Mechanisms of Synaptic Integration in Central Neurons

中枢神经元突触整合机制

• 批准号: 7688440
• 负责人: WILLIAM J SPAIN
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688440
• 关键词: Abbreviations; Action Potentials; Address; Affect; Agonist; Auditory; Automobile Driving; Back; Behavior; Behavioral; Brain; Brain Stem; Cells; Cerebral cortex; Classification; Data; Dendrites; Depressed mood; Detection; Disease; Distal; Electrodes; Epilepsy; Frequencies; Funding; Genes; Glutamates; Health; Healthcare; Human; Injury; Interneurons; Investigation; Ion Channel; Measures; Methods; Mutate; Mutation; Neocortex; Neuraxis; Neuromodulator; Neurons; Noise; Operative Surgical Procedures; Output; Pattern; Potassium; Potassium Channel; Potassium Channel Blockers; Property; Relative (related person); Reporting; Research; Role; Seizures; Serotonin; Simulate; Site; Slice; Staining method; Stains; Stimulus; Structure; Synapses; Temporal Lobe Epilepsy; Time; Training; Traumatic Brain Injury; Veterans; Work; abstracting; base; biocytin; computer generated; computerized data processing; design; functional outcomes; hippocampal pyramidal neuron; neocortical; neuronal cell body; patient population; photolysis; postsynaptic; presynaptic; prevent; receptor; research study; response; statistics; voltage

DESCRIPTION (provided by applicant): Project Summary / Abstract The proposed experiments of this Merit Review competitive renewal are part of the effort by many labs to determine how central nervous system neurons encode their synaptic inputs. In particular, the experiments are designed to determine how specific neurons (or abnormal function of those neurons) contribute to synchronous network activity that occurs during both normal signal processing and during seizure activity. The major questions ask 'What temporal aspects of natural patterns of synaptic activity are most effective for driving a neuron's action potential firing?' and 'What are the governing underlying mechanisms?'. The focus is on the responses of principal cells in neocortex (pyramidal neurons) to local circuit activity. The convergent synaptic activity generated by cortical networks has a frequency spectrum similar to broad- band noise. We have preliminary data that the pyramidal neurons show resonant firing to this type of input. That is, specific frequency components of their input drive firing better then others. Two input frequencies cause the resonance: theta (~7 Hz) and fast ripple (~250 Hz). We also have preliminary evidence that interactions between frequency components in the input cause differences in the resonance (i.e. the resonance is nonlinear). Additional preliminary studies point to certain potassium conductance mechanisms as being critical for the type and amount of resonance a pyramidal neuron has. A mutation in the gene (KCNQ) for one of these potassium channels (Kv7) is known to cause some forms of human epilepsy. There are three sets of experiments. In the first we will determine the basic interactions of the input frequencies that result in resonant firing. In the second set we will determine the influence of dendritic filtering on the resonant firing. In the third set we will determine how the resonant firing is transmitted across synapses to the different targets of the pyramidal neurons. In all three sets of experiments we will determine the role of specific potassium channels on the resonance. The methods employ patch pipettes (or sharp electrodes in some experiments) to record from visualized neurons in brain slices. Neurons are stimulated in current clamp and dynamic clamp using computer-generated waves that simulate the statistics of ongoing synaptic activity generated by the local cortical circuit (focusing mostly on excitatory inputs). Potassium channel blockers and openers and receptor agonists and antagonists are applied to the neurons during the electrical recording. We also add artificial potassium conductances to neurons with a method we devised called spike-triggered dynamic clamp. Anatomical classification of neurons is done by intracellular staining with biocytin. The second set of experiments uses photolysis to uncage glutamate to stimulate the dendrites. In the third set of experiments we simultaneously record from synaptically connected pairs of neurons. PUBLIC HEALTH RELEVANCE: Potential Impact on Veterans Health Care Traumatic brain injury is a major cause of epilepsy in our veteran patient population. Epilepsy caused by injury to the neocortex is hard to manage medically and the surgical options are more restricted than for temporal lobe epilepsy. So we need to find better ways to treat this problem. Particular frequency components of neocortical network activity are specifically associated with seizures and promote their initiation and propagation. Other frequencies may be suppressive. We expect that the proposed studies will close major gaps in our basic understanding of both normal and pathological neocortical oscillations and provide a rational basis for the design of new treatments for epilepsy.

描述（由申请人提供）： 项目摘要/摘要 本次优点评审竞争性更新中提出的实验是许多实验室为确定中枢神经系统神经元如何编码其突触输入而做出的努力的一部分。特别是，这些实验旨在确定特定神经元（或这些神经元的异常功能）如何促进正常信号处理和癫痫活动期间发生的同步网络活动。主要问题是“突触活动自然模式的哪些时间方面对于驱动神经元的动作电位放电最有效？”和“管理的根本机制是什么？”。 重点是新皮质主要细胞（锥体神经元）对局部回路活动的反应。皮质网络产生的会聚突触活动具有类似于宽带噪声的频谱。我们有初步数据表明锥体神经元对这种类型的输入表现出共振放电。也就是说，其输入驱动器的特定频率分量比其他分量发射得更好。两个输入频率会引起谐振：theta (~7 Hz) 和快速纹波 (~250 Hz)。我们还有初步证据表明，输入中频率分量之间的相互作用会导致谐振差异（即谐振是非线性的）。其他初步研究指出某些钾电导机制对于锥体神经元共振的类型和数量至关重要。已知这些钾通道 (Kv7) 之一的基因 (KCNQ) 突变会导致某些形式的人类癫痫。 一共有三组实验。首先，我们将确定导致谐振发射的输入频率的基本相互作用。在第二组中，我们将确定树突滤波对谐振点火的影响。在第三组中，我们将确定共振放电如何通过突触传输到锥体神经元的不同目标。在所有三组实验中，我们将确定特定钾通道对共振的作用。 这些方法使用贴片吸管（或某些实验中的锋利电极）来记录脑切片中可视化的神经元。使用计算机生成的波在电流钳和动态钳中刺激神经元，这些波模拟由局部皮质电路生成的持续突触活动的统计数据（主要集中于兴奋性输入）。在电记录过程中，将钾通道阻断剂和开放剂以及受体激动剂和拮抗剂应用于神经元。我们还通过我们设计的一种称为尖峰触发动态钳的方法向神经元添加人工钾电导。神经元的解剖学分类是通过生物胞素的细胞内染色来完成的。第二组实验利用光解作用释放谷氨酸以刺激树突。在第三组实验中，我们同时记录突触连接的神经元对。 公共卫生相关性： 对退伍军人医疗保健的潜在影响 创伤性脑损伤是退伍军人患者群体中癫痫的主要原因。新皮质损伤引起的癫痫很难通过药物治疗，而且手术选择比颞叶癫痫更受限制。所以我们需要找到更好的方法来治疗这个问题。新皮质网络活动的特定频率成分与癫痫发作特别相关，并促进癫痫发作的发生和传播。其他频率可能会受到抑制。我们期望所提出的研究将弥补我们对正常和病理性新皮质振荡的基本理解的主要差距，并为癫痫新疗法的设计提供合理的基础。