Use-dependent intrinsic plasticity in the cerebellum

小脑的使用依赖性内在可塑性

基本信息

批准号：
7862319
负责人：
DAVID J. LINDEN
金额：
$ 30.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7862319
关键词：
Action Potentials Acute Address Adenylate Cyclase Adolescent Adverse effects Affect Animals Apamin Area Axon Basic Science Biological Models Brain Brain Diseases Brain region Buffers Calcineurin Caliber Calmodulin Cations Cells Cerebellar Nuclei Cerebellum Chelating Agents Chemosensitization Complement Complex Cyclic AMP Cyclic Nucleotides Data Dendrites Diagnostic Disease Dorsal Drug usage Electrodes Ensure Enzymes Epilepsy Excitatory Amino Acid Antagonists Excitatory Postsynaptic Potentials Fiber GABA-A Receptor Glutamate Receptor Glutamates Glycine Receptors Hybrids Image Injection of therapeutic agent Ion Channel Knockout Mice Lasers Learning Link Lipase MAP Kinase Gene Measurement Memory Mental Depression Metabotropic Glutamate Receptors Microelectrodes Mind Modeling Molecular Monitor N-Methyl-D-Aspartate Receptors N-Methylaspartate NMDA receptor antagonist Neuronal Plasticity Neurons Norepinephrine Optical Methods Pathway interactions Pattern Peptide Hydrolases Perfusion Pharmaceutical Preparations Phorbol Esters Phospholipase Phospholipase A2 Phosphoric Monoester Hydrolases Phosphotransferases Physiologic pulse Pontine structure Potassium Channel Preparation Principal Investigator Process Protein Isoforms Protein Kinase Protein Phosphatase 2A Regulatory Subunit PR53 Protein phosphatase Proteins Protocols documentation Publishing Pump Purkinje Cells Rattus Recruitment Activity Reporting Research Personnel Rest Role Saline Second Messenger Systems Serotonin Signal Transduction Slice Spatial Distribution Specificity Spottings Structure Synapses Testing Tilia Toxin Training Work addiction attenuation base calmodulin-dependent protein kinase II conditioning experience eyelid conditioning indexing inhibitor/antagonist insight juvenile animal kainate lipoprotein lipase locus ceruleus structure mossy fiber neuronal cell body neuronal excitability noradrenergic patch clamp programs receptor research study response second messenger synaptic function theories tissue-factor-pathway inhibitor 2 ultraviolet voltage voltage clamp white matter

项目摘要

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.

描述（由申请人提供）：内存存储的现代理论主要集中在长期突触增强和抑郁（LTP＆LTD）等突触功能的持续性，依赖经验的变化上。这些现象在内存模型中具有吸引力，部分原因是它们通常显示一定程度的突触特异性，从而允许大量独立修改的单元，因此，很大的存储容量。除了这些突触变化外，现在还出现了证据表明，内在神经元兴奋性的持续变化，我们称之为“内在可塑性”，这是由某些形式的训练在行为动物中的某些形式而产生的，以及在脑切片和神经元文化中激活的人工激活模式。这些内在的变化可能是ENGRAM本身的一部分，或者是相关现象，例如触发记忆的巩固或适应性概括，尤其是非定性记忆。几年前，我们发表了第一份关于大脑内在兴奋性持续性突触驱动的变化的第一份报告。这是在深小脑核（DON）中，该区域对于某些任务（例如关联眼睑调节）的存储器存储至关重要。此后，我们对诱导要求和该现象的表达进行了广泛的参数描述。在这里，我们建议通过研究DCN中内在可塑性的细胞和分子基础来扩展这些初始观察。首先，我们希望表征与固有可塑性有关的受体，并特别强调谷氨酸，5-羟色胺和去甲肾上腺素的受体。其次，我们将解决第二信使级联反应的作用，包括蛋白激酶，磷酸酶，脂肪酶和Ca储存。第三，我们将寻求通过记录和遮挡实验来确定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脉冲来确定内在可塑性的空间范围。这是基础研究，旨在解决记忆存储基础的分子机制，使用定义明确的模型系统。希望这项工作对于创建记忆疾病的疗法和诊断有用。由于这些细胞和分子过程不仅参与记忆存储，因此这项工作对其他脑部疾病也有影响，包括癫痫和成瘾。