LONG TERM POTENTIATION AND DEPRESSION IN THE CEREBELLUM

描述（改编自申请人摘要）： 神经生物学认为大脑中的信息储存 持续的，使用突触强度的依赖性改变。 一个有用 这种奋进的模型系统是小脑长期抑郁症 (LTD)其中，爬行纤维和平行纤维输入的共同激活， 浦肯野神经元（PN），诱导持续的输入特异性抑制， 平行纤维PN突触。 这种现象被认为是 对于某些形式的运动学习是必要的， 眨眼条件反射和前庭眼反射的适应。 最近， 匡威现象，小脑长时程增强（LTP）也 其中平行纤维PN突触被加强， 以中频重复平行纤维刺激，因此 赋予这种突触使用依赖性双向的能力， 修改，一个计算上重要的属性。 近年来这一 实验室的重点是定义LTD感应的要求 使用细胞培养模型系统，其中并行纤维刺激被 替代谷氨酸脉冲和攀爬纤维刺激替代 PN的直接去极化。 最近，我们开发了几个 新的议定书，扩大了我们可以处理的问题的类型： 持续记录单个PN在文化中，以调查晚期 LTD阶段;两种超还原PN制剂的记录显示 LTD在没有树突棘室的情况下（急性分离的PN 和PN树突状大斑块）;以及小脑LTP和LTD的研究 在培养的颗粒细胞PN对中。 此外，我们现在承诺 使用脑切片制备的“常规”LTD实验。 我们提出 使用这些技术来解决以下问题。 首先是 小脑LTD，我们知道它在突触后表达，由 AMPA受体动力学的改变 第二，细胞内 信号通路参与了小脑LTD的晚期阶段？ 第三、 在颗粒细胞诱导LTP的条件是什么 浦肯野细胞突触及其表达位点在哪里？ 最后， 重新审视一个正在进行的争论，一氧化氮/cGMP的作用是什么？ 小脑LTD诱导中的信号传导？ 在基础科学的层面上， 研究是理解细胞基质的核心， 大脑区域中的信息存储， 输入和输出通常定义得很好。 另外这些 研究具有潜在临床相关性， 运动障碍，但也用于一般的学习和记忆障碍。

DESCRIPTION (Adapted from applicant's abstract): A guiding assumption in neurobiology has been that storage of information in the brain involves persistent, use dependent alterations in synaptic strength. One useful model system for this endeavor has been cerebellar long-term depression (LTD), in which co-activation of climbing fiber and parallel fiber inputs to a Purkinje neuron (PN), induces a persistent input specific depression of the parallel fiber PN synapse. This phenomenon has been suggested to be necessary for certain forms of motor learning including associative eye blink conditioning and adaptation of the vestibulo ocular reflex. Recently, the converse phenomenon, cerebellar long-term potentiation (LTP) has also been described, in which the parallel fiber PN synapse is strengthened by repetitive parallel fiber stimulation at intermediate frequencies, thus endowing this synapse with the capacity for use dependent bidirectional modification, a computationally important property. In recent years, this laboratory has focused upon defining the requirements for LTD induction using a cell culture model system in which parallel fiber stimulation is replaced by glutamate pulses and climbing fiber stimulation is replaced by direct depolarization of the PN. Most recently, we have developed several new protocols which have expanded the types of questions we may address: sustained recordings from single PNs in culture to investigate the late phase of LTD; recordings from two ultra reduced PN preparations that display LTD in the absence of dendritic spine compartments (acutely dissociated PNs and PN dendritic macropatches); and investigations of cerebellar LTP and LTD in granule cell PN pairs in culture. In addition, we now undertake "conventional" LTD experiments using a brain slice preparation. We propose to use these techniques to address the following questions. First, is cerebellar LTD, which we know to be expressed postsynaptically, mediated by an alteration in AMPA receptor kinetics? Second, which intracellular signaling pathways are engaged by the late phase of cerebellar LTD? Third, what are the requirements for the induction of LTP at the granule cell Purkinje cell synapse and where is its locus of expression? Finally, revisiting an ongoing controversy, what is the role of nitric oxide/cGMP signaling in cerebellar LTD induction? At the level of basic science, these investigations are central to an understanding of the cellular substrates of information storage in a brain area where the behavioral relevance of the inputs and outputs is unusually well defined. In addition, these investigations have potential clinical relevance not only for cerebellar motor disorders, but also for disorders of learning and memory generally.