Auditory Cortex: Synaptic organization and plasticity

描述（由申请人提供）：感觉系统即时地执行感觉环境的自适应处理。在皮层中，自适应处理开发了基本网络，优化了特定感知任务的感觉学习，并支持对感觉输入的长期变化的补偿反应。皮质可塑性取决于皮质内电路的组织以及局部微电路的内在可塑性。在本提案中，我们将探索初级听觉皮层音调轴内并与其正交的局部回路组织、调节这些回路中突触可塑性的机制，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，我们将测试初级听觉皮层 L2/3 中突触连接的组织相对于音调轴而言是各向异性的假设，并且我们将比较 L4 神经元的颗粒上输入与第 5 层和第 6 层的颗粒上输入的强度和组织。我们将测量音调图，然后使用丘脑皮质脑切片准备来剖析生理学定义区域中形态学上识别的神经元对丘脑刺激的反应，以及结合电生理学和光学方法进行局部皮质内刺激。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、动作电位反向传播的关键触发因素的细胞机制。刺激基底前脑胆碱能系统已被证明可以增强体内图谱可塑性，我们发现听觉皮层胆碱能受体的激活会影响尖峰时间依赖性可塑性。我们将测试以下假设：树突钾通道调节树突中反向传播动作电位产生的钙信号传导，并且这些通道反过来又受到毒蕈碱受体激活的调节。在第三个目标中，我们将检验以下假设：噪声引起的听力损失会增加正常听力区域和听力损失区域的 L2/3 锥体神经元之间的突触连接，并且听力损失也会降低突触可塑性。我们的实验旨在确定在皮质处理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应对听力损失。 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的损伤而改变，因此，残余的感知能力常常受到不利影响。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。我们还将确定噪声引起的高频听力损失如何影响这些网络连接和可塑性。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.