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Synaptic plasticity in the cerebellar nuclei

小脑核的突触可塑性

基本信息

批准号：
7805181
负责人：
Abigail L Person
金额：
$ 5.22万
依托单位：
NORTHWESTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7805181
关键词：
AMPA Receptors Acute Ataxia Autistic Disorder Behavior Brain Calcineurin Calcium Calcium Channel Cell Nucleus Cell physiology Cells Cerebellar Diseases Cerebellar Nuclei Cerebellum Chemosensitization Data Dystonia Electric Stimulation Endocytosis Enzymes Excision Excitatory Synapse Exocytosis Frequencies Gene Mutation Glutamate Receptor Goals Human Pathology Learning Lesion Link Logic Long-Term Depression Long-Term Potentiation Maintenance Mediating Membrane Protein Traffic Memory Mental Depression Mental Retardation Molecular Monitor Mus N-Methyl-D-Aspartate Receptors Neurons Nuclear Output Pathology Pattern Persons Pharmaceutical Preparations Physiologic pulse Plant Roots Preparation Process Proteins Protocols documentation Receptor Activation Recruitment Activity Research Research Proposals Role Scaffolding Protein Sensory Signal Induction Signal Pathway Signal Transduction Slice Source Stimulus Structure Synapses Synaptic plasticity Testing Tilia Training base calmodulin-dependent protein kinase II cell type classical conditioning metabotropic glutamate receptor type 1 mossy fiber motor learning postsynaptic public health relevance receptor relating to nervous system research study trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): The cerebellum is a highly conserved brain structure involved in motor learning and behavior. The aim of this research proposal is to elucidate the cellular mechanisms underlying synaptic plasticity in the cerebellar nuclei, the output of the cerebellum. This research will support the broader long-term goal of understanding the cellular mechanisms of learning and memory in cerebellum-dependent behaviors. Lesion studies suggest that the nuclei are a locus of learning and memory which specifically involve mossy fiber afferents carrying sensory information. We propose to investigate how two disparate forms of mossy fiber synaptic plasticity - potentiation and depression - are coordinated at the level of single neurons. These opposing forms of synaptic plasticity are generated following afferent stimulation patterns that differ only slightly, and thus likely converge on at least partly the same signaling pathways. Specifically, potentiation follows coincident excitation and inhibition while depression occurs after excitation alone. The requirement for inhibition in the potentiation protocol sets this form of plasticity apart from others investigated elsewhere in the brain and therefore promises to broaden our understanding of how synaptic plasticity is generated across different neuronal cell types. Our specific aims target h/vo levels of mechanistic organization: enzymatic signaling and transmitter receptor delivery to synapses. Whole cell voltage- and current-clamp recordings are made from neurons in an acute mouse brain slice preparation and electrical stimulation is used to elicit synaptic currents. Various pharmacological agents will be used to test the roles of molecular cascades mediating plasticity. PUBLIC HEALTH RELEVANCE: Several human pathologies are linked to cerebellar dysfunction such as ataxias, dystonias, autism and some forms of mental retardation. Understanding how cerebellar circuitry supports healthy behavior is essential to decipher the roots of neural pathologies. By targeting specific enzymes and proteins involved in a cellular function that likely underlies behavior, we lay the groundwork for linking gene mutations to observable pathologies.

描述（由申请人提供）：小脑是涉及运动学习和行为的高度保守的大脑结构。这项研究计划的目的是阐明小脑核（小脑的输出）突触可塑性的细胞机制。这项研究将支持更广泛的长期目标，即了解小脑依赖性行为中学习和记忆的细胞机制。损伤研究表明，细胞核是学习和记忆的场所，特别涉及携带感觉信息的苔藓纤维传入。我们建议研究两种不同形式的苔藓纤维突触可塑性——增强和抑制——如何在单个神经元水平上协调。这些相反形式的突触可塑性是在传入刺激模式后产生的，这些刺激模式仅略有不同，因此可能至少部分地集中在相同的信号通路上。具体来说，增强作用发生在同时发生的兴奋和抑制之后，而抑制则发生在单独兴奋之后。增强方案中抑制的要求将这种形式的可塑性与大脑其他地方研究的其他形式区别开来，因此有望拓宽我们对不同神经元细胞类型之间突触可塑性如何产生的理解。我们的具体目标是机械组织的 h/vo 水平：酶信号传导和递质受体传递到突触。全细胞电压和电流钳记录是由急性小鼠脑切片制剂中的神经元进行的，并使用电刺激来引发突触电流。将使用各种药理学试剂来测试介导可塑性的分子级联的作用。公共卫生相关性：多种人类病症与小脑功能障碍有关，例如共济失调、肌张力障碍、自闭症和某些形式的精神发育迟滞。了解小脑回路如何支持健康行为对于破译神经病理学的根源至关重要。通过针对可能构成行为基础的细胞功能中涉及的特定酶和蛋白质，我们为将基因突变与可观察到的病理联系起来奠定了基础。