Cellular Substrates of Cerebellar Information Storage

小脑信息存储的细胞基质

基本信息

批准号：
7246631
负责人：
DAVID J. LINDEN
金额：
$ 44.82万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7246631
关键词：
AMPA Receptors Action Potentials Address Adenylate Cyclase Adverse effects Amygdaloid structure Area Attenuated Axon Basic Science Behavior Behavioral Biolistics Biological Models Blinking Brain Brain Part Brain region C-terminal Cells Cerebellar cortex structure Cerebellum Chimeric Proteins Chromosome Pairing Class Classification Clathrin Complex Condition Cyclic AMP Cyclic AMP-Dependent Protein Kinases Drug usage Dynamin EAAT3 Electrodes Embryo Endocytosis Event Excitatory Synapse Extinction (Psychology)Failure Fiber Frequencies Funding GluR2 subunit AMPA receptor Glutamate Transporter Glutamates Goals Grant Hippocampus (Brain)Image Individual Information Storage Investigation Laboratories Lagomorpha Learning Learning Disorders Link Lip structure Location Long-Term Depression Long-Term Potentiation Measures Mediating Membrane Memory Mental Depression Modeling Modems Molecular Mono-S Motor Mus Mutant Strains Mice Mutation NCOA2 gene Neurobiology Neurons Numbers Operative Surgical Procedures Optics Other Finding Paper Pathway interactions Pattern Peptides Phase Phosphorylation Positioning Attribute Potassium Channel Preparation Production Property Proteins Publications Publishing Purkinje Cells Rate Rattus Reporting Research Resolution Rodent Series Signal Transduction Slice Solid Staging Stimulus Sum Synapses Synaptic plasticity System Tail Testing Transfection Transgenic Organisms Walking Work alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid amino 3 hydroxy 5 methylisoxazole 4 propionate amphiphysin analog clinically relevant conditioning detector extracellular granule cell in vivo motor disorder motor learning mutant nerve supply postsynaptic presynaptic programs receptor internalization research study secretory protein synaptic function transfection/expression vector vestibulo-ocular reflex

项目摘要

DESCRIPTION (provided by the applicant): A central hypothesis of modem 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 (LiP and LTD) of glutamatergic synapses. One limitation of this approach is that the brain regions where LTP and 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 associative eyeblink conditioning and vestibulo-ocular reflex adaptation. For example, it is possible to assign the conditioned (CS) and unconditioned stimuli (US) in associative eyeblink conditioning to specific pathways (the mossy/parallel fiber system and climbing fibers, respectively). Over the last 20 years, a series of experiments which have used behavioral tasks together with extracellular recording, reversible inactivation and transgenic manipulations have produced a strong case that the cerebellum is critical for these forms of motor learning. In particular, LTD and LTP of the parallel fiber-Purkinje cell synapse have been implicated in acquisition and extinction of eyeblink conditioning, respectively. In recent years, this laboratory has used both electrode and optical recording in cerebellar slice and culture model systems to explore the molecular requirements for induction and expression of these phenomena. In particular, we (and others) have found that induction of LiP in the parallel fiber synapse requires a presynaptic cascade of Ca influx/adenylyl cyclase JJcAMP/PKA and that its expression is also presynaptic. In contrast, induction of LTD at this synapse is triggered by postsynaptic activation of mGluRl and AMPA receptors together with Ca influx, resulting in activation of PKC and consequent clathrin-mediated internalization of AMPA receptors. Along the way, we discovered a new form of plasticity, LTD at the climbing fiber-Purkinje cell synapse, which was not anticipated in models of cerebellar learning and which appears to share some induction requirements with parallel fiber LTD. We propose additional electrophysiological experiments to address the following central questions. Which proteins of the secretory apparatus are modulated by PKA to produce the increase in glutamate release that underlies expression of parallel fiber LIP? During LTD induction at parallel fiber synapses, what are the events which link PKC activation with AMPA receptor internalization? Can climbing fiber LTD be induced using patterns of stimulation that more closely approximate natural signals recorded in vivo? What are the consequences of climbing fiber LTD for the function of the Purkinje cells and the cerebellar cortical circuit? Are climbing fiber-evoked Ca signals altered? Is climbing fiber LTD expressed presynaptically or postsynaptically? Can it be detected with recordings of climbing fiber-evoked glutamate transporter currents in the Purkinje cell? Can it be blocked with manipulations that interfere with clathrin-mediated internalization of AMPA receptors (as previously seen with parallel fiber LTD)? At the level of basic science, these investigations are central to an 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（申请人提供）：调制解调器的中心假设神经生物学是记忆是通过突触中的使用依赖性变化来存储的力量。该领域的大多数工作都集中在长期增强和谷氨酸能突触的抑郁症（Lip和Ltd）。一个限制方法是最常研究LTP和LTD的大脑区域，例如海马，接收到如此复杂的信息内容不能轻易表征。相反，在小脑中可以为某些简单的学习形式提出“电路图” 例如关联的眉毛调节和前庭反射适应。例如，可以分配条件（CS）和无条件的刺激（US）在缔合性的眼神调节中途径（分别是苔藓/平行纤维系统和攀爬纤维）。在过去的20年中，一系列使用了行为的实验任务以及细胞外记录，可逆失活和转基因的操纵产生了一个强烈的案例，即小脑是这些形式的运动学习至关重要。特别是，LTD和LTP 平行的纤维 - 普尔金耶细胞突触已与采集有关分别灭绝的调节。近年来，这个实验室在小脑切片中同时使用了电极和光学记录和培养模型系统以探索诱导的分子要求和这些现象的表达。特别是，我们（和其他）发现平行纤维突触中的唇部诱导需要突触前 CA涌入/腺苷酸环化酶JJCAMP/PKA的级联反应为也是突触前的。相反，该突触处的LTD诱导是由 MGLURL和AMPA受体的突触后激活以及CA流入，导致PKC的激活和随之而来的网格蛋白介导的内在化 AMPA受体。一路上，我们发现了一种新形式的可塑性，有限公司在攀爬纤维 - 普林吉细胞突触中，这在小脑学习的模型，并且似乎有一些归纳平行光纤有限公司的要求。我们提出了其他建议电生理实验以解决以下中心问题。 PKA调节分泌仪的哪些蛋白质以产生谷氨酸释放的增加，这是平行纤维唇表达的基础？在平行纤维突触的LTD诱导期间，链接的事件是什么 PKC激活AMPA受体内在化？可以攀登光纤有限公司使用刺激模式诱导的刺激模式更紧密近似自然信号记录在体内？攀登光纤有限公司的后果是什么 Purkinje细胞和小脑皮质回路的功能？是攀爬纤维引起的CA信号已更改？攀登光纤有限公司表达突触前还是突触后？可以通过录音检测到吗在浦肯野细胞中攀登纤维诱发的谷氨酸转运蛋白转运蛋白电流？能它被干扰网格蛋白介导的操作阻塞 AMPA受体的内在化（如先前用平行纤维LTD所示）吗？在基础科学层面上，这些调查是了解信息存储的细胞基板。另外，他们对于小脑运动障碍都有潜在的临床相关性和一般的学习和记忆障碍。