Dynamics of Kv channel function in identified populations of pyramidal neurons in neocortex

新皮质锥体神经元群体中 Kv 通道功能的动态变化

基本信息

批准号：
9514597
负责人：
Robert C Foehring
金额：
$ 49.16万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514597
关键词：
Action Potentials Anesthesia procedures Attention Behavior Cells Central Nervous System Diseases Cerebral cortex Charge Closure by clamp Code Coupled Dendrites Devices Distal Down-Regulation ETV1 gene Electrophysiology (science)Elements Epilepsy Foundations Frequencies Generations Goals Gramicidin Individual Injections Ion Channel Kinetics Learning Long-Term Depression Long-Term Potentiation Memory Molecular Morphology Motor Neocortex Neurons Noise Output Pathologic Pattern Perfusion Periodicity Physiological Population Potassium Potassium Channel Predisposition Process Property Protocols documentation Pyramidal Tracts Regulation Research Rodent Role Seizures Signal Pathway Signal Transduction Spain Stimulus Structure Sum Synapses Testing Time Training Transgenic Mice Up-Regulation Work base biophysical properties cell cortex conditioning design experimental study hippocampal pyramidal neuron imaging system in vivo information processing insight neocortical neuronal cell body neuronal excitability postsynaptic relating to nervous system response somatosensory tool transmission process two-photon voltage

项目摘要

Our research is aimed at elucidating how ion channels regulate the processing of information by neurons in the cerebral cortex, i.e., the diverse mechanisms neurons use to convert synaptic input into action potentials. The proposed experiments will determine basic principles of how voltage-gated potassium (Kv) channels regulate postsynaptic processing of inputs in layer 5 (L5) neocortical pyramidal neurons (PNs). PNs are the output cells of cortex and key players in learning, memory, and sensorimotor processing, as well as the targets of central nervous system diseases (e.g., epilepsy). The proposed studies go beyond the standard notion that potassium channels act as an intrinsic brake on excitability. They are designed to determine the influence Kv2 and Kv7 channels have on the types of information that L5 PNs respond to and how that information is filtered before downstream transmission. We will study mechanisms controlling firing behavior in two classes of pyramidal neurons: intratelencephalic-projecting (IT) and pyramidal tract (PT) type, represented by two genetically-identified PNs with GFP expressed in populations of L5 PNs under control of unique genes: etv1 (IT) and thy1 (PT). We will test hypotheses concerning how Kv2 and Kv7 channels regulate burst firing (Aim 1) and continuous firing (repetitive bursting and suprathreshold resonance: Aim 2). Kv channel properties and expression are dynamic. They can undergo plastic changes in response to activity or signaling pathways and thus change neuronal filtering properties. Thus, we will also study use-dependent plasticity of intrinsic excitability (Aim 3). We use transgenic mouse lines and state-of-the-art electrophysiological approaches, including somatic / dendritic paired recordings, dynamic clamp, internal pipet perfusion, nucleated patch and on-cell patch recordings, as well as whole cell and gramicidin perforated patch. We also use two-photon and charge-coupled device (CCD)-based Ca2+ imaging systems. Our stimulus protocols are designed to mimic natural synaptic activity arriving at the soma of a neuron (the common summing point for all dendrites) and will be systematically varied to simulate different levels or composition of inputs. Our findings will have major implications for cortical processing, ion channel function, understanding neural computations, and mechanisms underlying epilepsy, anesthesia, learning and memory.

我们的研究旨在阐明离子通道如何调节神经元的信息处理大脑皮层，即神经元用于将突触输入转换为动作电位的多种机制。这拟议的实验将确定电压门控钾 (Kv) 通道如何调节的基本原理第 5 层 (L5) 新皮质锥体神经元 (PN) 中输入的突触后处理。 PN 是输出单元皮质和学习、记忆和感觉运动处理的关键参与者，以及中枢的目标神经系统疾病（例如癫痫）。拟议的研究超出了钾的标准概念通道对兴奋性起到内在的制动作用。它们旨在确定 Kv2 和 Kv7 的影响通道具有有关 L5 PN 响应的信息类型以及之前如何过滤该信息的信息下行传输。我们将研究控制两类金字塔放电行为的机制神经元：端脑内投射 (IT) 和锥体束 (PT) 类型，由两个基因鉴定的 PN 代表，在独特基因控制下的 L5 PN 群体中表达 GFP：etv1 (IT) 和 thy1 （PT）。我们将测试有关 Kv2 和 Kv7 通道如何调节突发发射的假设（目标 1）以及连续射击（重复爆发和阈上共振：目标 2）。 Kv 通道特性和表达是动态的。它们可以响应活动或信号通路而发生塑性变化，从而改变神经元的过滤特性。因此，我们还将研究内在的使用依赖性可塑性兴奋性（目标 3）。我们使用转基因小鼠品系和最先进的电生理学方法，包括体细胞/树突配对记录、动态钳、内部移液管灌注、有核贴片和细胞贴片记录，以及全细胞和短杆菌肽穿孔贴片。我们还使用双光子和基于电荷耦合器件 (CCD) 的 Ca2+ 成像系统。我们的刺激方案旨在模仿自然突触活动到达神经元的胞体（所有树突的共同总结点）并将可以系统地改变以模拟不同水平或输入的组成。我们的发现将产生重大影响对皮质处理、离子通道功能、理解神经计算和机制的影响潜在的癫痫、麻醉、学习和记忆。