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：
7650437
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650437
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 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 depression 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）：现代记忆存储理论主要关注突触功能的持久性、依赖于经验的变化，例如长期突触增强和抑制（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某种程度的突触特异性，允许大量独立可修改的单元，因此具有非常大的存储容量。除了这些突触变化之外，现在还出现了证据表明内在神经元兴奋性发生了持续变化，即我们所说的“内在可塑性”，这种变化是由行为动物的某些形式的训练以及脑切片和神经元培养物中的人工激活模式产生的。这些内在变化可能充当印迹本身的一部分，或者充当相关现象，例如记忆巩固或适应性概括的触发因素，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。这个区域位于小脑深部核团（DON）中，该区域对于某些任务（例如关联眼睑调节）的记忆存储至关重要。此后，我们对归纳要求和这种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 内在可塑性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、血清素和去甲肾上腺素受体。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、脂肪酶和钙储存。第三，我们将通过记录和闭塞实验来寻求识别参与内在可塑性表达的特定离子通道。第四，我们将使用共焦成像和解锁来确定内在可塑性的空间范围。这是一项基础研究，旨在使用异常明确的模型系统来解决内存存储背后的分子机制。希望这项工作有助于创建记忆疾病的治疗和诊断方法。因为这些细胞和分子过程不仅涉及记忆存储，这项工作也对其他脑部疾病有影响，包括癫痫和成瘾。