Auditory Cortex: Synaptic organization and plasticity

描述（由申请人提供）：感觉系统在每时每刻的基础上执行感觉环境的自适应处理。在皮层，适应性处理发展了基本网络，优化了特定感知任务的感觉学习，并支持对感觉输入长期变化的补偿反应。皮质可塑性取决于皮质内回路的组织以及局部微回路的内在可塑性。在这个建议中，我们将探讨局部电路组织内和正交的初级听觉皮层的tonotopic轴，调节突触可塑性的机制，在这些电路，和听力损失的影响电路组织和突触可塑性。在第一个目标中，我们将测试的假设，在初级听觉皮层的L2/3的突触连接的组织是各向异性的tonotopic轴，我们将比较的强度和组织的颗粒上输入L4神经元从第5和第6层。我们将测量的tonotopic地图，然后使用丘脑皮质脑切片制备解剖的生理定义的区域，丘脑刺激和局部皮质内刺激，使用电生理学和光学方法相结合的形态学识别的神经元的反应。在第二个目标中，我们将研究在L4和L2/3神经元树突中调节突触可塑性的关键触发器，动作电位反向传播的细胞机制。基底前脑胆碱能系统的刺激已被证明可以增强体内地图的可塑性，我们发现，听觉皮层胆碱能受体的激活影响尖峰时间依赖的可塑性。我们将测试的假设，树突钾通道调节钙信号产生的反向传播动作电位在树突，而这些通道反过来又调节毒蕈碱受体激活。在第三个目标中，我们将测试噪声诱导的听力损失增加正常听力区域和听力损失区域中的L2/3锥体神经元之间的突触连接性，并且听力损失也降低突触可塑性的假设。我们的实验旨在确定在皮层处理的初始阶段支持自适应处理功能的关键电路和细胞机制，并了解这些机制如何对听力损失做出反应。 公共卫生相关性：大脑中感觉处理的神经机制是我们正常感知能力的基础，包括识别声源和通过声音进行交流的能力。这些机制因感觉器官受损而改变，因此，残余的感知能力往往受到不利影响。在这个项目中，我们试图了解初级听觉皮层的功能性突触组织，以及皮层中发生的一种可塑性的机制。我们还将确定这些网络连接和可塑性如何受到噪声引起的高频听力损失的影响。我们的目标是了解听力损失如何影响听觉感知的神经基质，以便我们能够确定有助于优化听力的策略。

DESCRIPTION (provided by applicant): Sensory systems perform adaptive processing of the sensory environment on a moment-to- moment basis. In the cortex, adaptive processing develops the basic network, optimizes sensory learning for specific perceptual tasks, and supports compensatory responses to long- term changes in sensory input. Cortical plasticity depends on the organization of intracortical circuits as well as the intrinsic plasticity of local microcircuits. In this proposal, we will explore local circuit organization within and orthogonal to the tonotopic axes of the primary auditory cortex, the mechanisms regulating synaptic plasticity in those circuits, and the effects of hearing loss on circuit organization and synaptic plasticity. In the first aim, we will test the hypothesis that the organization of synaptic connections in L2/3 in primary auditory cortex is anisotropic with respect to the tonotopic axes, and we will compare the strength and organization of the supragranular input to L4 neurons with that from layers 5 and 6. We will measure the tonotopic map, then use a thalamocortical brain slice preparation to dissect the responses of morphologically identified neurons in physiologically defined regions to thalamic stimulation and to local intracortical stimulation, using a combination of electrophysiological and optical methods. In the second aim, we will examine cellular mechanisms that regulate a key trigger of synaptic plasticity, action potential back-propagation, in dendrites of L4 and L2/3 neurons. Stimulation of basal forebrain cholinergic systems has been shown to enhance map plasticity in vivo, and we find that activation of cholinergic receptors in auditory cortex affects spike timing-dependent plasticity. We will test the hypotheses that dendritic potassium channels regulate calcium signaling produced by back-propagating action potentials in dendrites, and that these channels are in turn regulated by muscarinic receptor activation. In the third aim we will test the hypothesis that noise-induced hearing loss increases synaptic connectivity between L2/3 pyramidal neurons in the normal-hearing region and the hearing- loss region, and that the hearing loss also decreases synaptic plasticity. Our experiments are aimed at identifying key circuits and cellular mechanisms that support adaptive processing functions at the initial stages of cortical processing, and to understand how those mechanisms respond to hearing loss. PUBLIC HEALTH RELEVANCE: The neural mechanisms of sensory processing in the brain underlie our normal perceptual abilities, including the identification of sound sources and the ability to communicate through sound. These mechanisms are changed by damage to the sensory organs, and consequently, residual perceptual abilities are often adversely affected. In this project, we seek to understand the functional synaptic organization of the primary auditory cortex, and the mechanisms that underlie one kind of plasticity that occurs in cortex. We will also determine how these network connections and plasticity are affected by a noise-induced high- frequency hearing loss. Our goal is to understand how hearing loss affects the neural substrate for auditory perception, so that we can identify strategies that can help optimize hearing.