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，特别是在准备活动中发挥主要作用的额叶皮质结构。然而，特定的额叶皮质区域将大脑的处理资源分配给预期的感觉刺激的关键电路机制在很大程度上仍不清楚。因此，精神分裂症、自闭症和ADHD等具有注意力缺陷的多发性疾病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沟通的神经回路机制，以促进刺激处理和改善行为，并利用这些信息指导新疗法的开发。这项建议的直接目标是定义在准备阶段的神经元网络相互作用，并建立与表现的因果联系。我的中心假设是，直接电路和间接电路通过相互竞争的机制协同控制听觉感知：直接连接增加AC的诱发反应，而通过LC的间接电路抑制AC的自发和诱发的尖峰放电。为了实现提出的目标，我将使用强大的神经生理学和光遗传学技术的组合来表现大鼠的行为。我最近证明，听觉皮质中声音表达的可塑性变化可以改善知觉表现。然后我发现，预备组动态地调节听觉皮质中诱发的和自发的放电，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，我在表现良好的大鼠中记录了内侧无颗粒额叶皮质(MaFC)的单个单位活动，maFC是一种直接或间接与听觉皮质相连的大脑结构。我为MAFC的预备布景确定了一个生理学标记。对于这一奖项的指导部分(额外两年的博士后研究)，我将通过分析从maFC到听觉皮质的直接投射在感觉处理和知觉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maFC和听觉皮质之间间接联系的突触机制和行为功能，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和记录技术，这是一个出色的研究环境，提供了拟议目标所需的所有设备和设施。同样在纽约大学工作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，该委员会将监督我的进展，并在获奖期间和以后提供智力和技术投入。我的培训计划将使我能够进行拟议的研究，并获得我独立职业所需的技能和一般知识。我相信，我的研究将使我对调节行为参与的回路相互作用有一个透彻的了解，并将使我能够为开发更好的精神障碍治疗方法做出贡献。

 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.