Rapid formation and selective stabilization of synapses for enduring motor memories

Abstract

Novel motor skills are learned through repetitive practice and, once acquired, persist long after training stops 1,2 . Earlier studies have shown that such learning induces an increase in the efficacy of synapses in the primary motor cortex, the persistence of which is associated with retention of the task [3][4][5] . 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 unknown. Here we show that synaptic connections in the living mouse brain rapidly respond to motor-skill learning and permanently rewire. Training in a forelimb reaching task leads to rapid (within an hour) formation of postsynaptic dendritic spines on the output pyramidal neurons in the contralateral motor cortex. Although selective elimination of spines that existed before training gradually returns the overall spine density back to the original level, the new spines induced during learning are preferentially stabilized during subsequent training and endure long after training stops. Furthermore, we show that different motor skills are encoded by different sets of synapses. Practice of novel, but not previously learned, tasks further promotes dendritic spine formation in adulthood. Our findings reveal that rapid, but long-lasting, synaptic reorganization is closely associated with motor learning. The data also suggest that stabilized neuronal connections are the foundation of durable motor memory.Fine motor movements require accurate muscle synergies that rely on coordinated recruitment of intracortical synapses onto corticospinal neurons 6,7 . Obtaining new motor skills has been shown to strengthen the horizontal cortical connections in the primary motor cortex 4,5 . In this study, we taught mice a single-seed reaching task (Supplementary Movie 1). The majority of 1-month-old mice that underwent training gradually increased their reaching success rates during the initial 4 days, and then levelled off (n = 42, Fig. 1a, b). There were a few mice (n = 5) that engaged in extensive reaching, but continually failed to grasp the seeds. These mice normally gave up reaching after 4-8 days (Fig. 1b) investigate the process of learning-induced synaptic remodelling in the intact motor cortex, we repeatedly imaged the same apical dendrites of layer V pyramidal neurons marked by the transgenic expression of yellow fluorescent protein (YFP-H line) in various cortical regions during and after motor learning, using transcranial two-photon microscopy 8 ( Supplementary Fig. 1). Dendritic spines are the postsynaptic sites of most excitatory synapses in the brain and changes in spine morphology and dynamism serve as good indicators of synaptic plasticity 9,10 . Spines that were formed and eliminated were identified by comparing images from two time points, and then normalized to the initial images. Imaged regions were guided by stereotaxic measurements, ensuring the imaged neurons resided in the primary motor cortex. In several experiments,...

Biphasic plasticity of dendritic fields in layer V motor neurons in response to motor learning

“…With respect to spine formation and the size of the forelimb representations in M1, a return to baseline was observed one week after the training ended [5,12]. Thus, in comparison with synapses and motor maps, the plastic modifications of dendritic morphology follow a slower timecourse.…”

“…In rodents that learn a motor task [3], plastic changes within M1 have been observed in the form of structural modification in dendrites [4] and their spines [5], in gene expression [6,7], synaptic weights [8] and motor maps [9]. With respect to the temporal profile of plastic changes, an initial phase of growth is followed by a subsequent phase of maturation [10].…”

“…With respect to the temporal profile of plastic changes, an initial phase of growth is followed by a subsequent phase of maturation [10]. An initial increase in spine formation for example is followed by an enhanced turnover that reduces the number of spines to baseline levels [5]. Whereas this concept of biphasic reorganization has been well demonstrated for spines [5], synaptic weights [11] and motor maps [12] it is unknown whether learning-induced growth of dendritic fields [4,13,14] is a lasting phenomenon or if a pruning occurs after a delay.…”

“…An initial increase in spine formation for example is followed by an enhanced turnover that reduces the number of spines to baseline levels [5]. Whereas this concept of biphasic reorganization has been well demonstrated for spines [5], synaptic weights [11] and motor maps [12] it is unknown whether learning-induced growth of dendritic fields [4,13,14] is a lasting phenomenon or if a pruning occurs after a delay. To address this question, we measured dendritic morphology of layer V motoneurons at different time-points (day 0, day 30 and day 60) following acquisition of a skilled reaching task in rats.…”

Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus

“…Sensory manipulation (either enrichment or withdrawal) strongly alters spine dynamics in vivo in various areas of the cortex of adult mice 39 . As a rule, established spines are pruned during the initial experience of the new stimulus, while new ones are established, which may result in some studies of fixed tissue showing no net change in spine density 40, 41 . Consistent with the change in spine dynamics initiated by enrichment, a recent imaging study in the hippocampus identified two phases in spine dynamics following repeated induction of LTP.…”