Motor skill learning depends on protein synthesis in motor cortex after training

Abstract

The role of protein synthesis in memory consolidation is well established for hippocampus-dependent learning and synaptic plasticity. Whether protein synthesis is required for motor skill learning is unknown. We hypothesized that skill learning is interrupted by protein synthesis inhibition (PSI). We intended to test whether local protein synthesis in motor cortex or cerebellum is required during skill acquisition and consolidation. Anisomycin (ANI; 100 microg/microl in 1 microl of PBS) injected into motor cortex, posterior parietal cortex, or cerebellum produced 84.0 +/- 1.44% (mean +/- SEM), 85.9 +/- 2.31%, and 87.3 +/- 0.17% of PSI 60 min after administration, respectively. In motor cortex, protein synthesis was still reduced at 24 hr (72.0 +/- 4.68% PSI) but normalized at 48 hr after a second injection given 24 hr after the first. To test for the effects of PSI on learning of a skilled reaching task, ANI was injected into motor cortex contralateral to the trained limb or into ipsilateral cerebellum immediately after daily training sessions 1 and 2. Two control groups received motor cortex injections of vehicle or ANI injections into contralateral parietal cortex. Control and cerebellar animals showed a sigmoid learning curve, which plateaued after day 4. PSI in motor cortex significantly reduced learning during days 1-4. Thereafter, when protein synthesis normalized, learning was reinitiated. ANI injections into motor cortex did not induce a motor deficit, because animals injected during the performance plateau did not deteriorate. This demonstrates that motor skill learning depends on de novo synthesis of proteins in motor cortex after training.

Figure 1.

Spread of ink injected into motor cortex and cerebellum (experiment 2). India ink was used as a visual stimulant to estimate the initial spread of ANI in cortex (top) and in cerebellum (bottom). Sections from one exemplary animal are shown.

Figure 2.

Effects of protein synthesis inhibition on motor skill learning (experiment 3). Inhibition of protein synthesis in motor cortex by local injection of ANI at the time points indicated by arrows impairs motor skill acquisition for 4 d. In contrast, ANI injections into cerebellum or parietal cortex do not affect motor skill learning (^*p < 0.05). After protein synthesis is restored (day 4), learning resumes but at a lower rate (see Discussion).

Figure 3.

Effects of PSI on latencies between pellet removal and door opening (experiment 3). A, During pretraining (sessions 3-0, pellet accessible by tongue) and subsequent forelimb reach training (sessions 1-8), latencies decrease exponentially. PSI in motor cortex (ANI-motor cortex group) does slightly but nonsignificantly increase latencies. B shows this increase on a stretched y-scale. Time points of ANI injections are indicated by arrows.

Figure 4.

Effects of PSI on motor performance (experiment 4). A, To test whether PSI in motor cortex induces motor deficits, animals were injected with anisomycin during the plateau phase of performance (immediately after sessions 11 and 12). No performance decline is observed. B, Motor cortical histology (cresyl violet) obtained from one exemplary animal implanted with the cannula system and injected twice with ANI provides no evidence for cortical injury apart from the needle tract and a small area of hemorrhagic transformation just below the tip of the cannula.