Modeling memory consolidation during posttraining periods in cerebellovestibular learning

Abstract

Long-term depression (LTD) at parallel fiber-Purkinje cell (PF-PC) synapses is thought to underlie memory formation in cerebellar motor learning. Recent experimental results, however, suggest that multiple plasticity mechanisms in the cerebellar cortex and cerebellar/vestibular nuclei participate in memory formation. To examine this possibility, we formulated a simple model of the cerebellum with a minimal number of components based on its known anatomy and physiology, implementing both LTD and long-term potentiation (LTP) at PF-PC synapses and mossy fibervestibular nuclear neuron (MF-VN) synapses. With this model, we conducted a simulation study of the gain adaptation of optokinetic response (OKR) eye movement. Our model reproduced several important aspects of previously reported experimental results in wild-type and cerebellum-related gene-manipulated mice. First, each 1-h training led to the formation of short-term memory of learned OKR gain at PF-PC synapses, which diminished throughout the day. Second, daily repetition of the training gradually formed long-term memory that was maintained for days at MF-VN synapses. We reproduced such memory formation under various learning conditions. Third, long-term memory formation occurred after training but not during training, indicating that the memory consolidation occurred during posttraining periods. Fourth, spaced training outperformed massed training in long-term memory formation. Finally, we reproduced OKR gain changes consistent with the changes in the vestibuloocular reflex (VOR) previously reported in some genemanipulated mice.cerebellum | plasticity | memory consolidation | posttraining period | Marr-Albus-Ito theory L ong-term depression (LTD) at parallel fiber-Purkinje cell (PF-PC) synapses in the cerebellar cortex has been thought to be the major mechanism of motor learning (1). This MarrAlbus-Ito hypothesis (2, 3), however, has been challenged since Miles and Lisberger's proposal (4) that long-term potentiation (LTP) at mossy fiber-vestibular nuclear neuron (MF-VN) synapses, not LTD at PF-PC synapses, underlies vestibuloocular reflex (VOR) gain adaptation (4-7). In a recent study on optokinetic response (OKR) gain adaptation, we found evidence that might resolve the controversy: LTD at PF-PC synapses (PF-LTD) and LTP at MF-VN synapses (MF-LTP) play different roles in OKR adaptation (8-10). Namely, PF-LTD accounts for short-term memory in PCs during 1-h training, whereas MF-LTP forms long-term memory in VN after the 1-h training that accumulates during repeated trials of 1-h training. It thus appears as if short-term memory formed in PCs during 1-h training is transferred to VN after training to consolidate as long-term memory (8-10).To investigate the mechanisms of this memory transfer and posttraining consolidation, we conducted a computer simulation study using a simple theoretical model of the cerebellovestibular system including both LTD and LTP at PF-PC synapses and MF-VN synapses. Although several theoretical models have addressed the question of ...

Intrinsic plasticity of cerebellar Purkinje cells in motor learning circuits

“…A large population of VN neurons receive information from floccular PCs (Matsuno et al, 2016; Shin et al, 2011). Furthermore, the output of the cerebellar PCs serve as an instructive signal in the neuronal plasticity between MFs and VN neurons (Clopath et al, 2014; Dean, Porrill, Ekerot, & Jörntell, 2010; McElvain et al, 2010; Medina, 2010; Porrill & Dean, 2007; Shutoh, Ohki, Kitazawa, Itohara, & Nagao, 2006; Yamazaki et al, 2015). Thus, we hypothesized that the impairment of the intrinsic plasticity of the cerebellar cortex that was observed in STIM1 PKO mice would lead to an inadequate alteration of the VN neuron activity following VOR adaptation.…”

“…The authors pointed out that the output of PCs may be responsible for the VN plasticity as Miles and Lisberger suggested. More recently, numerous computational modeling studies have supported the theory that synaptic plasticity in both regions is required for successful memory storage (Clopath et al, 2014; Dean et al, 2010; Porrill and Dean, 2007; Yamazaki et al, 2015). This theory highlights the importance of the communication between these brain regions.…”

“…However, several works proposed that the synaptic plasticity at the PF-PC synapse is not sufficient to explain motor learning (Ito, 2013; Ke, Guo, & Raymond, 2009; Schonewille et al, 2011; Wulff et al, 2009). Emerging evidence suggests that neural plasticity at multiple sites, including the cerebellar cortex and vestibular nucleus (VN), is required for motor learning (Boyden, Katoh, & Raymond, 2004; Clopath, Badura, Zeeuw, & Brunel, 2014; Porrill & Dean, 2007; Yamazaki, Nagao, Lennon, & Tanaka, 2015). Furthermore, it has been suggested that motor memory is formed in cortical areas through PF-PC plasticity at the early phase of adaption and transferred to sub-cortical area, especially in the VN (Ito, 2013).…”

The Sleeping Cerebellum

“…(B) Temporal learning. In a motor timing task vestibular nuclei, downstream [94][95][96][97][98]. The role of sleep in consolidation of cerebellar memory formation is also supported by the precise sequence of changes that occur over the course of long-term skill learning.…”

Revealing an extended critical window of recovery post-stroke

“…This design introduces task variability during the training sessions and provides a practice schedule that is structured, including rest periods. These components have shown to optimize the acquisition, retention, and generalization of motor skills (Yamazaki et al, 2015; Hanlon, 1996). In order to promote the usage of the affected limb, the scenarios contain contextual restrictions that limit both the overuse of the non-affected arm and compensatory movements, thus supporting use-dependent restoration towards non-pathological motor patterns.…”