Auditory Cortex: Synaptic organization and plasticity

描述(由申请人提供)：感官系统每时每刻都会对感觉环境进行适应性处理。在大脑皮层，自适应处理发展基本网络，优化特定知觉任务的感觉学习，并支持对感觉输入的长期变化的补偿性反应。皮质的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。在这项研究中，我们将探讨初级听觉皮质紧张轴内和与之垂直的局部回路组织，这些回路中调节突触可塑性的机制，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，我们将检验一种假设，即初级听觉皮质L2/3的突触连接的组织相对于紧张轴是各向异性的，我们将比较颗粒上输入L4神经元的强度和组织，以及来自L4层和L6层的突触连接的强度和组织。我们将测量紧张性地图，然后使用丘脑皮质脑片制备，使用电生理和光学相结合的方法，解剖生理定义区域中形态识别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，我们将研究在L4和L2/3神经元的树突中调节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可以增强MAP的可塑性，我们发现听觉皮质胆碱能受体的激活影响了棘波时间依赖性的可塑性。我们将检验以下假设：树突状钾通道调节树突中反向传播动作电位产生的钙信号，而这些通道又受M受体激活的调节。在第三个目标中，我们将检验一个假设，即噪声引起的听力损失增加了听力正常区和听力损失区L2/3锥体神经元之间的突触连接，并且听力损失也降低了突触的可塑性。我们的实验旨在识别在皮质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，并了解这些机制对听力损失的反应。 与公共健康相关：大脑中感觉处理的神经机制构成了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。这些机制会因感觉器官受损而改变，因此，残留的感知能力往往会受到不利影响。在这个项目中，我们试图了解初级听觉皮质的功能性突触组织，以及大脑皮质发生一种可塑性的机制。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底物，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.