Novel motor skills are learned through repetitive practice and, once acquired, can persist long after training stops. Earlier studies have shown that such learning induces a change in functional map in the primary motor cortex. However, how motor learning affects neuronal circuitry at the level of individual synapses and how long-lasting memory is structurally encoded in the intact brain remain elusive. The majority of excitatory glutamatergic synapses in the mammalian central nervous system (CNS) are located on postsynaptic dendritic spines, which contain all the essential components required for postsynaptic signaling and, thus, serve as a good indicator of synaptic connectivity. Using transcranial two-photon microscopy to visualize fluorescently labeled dendritic spines in the brain of transgenic mice (YFP-H line), my lab examines circuit plasticity mediated by structural remodeling during motor learning and memory formation.
Temporal rules of synapse remodeling: Training mice with a forelimb specific task, we found that new spines of the output pyramidal neurons form rapidly (within one hour of training) in the motor cortex contralateral to the trained limb. Interestingly, the amount of spines formed within the first training session is linearly correlated with the number of successful reaches during that training session, revealing a direct link between learning and spine formation. Although selective elimination of the synapses that existed before training gradually returned the overall synaptic density to the baseline level, learning-induced new synapses were preferentially stabilized during subsequent training. Furthermore, we demonstrated that learning-induced circuit rewiring could endure long after training had stopped. Practice of novel, but not previously learned, tasks further promoted synaptogenesis in adulthood. These findings reveal that rapid, but long-lasting synaptic reorganization is closely associated with motor learning. They also suggest that stabilized neuronal connections are the foundation of durable motor memory. This work was published in Nature (Xu et al., 2009).
Spatial rules of synapse remodeling: Many lines of evidence suggest that memory in the mammalian brain is stored in distinct spatiotemporal patterns. Despite recent progresses in identifying neuronal populations involved in memory coding, the synapse-level mechanism is still poorly understood. To address this question, we recently investigated the spatial distribution of learning-induced new spines. We found that spines are not uniformly distributed along dendrites, and spine formation and elimination are regulated by local spine density. While spines formed during the same task are spatially correlated, spines formed during different tasks are not. These new findings reveal that distribution of spines along dendrites is actively regulated in vivo, and that memory traces for a motor task may be encoded by the spatial distribution of synapses in the mammalian brain. This work has been recently published in Nature (Fu et al., 2012).
Combining behavioral analysis with in vivo imaging opens the possibility of understanding synapse remodeling during learning. Many questions remained unanswered. To what degree does the brain change in response to learning? Is learning-induced synapse remodeling specific to certain neuronal types or cortical layers? How do cortical changes contribute to the motor engram? Can we perturb learning? How do different motor skills interfere with each other? What happens if the motor cortex is injured? Can motor rehabilitation help with the functional recovery of the brain? Currently we are actively developing tools and experimental paradigms to address these questions.
Xu T, Yu X, Perlik A, Tobin W, Zweig J, Tennant K, Theresa J, and Zuo Y (2009) Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 462(7275):915-919. [PDF]
Fu M, Yu X, Lu J, Zuo Y. (2012) Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo. Nature. 2012 Feb 19;483(7387):92-5. [PDF]
Yu X and Zuo Y (2011) Spine plasticity in the motor cortex. Curr. Opin. Neurobiol. 21(1):169-174. [PDF]