Preliminary evidence indicates that dopamine given by mouth facilitates the learning of motor skills and improves the recovery of movement after stroke. The mechanism of these phenomena is unknown. Here, we describe a mechanism by demonstrating in rat that dopaminergic terminals and receptors in primary motor cortex (M1) enable motor skill learning and enhance M1 synaptic plasticity. Elimination of dopaminergic terminals in M1 specifically impaired motor skill acquisition, which was restored upon DA substitution. Execution of a previously acquired skill was unaffected. Reversible blockade of M1 D1 and D2 receptors temporarily impaired skill acquisition but not execution, and reduced long-term potentiation (LTP) within M1, a form of synaptic plasticity critically involved in skill learning. These findings identify a behavioral and functional role of dopaminergic signaling in M1. DA in M1 optimizes the learning of a novel motor skill.

Activity-dependent synaptic plasticity is likely to provide a mechanism for learning and memory. Cortical synaptic responses that are strengthened within a fixed synaptic modification range after 5 days of motor skill learning are driven near the top of their range, leaving only limited room for additional synaptic strengthening. If synaptic strengthening is a requisite step for acquiring new skills, near saturation of long-term potentiation (LTP) should impede further learning or the LTP mechanism should recover after single-task learning. Here we show that the initial learning-induced synaptic enhancement is sustained even long after training has been discontinued and that the synaptic modification range shifts upward. This range shift places increased baseline synaptic efficacy back within the middle of its operating range, allowing prelearning levels of LTP and long-term depression. Persistent synaptic strengthening might be a substrate for long-term retention in motor cortex, whereas the shift in synaptic modification range ensures the availability for new synaptic strengthening.

We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a micro-RNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in longterm potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient micro-RNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.animal model | Rtn4 | learning | memory G ene knockout (KO) technology has spurred the analysis of gene functions in mice during the past two decades (1) and has recently been expanded to other species using new genome modification technologies (2). Although germ-line gene ablation is a very powerful tool for investigating gene function in vivo, its most important drawback is that the complete loss of gene function often leads to molecular compensation, obscuring the role of the deleted gene. Tissue-or cell-specific KOs are more specific but are currently confined to mice as a model system. RNA interference (RNAi) is a viable alternative to the KO approach and represents a fast and powerful tool for manipulating gene expression (3). RNAi technology not only allows keeping the endogenous genomic locus intact, but it also enables the knockdown of multiple genes at the same time or the selective depletion of a specific isoform of mRNA transcripts (4). Another advantage is offered by the possibility of creating hypomorphic alleles instead of complete KOs, which can avoid embryonic lethality and better mirrors many human diseases and therapeutic interventions.Elucidating gene functions in transgenic rats has several important advantages over using mice (5). Their larger size simplifies interventions, such as microsurgery and multiple site in vivo electrophysiological recordings (6). Furthermore, higher-order cognitive functions are more developed in this social rodent species than in the more solitarily living mice (7,8). Hence, many behavioral tests are more advanced or validated for the rat species, especially regarding the behavioral assessment of complex neuropsychiatric disease phenotypes, such as negative symptoms in schizophrenia.For the rat, only polymerase (Pol) III-controlled shRNA RNAi models have been cre...