Sites and mechanisms of motor learning and memory

运动学习对于确保快速、准确的动作是必要的。小脑被认为是学习的初始阶段的可塑性的场所，但对于任何脊椎动物的运动系统来说，涉及运动学习的机制还没有完全确定。我们建议使用所有脊椎动物共有的原始系统，前庭-眼睛反射(VOR)，来研究大脑机制，通过它来完善运动和存储记忆。VOR的幅度或增益可以通过经验增加或减少。我们建议确定特定类型的小脑突触可塑性对VOR运动学习和运动记忆的巩固(和破坏)的贡献。我们假设小脑长期抑制(LTD)与增益增加有关，而相同突触的长时程增强(LTP)与增益降低相关。LTP的突触前和突触后机制都已被发现，但到目前为止只发现了突触后LTP。因此，增益降低(而不是增加)可能与突触前和突触后的变化有关。我们还提出，增益降低的巩固需要相对更多的突触前记忆存储。这些想法将使用简单的行为协议进行间接测试。在第二种更直接的方法中，LTD中一个成熟步骤的抑制剂(具体地说，代谢性谷氨酸受体拮抗剂)将局部注射到小脑皮质，试图防止增益增加。LTP的抑制剂，如大麻素激动剂，将被用来试图防止增益下降。同样的药物对记忆巩固和记忆破坏的影响也将被调查。

Motor learning is necessary to ensure rapid, accurate movements. The cerebellum is believed to be a site for the plasticity underlying the initial phase of learning, but the mechanisms involved in motor learning have not been fully determined for any vertebrate motor system. We propose to use a primitive system common to all vertebrates, the vestibulo-ocular reflex (VOR), to investigate the brain mechanisms by which movements are perfected and memories are stored. The amplitude, or gain, of the VOR can either be increased or decreased by experience. We propose to identify the contribution of specific types of cerebellar synaptic plasticity to VOR motor learning and to consolidation (and disruption) of motor memory. We hypothesize that cerebellar long-term depression (LTD) is associated with gain increases, while long-term potentiation (LTP) at the same synapses is associated with gain decreases. Both pre-and postsynaptic mechanisms have been identified for LTP, but only postsynaptic LTD has been identified so far. Thus, gain decreases (but not increases) may be associated with both pre-and postsynaptic changes. We also propose that consolidation of gain decreases requires relatively more presynaptic memory storage. These ideas will be tested indirectly using simple behavioral protocols. In a second, more direct approach, inhibitors of a well-established step in LTD (specifically, metabotropic glutamate-receptor antagonists) will be injected locally into the cerebellar cortex to attempt to prevent gain increases. Inhibitors of LTP, such as cannabinoid agonists, will be used to attempt to prevent gain decreases. Effects of the same pharmacological agents on memory consolidation and memory disruption will also be investigated.