrated to mimic transients evoked by rewards is also insufficient to increase the speed and amplitude of forelimb movements. Together, our data show that phasic dopamine transients are unlikely to specify the vigor of forelimb movements online as they are being executed, and suggest instead that dopamine plays a permissive role in the selection and production of vigorous movements. Our findings have important implications for our understanding of how the basal ganglia contribute to motor control under physiological conditions and in Parkinson's disease.

Striatal dopamine contributions to skilled motor learning

“…Repeated dopamine neuron stimulation or inhibition progressively altered forelimb kinematics across many reaches, but did not instantaneously affect reaching or grasping (Bova et al, 2020). This is consistent with a recent report that restoring tonic striatal dopamine levels permits non-dexterous forelimb movements in dopamine-depleted mice, but that phasic dopamine release is not required (Liu et al, 2022). Thus, it is unlikely that phasic striatal dopamine release regulates reach “vigor” on short timescales.…”

Dopamine release in the nucleus accumbens promotes REM sleep and cataplexy

“… 28 SNc projections to the dorsolateral striatum (DLS) are generally associated with motor control and habit formation, while VTA projections to ventral regions such as the nucleus accumbens (NAc) and its core (NAcc) and shell (NAcSh) subregions are associated with reward and learning. 28 , 29 , 30 , 31 During REM sleep, activity in the ventral striatum increases to levels similar to wakefulness, with DA release also increasing to wake-like levels. 18 , 32 , 33 Furthermore, relative to healthy subjects, patients with narcolepsy show increased activity in the ventral striatum in response to cataplexy-evoking stimuli, 34 while lesions to this region attenuate cataplexy frequency.…”

Striatal dopamine regulates sleep states and narcolepsy-cataplexy

“…The striatum is composed of functionally and anatomically distinct regions 27 , and the activity of DA terminals differs between dorsal and ventral striatal structures 28 . SNc projections to the dorsolateral striatum (DLS) are generally associated with motor control and habit formation, while VTA projections to ventral regions such as the nucleus accumbens (NAc) and its core (NAcc) and shell (NAcSh) subregions are associated with reward and learning [28][29][30][31] . During REM sleep, activity in the ventral striatum increases to levels similar to wakefulness, with DA release also increasing to wake-like levels 18,32,33 .…”