NEURONAL INFORMATION STORAGE IN CEREBELLAR DEEP NUCLEI

小脑深核中的神经信息存储

• 批准号: 6655547
• 负责人: DAVID J. LINDEN
• 金额: $ 32.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-26 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655547
• 关键词: acetylcholine; biological signal transduction; calcium flux; cell cell interaction; cerebellar Purkinje cell; cerebellar nuclei; cerebellum; electrophysiology; laboratory rat; learning; long term potentiation; memory; mossy fiber; neural information processing; second messengers; serotonin; synapses

DESCRIPTION: (Adapted from the Investigator's Abstract) A central hypothesis of modern neurobiology is that memory is stored through use-dependent changes in synaptic strength. Most work in this area has focused upon long-term potentiation and depression (LTP & LTD) of excitatory, glutamatergic synapses. One limitation of this approach is that the brain regions where LTP/LTD are most often studied, such as the hippocampus, receive information that is so complex that its content cannot be easily characterized. In contrast, in the cerebellum it has been possible to propose a "circuit diagram" for some simple forms of learning such as adaptation of the vestibulo-ocular reflex, and associative eyeblink conditioning. For example, it is possible to assign the conditioned (CS) and unconditioned stimuli (US) in associative eyeblink conditioning to specific pathways (mossy and climbing fibers, respectively). Over the last 20 years, a series of experiments that have used behavioral tasks together with extracellular recording, lesion and reversible inactivation have produced a strong case that the cerebellum is critical for these forms of motor learning. However, the precise synaptic location of the cerebellar engram has been elusive, with some studies favoring the synapses received by the Purkinje cell while others have implicated those received by the deep cerebellar nuclei (DCN). While the cellular electrophysiology of the Purkinje cell has been widely investigated, there are few studies which have examined the DCN. Recently, this laboratory has performed intracellular recordings from neurons of the DCN using a brain slice preparation. These have shown that activation of GABAergic Purkinje cell-to-DCN synapses (with a burst and pause stimulus that mimics natural firing patterns) results in a prominent rebound depolarization and associated spike burst which are evoked upon release from hyperpolarization, providing a mechanism by which inhibitory inputs can drive postsynaptic excitation. In these cells, LTP can be elicited by short, high-frequency.trains of IPSPs that reliably evoke a rebound depolarization in the DCN neurons. LTD is induced if the same protocol is applied while the amount of postsynaptic excitation is reduced (by postsynaptic hyperpolarization or an internal Na channel blocker). The polarity of the change in synaptic strength is correlated with the amount of rebound depolarization-evoked spike firing and the amplitude of the resulting postsynaptic Ca transient. In addition, we have preliminary data demonstrating LTD of the glutamatergic mossy fiber-DCN synapse. The present proposal seeks to build upon these initial results by addressing the following questions: What specific conductances contribute to the intrinsic excitability of DCN cells and how are they altered by neuromodulators such as acetylcholine and serotonin? What are the basic computational properties of LTP and LTD at the Purkinje cell-DCN synapse (optimal induction, saturability, reversibility, input specificity)? What Ca signals and second messenger systems are required for induction of LTP and LTD at the Purkinje cell-DCN synapse? What are the requirements for the induction of LTP and LTD at the mossy fiber-DCN synapse? At the level of basic science, these investigations are central to understanding the cellular substrates of information storage. In addition, they have potential clinical relevance for both cerebellar motor disorders and disorders of learning and memory generally.

描述：（改编自研究者摘要） 现代神经生物学的一个核心假设是，记忆是通过 突触强度的使用依赖性变化。这一领域的大部分工作都集中在 在兴奋性的长时程增强和抑制（LTP & LTD）后， 神经元突触。这种方法的一个局限性是， LTP/LTD最常被研究的区域，如海马， 非常复杂的信息，其内容难以描述。 与此相反，在小脑中， 图”的一些简单形式的学习，如适应的 前庭眼反射和关联性眨眼条件反射。例如它 可以将条件刺激（CS）和非条件刺激（US）分配给 特定通路的关联眨眼条件反射（苔藓和攀缘 纤维）。在过去的20年里，一系列的实验， 将行为任务与细胞外记录、损伤和 可逆失活产生了一个强有力的例子，小脑是 对这些运动学习形式至关重要。然而，精确的突触 小脑印迹的位置一直难以捉摸，一些研究倾向于 浦肯野细胞接受的突触，而其他人则认为这些突触 小脑深核（Deep Cerebellar Nucleus，DCN）当蜂窝 浦肯野细胞的电生理学已经被广泛研究， 一些研究已经检查了DCN。最近，这个实验室 使用脑切片对DCN的神经元进行细胞内记录 准备.这些结果表明，GABA能浦肯野细胞活化为DCN 突触（具有模仿自然放电模式的突发和暂停刺激） 导致显著的反弹去极化和相关的尖峰爆发， 在从超极化释放时被诱发，提供了一种机制， 抑制性输入可以驱动突触后兴奋。在这些细胞中，LTP可以是 由短的、高频率的IPSP引起，这些IPSP可靠地引起反弹 DCN神经元的去极化。如果相同的方案是 当突触后兴奋的量减少时施加（通过突触后 超极化或内部Na通道阻滞剂）。的极性 突触强度的变化与反弹量相关 去极化诱发的尖峰放电和由此产生的 突触后钙瞬变。此外，我们有初步数据表明， LTD-DCN突触。本建议旨在 在这些初步结果的基础上，解决以下问题：什么 比电导有助于DCN细胞的固有兴奋性， 它们是如何被神经调节剂如乙酰胆碱和血清素改变的？ 浦肯野LTP和LTD的基本计算属性是什么 细胞-DCN突触（最佳诱导、饱和性、可逆性、输入 特异性）？Ca信号和第二信使系统需要什么 在浦肯野细胞-DCN突触诱导LTP和LTD？有哪些 在苔藓纤维-DCN突触诱导LTP和LTD的要求？ 在基础科学的层面上，这些研究是核心， 理解信息存储的细胞基质。此外他们 对小脑运动障碍和 学习和记忆障碍