PT  - JOURNAL ARTICLE
AU  - Peng P. Gao
AU  - Jeffrey H. Goodman
AU  - Todd C. Sacktor
AU  - Joseph T. Francis
TI  - The Molecular Engram of Procedural Motor Skill Memories resides in Layer 5 of the Primary Motor cortex
AID  - 10.1101/193508
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 193508
4099  - http://biorxiv.org/content/early/2017/12/03/193508.short
4100  - http://biorxiv.org/content/early/2017/12/03/193508.full
AB  - Procedural motor learning and memories, such as those associated with learning to ride a bike, are thought to be supported by reorganization and plasticity of the sensorimotor cortex (S1, M1). Several studies have shown that procedural learning is accompanied by enhanced synaptic strength and structural modification in the primary motor cortex (M1) at distinct layers (e.g. layers II/III and V). However, an investigation that causally links these changes with synaptic molecular machinery and behavior has been elusive. This study aims to fill this gap in our current knowledge by tracking layer specific changes in a key molecule, PKMζ, that has been shown necessary and sufficient for the maintenance of long term potentiation (LTP), in S1 and M1. In addition, we correlate change in PKMζ with changes in task performance. We show that PKMζ levels decrease in Layers II/III of S1 during an early pause in performance gains on day 3 of training. Subsequently, PKMζ levels increase in S1/M1 layers II/III and V as performance improves to an asymptote on day 9, and, after training ends, the increase persists for more than 1 month in M1 layer V. Lastly, we utilized genetic and pharmacological methods to causally perturb PKMζ during and after learning, which slowed the memory formation and weakened its maintenance, but didn’t change the asymptotic level of task performance. Blocking aPKC activity erased sensorimotor memories that were maintained without reinforcement after a consolidation window of greater than 48 hrs. Thus, PKMζ sustains the molecular engram for motor memories maintained without practice within M1 layer V.Significance Statement Procedural memories of motor skill, such as for learning to ride a bicycle, can be retained without practice for long periods of time, but the location and mechanism of storage of these long-term memories are unknown. To link dynamic changes in synaptic molecular machinery with the evolving phases of sensorimotor learning and memory, we examined changes in PKMζ in the sensorimotor cortex. PKMζ is a protein shown necessary and sufficient for the maintenance of long term potentiation (LTP). We show that PKMζ is necessary for maintaining sensorimotor memories, only, if practice on a task is paused for more than 48 hrs, that new PKMζ is necessary for normal learning and memory, and such memories are maintained by PKMζ in layer IV of M1.