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

描述（申请人提供）：听觉系统的主要任务是处理声音刺激中包含的时间和强度信息，这是通过整合来自不同来源的兴奋性和抑制性输入来完成的。这种整合发生在中枢神经系统的第一个核是下丘（IC）。IC是脑干核。它接受来自脑干大部分听觉核的直接输入，并反过来向听觉前脑提供几乎所有的输入。除了在听觉加工中的重要性外，IC还是导致声音诱发性癫痫发作的病理性高兴奋性的起源部位。尽管其地理位置优越，输入信号广泛收敛，但输入信号对兴奋性的调节和神经元的内在特性尚未得到研究，而且根据细胞和连接的定义来定义基本电路对于理解其功能是必要的。我们最近证明了IC的兴奋性和抑制性输入选择性地调节增益控制和神经元兴奋性。这种增益控制的调节决定了IC中的神经元对声音强度的编码有多好。我们还发现了IC中局部兴奋性循环回路的证据。此外，活动在IC的两侧之间以复杂的方式传播。我们将结合单个神经元活动的电生理记录，神经元群体响应的光学监测与电压敏感染料和计算建模技术，以解决以下具体目标：确定模式突触输入如何调节单个IC神经元的兴奋/抑制比。2. 确定细胞类型特异性在局部和丘间电路中的重要性。3. 确定细胞间连接的要求。我们的研究结果将描述正常听觉系统中由网络和细胞组成部分对兴奋性的限制，并将进一步了解导致过度兴奋状态的因素，从而导致癫痫发作。

DESCRIPTION (provided by applicant): A principal task of the auditory system is to process the temporal and intensity information contained in a sound stimulus, which it does by integrating excitatory and inhibitory input from different sources. The first nucleus in the central nervous system, where such integration occurs, is the inferior colliculus (IC). The IC is a brainstem nucleus. It receives direct input from most of the auditory nuclei in the brainstem and, in turn, provides nearly all of the input to the auditory forebrain. In addition to its importance in auditory processing, the IC is the site of origin of pathological hyperexcitability that leads to sound-evoked seizures. Despite its strategic location and extensive input convergence, the regulation of excitability by inputs and intrinsic neuronal properties has not been investigated, and the definition of a basic circuit in terms of defined classes of cells and connections is necessary to understand its function. We recently demonstrated that excitatory and inhibitory inputs to the IC selectively regulate gain control and neuronal excitability. This regulation of gain control determines how well neurons in the IC can code sound intensity. We have also found evidence for local excitatory recurrent circuits in the IC. Furthermore, activity is propagated in a complex fashion between the two sides of IC. We will combine electrophysiological recordings of activity in single neurons, optical monitoring of neuronal population responses with voltage-sensitve dyes and computational modeling techniques to address the following specific aims: 1. Determine how patterned synaptic input regulates the excitatory/inhibitory ratio in single IC neurons. 2. Determine the importance of cell type specificity in local and inter-collicular circuitry. 3. Determine the requirements for inter-collicular connectivity. Our results will delineate the constraints on excitability in the normal auditory system set by network and cellular components, and will further our understanding of the factors that lead to the hyperexcitable state that gives rise to epileptic seizures.