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

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，神经元用来将突触输入转换成动作电位的不同机制。的 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）中的输入的突触后处理。PN是输出像元 大脑皮层和学习、记忆和感觉运动处理的关键参与者，以及中枢神经系统的靶点。 神经系统疾病（例如，癫痫）。拟议中的研究超越了钾的标准概念， 通道作为兴奋性的内在制动器。它们旨在确定Kv 2和Kv 7的影响 通道对L5 PN响应的信息类型以及在L5 PN响应之前如何过滤该信息的影响。 下游传输。我们将研究控制两类锥体神经元放电行为的机制。 神经元：端脑内投射（IT）和锥体束（PT）型，由两种遗传鉴定的PN代表，其中GFP在L5 PN群体中表达，受独特基因：etv 1（IT）和thy 1 （PT）。我们将测试关于Kv 2和Kv 7通道如何调节突发放电的假设（目的1）， 持续放电（重复爆发和阈上共振：目标2）。KV通道特性和 表达是动态的。它们可以在活动或信号通路的作用下发生可塑性变化， 从而改变神经元过滤特性。因此，我们也将研究使用依赖的可塑性的内在 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、动态钳夹、内部移液管灌注、有核斑和 细胞上斑片记录，以及全细胞和短杆菌肽穿孔斑片。我们也使用双光子， 电荷耦合器件（CCD）为基础的Ca 2+成像系统。我们的刺激方案旨在模拟 自然的突触活动到达神经元的索马（所有树突的共同点）， 系统地变化，以模拟不同的输入水平或组成。我们的发现将对 对皮层处理、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。

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.