Use-dependent intrinsic plasticity in the cerebellum

描述（由申请人提供）：记忆储存的现代理论主要集中在突触功能的持续性、经验依赖性变化，如长时程突触增强和抑制（LTP & LTD）。这些现象在记忆模型中很有吸引力，部分原因是它们通常表现出一定程度的突触特异性，允许大量的独立可修改单元，因此，存储容量非常大。除了这些突触变化之外，现在已经出现了内在神经元兴奋性的持续变化的证据，我们称之为“内在可塑性”，由行为动物的某些形式的训练和脑切片和神经元培养物中的人工激活模式产生。这些内在的变化可以作为记忆痕迹本身的一部分，或者作为相关的现象，例如记忆的巩固或适应性概括的触发器，特别是非陈述性记忆。几年前，我们发表了第一份关于大脑内在兴奋性持续突触驱动变化的报告。这是位于小脑深部核（DON）中的一个区域，该区域对于某些任务（如关联眼睑调节）的记忆存储至关重要。我们已经进行了广泛的参数描述的诱导要求和表达这种现象。在这里，我们建议通过调查内在可塑性在DCN的细胞和分子基础来扩展这些初步观察。首先，我们希望描述参与内在可塑性的受体，特别强调谷氨酸、5-羟色胺和去甲肾上腺素的受体。其次，我们将讨论第二信使级联的作用，包括蛋白激酶，磷酸酶，脂肪酶和钙商店。第三，我们将试图通过记录和闭塞实验来识别参与内在可塑性表达的特定离子通道。第四，我们将使用共聚焦成像和uncaging来确定内在可塑性的空间范围。这是一项基础研究，旨在利用一个异常明确的模型系统来解决记忆存储的分子机制。希望这项工作将有助于创造治疗和诊断记忆疾病。由于这些细胞和分子过程不仅涉及记忆储存，这项工作也对其他大脑疾病有影响，包括癫痫和成瘾。

DESCRIPTION (provided by applicant): Modern theories of memory storage have largely focused on persistent, experience-dependent changes in synaptic function such as long-term synaptic potentiation and depression (LTP & LTD). These phenomena are appealing in models of memory, in part because they typically display some degree of synapse-specificity, allowing for a very large number of independently modifiable units and, consequently, a very large storage capacity. In addition to these synaptic changes, evidence has now emerged for persistent changes in intrinsic neuronal excitability, what we call "intrinsic plasticity", produced by certain forms of training in behaving animals and artificial patterns of activation in brain slices and neuronal cultures. These intrinsic changes may function as a portion of the engram itself, or as a related phenomenon such as a trigger for the consolidation or adaptive generalization of memories, particularly non-declarative memories. Several years ago, we published the first report of persistent synaptically driven changes in intrinsic excitability in the brain. This, in the deep cerebellar nuclei (DON), a region which is central to memory storage for certain tasks such as associative eyelid conditioning. We have since performed an extensive parametric description of the induction requirements and the expression of this phenomenon. Here, we propose to extend these initial observations by investigating the cellular and molecular basis of intrinsic plasticity in the DCN. First, we wish to characterize the receptors involved in intrinsic plasticity with particular emphasis on receptors for glutamate, serotonin and norepinephrine. Second, we will address the role of second messenger cascades including protein kinases, phosphatases, lipases and Ca stores. Third, we shall seek to identify the particular ion channel(s) involved in the expression of intrinsic plasticity through recording and occlusion experiments. Fourth, we shall use confocal imaging and uncaging to determine the spatial extent of intrinsic plasticity. This is basic research to address the molecular mechanisms that underlie memory storage, using an unusually well-defined model system. It is hoped that this work will be useful for creating therapies and diagnostics for diseases of memory. Because these cellular and molecular processes are not only involved in memory storage, this work has implications for other brain diseases as well, including epilepsy and addiction.