Auditory Cortex: Synaptic organization and plasticity

描述（由申请人提供）：感觉系统在时刻到时刻的基础上对感觉环境进行适应性处理。在皮层中，适应性加工发展了基本网络，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性反应。皮层的可塑性不仅取决于局部微回路的内在可塑性，还取决于皮层内回路的组织。在本研究中，我们将探讨初级听觉皮层内和正交的局部回路组织，这些回路中突触可塑性的调节机制，以及听力损失对回路组织和突触可塑性的影响。在第一个目标中，我们将检验初级听觉皮层L2/3的突触连接组织相对于张力轴是各向异性的假设，我们将比较L4神经元与第5层和第6层的核上输入的强度和组织。我们将测量张力图，然后使用丘脑皮质脑切片制备，使用电生理和光学方法的结合，解剖生理定义区域中形态学上确定的神经元对丘脑刺激和局部皮质内刺激的反应。在第二个目标中，我们将研究调节L4和L2/3神经元树突中突触可塑性的关键触发因素——动作电位反向传播的细胞机制。刺激基底前脑胆碱能系统在体内已被证明可以增强图的可塑性，我们发现听觉皮层胆碱能受体的激活会影响峰值时间依赖性的可塑性。我们将测试树突钾通道调节由树突反向传播动作电位产生的钙信号的假设，并且这些通道反过来受到毒蕈碱受体激活的调节。在第三个目标中，我们将验证噪声性听力损失增加了正常听力区和听力损失区L2/3锥体神经元之间的突触连通性，听力损失也降低了突触可塑性的假设。我们的实验旨在确定在皮层处理的初始阶段支持适应性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作出反应。

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.