Neural circuitry for state-dependent control of cortical auditory processing and perception

 描述（由申请人提供）：行为参与通过管理神经系统处理信息的有限能力来改善感知和学习。多个大脑区域有助于控制行为状态，特别是在准备参与中发挥主要作用的额叶皮层结构。然而，特定的额叶皮层区域分配大脑的处理资源，以预期的感官刺激的关键电路机制仍然在很大程度上未知。因此，精神分裂症、自闭症和多动症等多种注意力缺陷障碍仍然缺乏了解和治疗。我的长期职业目标是了解额叶皮质与感觉和神经调节系统通信的神经元回路机制，以促进刺激处理并改善行为，并利用这些信息指导新型治疗方法的开发。这个建议的直接目标是定义神经网络的相互作用，在预备集，并建立因果关系与性能。我的中心假设是，直接和间接电路合作控制听觉感知的竞争机制：直接连接增加诱发反应AC，而间接电路通过LC抑制自发和诱发尖峰AC。为了实现所提出的目标，我将在行为大鼠中使用强大的神经生理学和光遗传学技术的组合。我最近的研究表明，听觉皮层中声音表征的可塑性变化可以提高感知能力。然后，我发现预备组动态地调节听觉皮层中的诱发和自发放电，以控制行为。为了确定准备控制刺激表征和表现的电路机制，我记录了行为大鼠内侧无颗粒额叶皮质（maFC）中的单个单元活动，这是一种直接和间接连接到听觉皮质的大脑结构。我在maFC中确定了预备组的生理标志物。对于该奖项的指导部分（额外两年的博士后研究），我将通过分析从maFC到听觉皮层的直接投射在感觉处理和感知表现中的作用来扩展这项工作（目标1）。在独立阶段（三年），我将研究突触机制和行为功能的间接连接maFC和听觉皮层，重点是去甲肾上腺素能神经调节（目标2）。为此，我将在纽约大学医学院的Froemke和Buszáki实验室学习复杂的光遗传学和记录技术，这是一个出色的研究环境，提供了所提出的目标所需的所有设备和设施。纽约大学的林大宇博士将担任顾问。我已经组建了一个强大的咨询委员会，将监督我的进展，并在获奖期间及以后提供智力和技术投入。我的培训计划将使我能够开展拟议的研究，并获得我的独立职业所需的技能和一般知识。我相信，我的研究将赋予电路相互作用调节行为参与的透彻理解，并将使我能够为精神疾病的上级治疗的发展做出贡献。

 DESCRIPTION (provided by applicant): Behavioral engagement improves perception and learning by managing the limited capacity of the nervous system to process information. Multiple brain regions contribute to controlling behavioral states, in particular frontal cortical structure that play major roles in preparatory engagement. However, the key circuit mechanisms by which specific frontal cortical regions allocate the processing resources of the brain to prospective sensory stimuli remain largely unknown. Consequently, multiple disorders with an attention deficit, such as schizophrenia, autism and ADHD remain poorly understood and treated. My long-term career goal is to understand the neuronal circuit mechanisms by which the frontal cortex communicates with sensory and neuromodulatory systems to facilitate stimulus processing and to improve behavior, and use this information to guide development of novel treatments. The immediate goal of this proposal is to define neuronal network interactions during preparatory set and to establish causal links with performance. My central hypothesis is that direct and indirect circuits cooperatively control auditory perception by competing mechanisms: direct connections increase evoked responses in AC whereas indirect circuits via LC suppress spontaneous and evoked spiking in AC. To accomplish the proposed aims, I will use a combination of powerful neurophysiological and optogenetic techniques in behaving rats. I have recently shown that plastic changes in sound representation in the auditory cortex can improve perceptual performance. I then found that preparatory set dynamically modulates evoked and spontaneous firing in the auditory cortex in order to control behavior. To determine the circuit mechanism by which preparation controls stimulus representation and performance, I recorded in behaving rats single unit activity in the medial agranular frontal cortex (maFC), a brain structure directly and indirectly connected to the auditory cortex. I identified a physiologial marker for preparatory set in maFC. For the mentored part of this award (two additional years of postdoctoral studies) I will extend this work by analyzing the role of direct projections from maFC to the auditory cortex in sensory processing and perceptual performance (Aim 1). During the independent phase (three years) I will investigate synaptic mechanisms and behavioral function of indirect connections between maFC and the auditory cortex, with a focus on noradrenergic neuromodulation (Aim 2). For this, I will learn complex optogenetic and recording techniques in the Froemke and Buszáki labs at the NYU School of Medicine, an outstanding research environment that provides all the equipment and facilities needed for the proposed aims. Dr. Dayu Lin, also at NYU, will act as a consultant. I have assembled a strong advisory committee that will oversee my progress and provide intellectual and technical input during the award period and beyond. My training plan will enable me to carry out the proposed research and to acquire the skill set and the general knowledge required for my independent career. I am confident that my studies will impart a thorough understanding of circuit interactions regulating behavioral engagement and will enable me to contribute to the development of superior treatments for psychiatric disorders.