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Hosp J.A.,University of Zürich | Hosp J.A.,Rehabilitation Initiative and Technology Center Zurich | Nolan H.E.,University of Zürich | Nolan H.E.,Rehabilitation Initiative and Technology Center Zurich | And 3 more authors.
Experimental Brain Research | Year: 2015

Dopaminergic signaling within the primary motor cortex (M1) is necessary for successful motor skill learning. Dopaminergic neurons projecting to M1 are located in the ventral tegmental area (VTA, nucleus A10) of the midbrain. It is unknown which behavioral correlates are encoded by these neurons. The objective here is to investigate whether VTA-M1 fibers are collaterals of projections to prefrontal cortex (PFC) or nucleus accumbens (NAc) or if they form a distinct pathway. In rats, multiple-site retrograde fluorescent tracers were injected into M1, PFC and the core region of the NAc and VTA sections investigated for concomitant labeling of different tracers. Dopaminergic neurons projecting to M1, PFC and NAc were found in nucleus A10 and to a lesser degree in the medial nucleus A9. Neurons show high target specificity, minimal collateral branching to other than their target area and hardly cross the midline. Whereas PFC- and NAc-projecting neurons are indistinguishably intermingled within the ventral portion of dopaminergic nuclei in middle and caudal midbrain, M1-projecting neurons are only located within the dorsal part of the rostral midbrain. Within M1, the forelimb representation receives sevenfold more dopaminergic projections than the hindlimb representation. This strong rostro-caudal gradient as well as the topographical preference to dorsal structures suggest that projections to M1 emerged late in the development of the dopaminergic systems in and form a functionally distinct system. © 2015, Springer-Verlag Berlin Heidelberg.

Rioult-Pedotti M.-S.,University of Zürich | Rioult-Pedotti M.-S.,Rehabilitation Initiative and Technology Center Zurich | Rioult-Pedotti M.-S.,Brown University | Pekanovic A.,University of Zürich | And 6 more authors.
PLoS ONE | Year: 2015

Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease. © 2015 Rioult-Pedotti et al.

Hosp J.A.,University of Zürich | Hosp J.A.,Rehabilitation Initiative and Technology Center Zurich | Luft A.R.,University of Zürich | Luft A.R.,Rehabilitation Initiative and Technology Center Zurich | Luft A.R.,Johns Hopkins University
Frontiers in Neurology | Year: 2013

Although the architecture of a dopaminergic (DA) system within the primary motor cortex (M1) was well characterized anatomically, its functional significance remained obscure for a long time. Recent studies in rats revealed that the integrity of DA fibers in M1 is a prerequisite for successful acquisition of motor skills. This essential contribution of DA for motor learning is plausible as it modulates M1 circuitry at multiple levels thereby promoting plastic changes that are required for information storage: at the network level, DA increases cortical excitability and enhances the stability of motor maps. At the cellular level, DA induces the expression of learning-related genes via the transcription factor c-Fos. At the level of synapses, DA is required for the formation of long-term potentiation, a mechanism that likely is a fingerprint of a motor memory trace within M1. DA fibers innervating M1 originate within the midbrain, precisely the ventral tegmental area (VTA) and the medial portion of substantia nigra (SN). Thus, they could be part of the meso-cortico-limbic pathway - a network that provides information about saliency and motivational value of an external stimulus and is commonly referred as "reward system." However, the behavioral triggers of the release of dopamine in M1 are not yet identified. As alterations in DA transmission within M1 occur under various pathological conditions such as Parkinson disease or ischemic and traumatic brain injury, a deeper understanding of the interaction of VTA/SN and M1 may reveal a deeper insight into a large spectrum of neurological disorders. © 2013 Hosp and Luft.

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