Regulation of excitability in a sensory system by cellular and network components

描述（由申请人提供）：增益控制机制介导神经元传递函数，并动态调整神经元或神经系统的输出响应范围以匹配其输入信号的范围。这种神经元增益的连续调整使编码效率最大化。单个神经元主要通过兴奋性和抑制性输入的倍增来调节其输出增益，并通过电压门控通道进一步增强。在中枢神经系统的许多感觉核中，神经元可能是广泛的局部回路的一部分，但尽管局部回路的自发活动已被证明通过对强直兴奋性的影响来调节输入输出功能，但在受控刺激变化期间，局部回路在增益控制中的作用仍未明确。在这里，我们建议在清醒（未麻醉）的小鼠体内使用高二价阳离子阻断局部电路来检查局部电路在编码听觉刺激中的作用，从而使我们能够将电路特性的影响与CNS编码信息的外部输入的影响分开。中脑听觉核下丘的神经元被分离成不同的兴奋性和抑制性局部回路。这些非线性回路决定了声强的动态范围，在不同局部回路的神经元中产生不同的速率级功能。我们将测试下丘局部电路的激活对于编码声音强度是必要的假设，声音强度编码是听觉编码的一个特征，需要输入招募，并表现出动态增益控制的症状，并且声音强度编码是IC的一个紧急属性。成功地利用高二价阳离子将体内局部电路效应与外部输入分离开来，将成为研究听觉系统以外系统中中枢神经系统功能的一个非常有价值的工具，并将是研究中枢神经系统病理状态的一个重大进展。

DESCRIPTION (provided by applicant): Gain control mechanisms mediate neuronal transfer functions, and dynamically adjust a neuron or neural system's output response range to match the range of its input signal. This continuous adjustment of neuronal gain maximizes coding efficiency. Individual neurons regulate their output gain primarily through multiplication of excitatory and inhibitory inputs, with further enhancement by voltage- gated channels. In many sensory nuclei in the CNS, neurons may be part of extensive local circuits, but although spontaneous activity in local circuits has been shown to modulate input-output functions through an effect on tonic excitability, the role of local circuitry in gain control during a changing controlled stimulus remains undefined. Here we propose to examine the role of local circuits in coding auditory stimuli in vivo in awake (unanesthetized) mice using high-divalent cations to block local circuits, thus allowing us to separate the effects of circuit properties from those of extrinsic inputs in coding information in the CNS. Neurons in the inferior colliculus, an auditory midbrain nucleus, are segregated into different excitatory and inhibitory local circuits. These non-linear circuits determine the dynamic range of sound intensity, with different rate-level functions arising in neurons that are parts of different local circuits. We will test the hypothesis that the activation of local circuits in the inferior colliculus is necessary for coding sound intensity, a feature of auditory coding that requires input recruitment, and exhibits symptoms of dynamic gain control, and that sound intensity coding is an emergent property of the IC. More importantly, the successful use of high-divalent cations to separate local circuit effects from extrinsic inputs in vivo will become a very valuable tool for the study of CNS function in systems other than the auditory system and will be a major advance in the study of pathological states in the CNS. PUBLIC HEALTH RELEVANCE: The coding of information in the central nervous system is a complex task that requires the synergistic interaction between the properties of individual nerve cells and the neural networks formed between large populations of nerve cells. It is thus necessary to develop a tool which can be used ubiquitously to separate these two features of neural coding, so that their individual influences on responses in the nervous system can be understood. In this manner, both the normal functioning of the nervous system as well as pathological disease states can be better understood. In this proposal we aim to develop these tools to examine the coding of sound information in the auditory system of mammals. This will help elucidate the mechanism of normal and pathological auditory processing.