Dopamine (DA) is a classic neurotransmitter that can modulate synaptic plasticity. Anatomically, the primary motor cortex (M1) receives dopaminergic inputs from the mesocortical projection, yet the functional significance of this pathway on cortical plasticity has long remained elusive. In this study, we investigated the role of cortical dopamine in motor skill learning under pathophysiological condition using ischemic stroke models, as well as explored the underlying dopaminergic mechanisms that mediate skill learning in healthy condition.

Recent clinical evidence has shown that dopaminergic treatment for patients with ischemic stroke enhances sensorimotor motor learning, however the mechanisms involved are poorly understood. In the first study, we investigated the effects of dopaminergic treatment on motor recovery using rodent ischemic stroke models. Through a battery of motor tasks, we revealed that levodopa/benserazide treatment specifically enhanced the performance of tasks which required motor learning, both in the acute and chronic stages of stroke. Furthermore, the differential effects on distal and proximal limb performance suggests that dopamine carries a precise role in the recovery of motor skills.

The second study aims to determine the impacts of ischemic stroke on cortical dopamine and the effects of dopaminergic treatment on structural and synaptic plasticity of cortical neurons. Evidence was obtained to show that dopamine level of peri-infarct region, and not just the core of infarct, was decreased by stroke. By replenishing dopamine level, post-stroke alteration in spine dynamics and synaptic plasticity can be restored. We further determined that both D1 and D2 receptor subtype activity is necessary for stroke recovery, and identified the involvement of mesocortical dopaminergic pathway in the recovery process through pharmacological and optogenetic tools.

In recent year, increase evidence has emerged on the role of glial cells in neuroplasticity. Coupled with evidence for DA actions in astrocytes, we postulated that astrocytes are also involved in the motor skill learning process. Our final study demonstrated that astrocytic morphological plasticity occurs in the trained motor cortical hemisphere. Through chemogenetic and pharmacological tools that inhibit cortical astrocytes, we demonstrated that GPCR-linked astrocytic activity during skill training play a crucial role in motor skill consolidation. Coincidentally, depletion of motor cortical dopamine which produces similar impairment in the animals led to the hypothesis that dopamine acts on astrocyte to mediate plasticity necessary for skill consolidation. Using live imaging of calcium activity in cortical astrocyte culture, we revealed that D2 receptor activation can modulate the synchronization of glutamateinduced acceleration of spontaneous calcium oscillation suggests dopamine can modulate the activity of astrocytic network.

Our work has established the scientific basis for DA actions on cortical plasticity and motor recovery after ischemic stroke. Further investigation of astroglia involvement and the specific effects of DA on astrocyte activity may provide targets for therapeutic strategies designed to improve outcome for patients with stroke and other motor impairments, in addition to greater understanding the physiological process of motor learning.