Physiology and structure of prefrontal projections to memory and motor circuits

记忆和运动回路前额叶投射的生理学和结构

基本信息

批准号：
9301650
负责人：
Maria Medalla
金额：
$ 24.77万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301650
关键词：
Acetylcholine Action Potentials Acute Address Adult Agonist Anatomy Anterior Anxiety Disorders Area Axon Biological Sciences Biology Biomedical Research Boston Brain Carbachol Cells Collaborations Coupling Data Dendrites Efferent Neurons Electron Microscope Electron Microscopy Electrons Electrophysiology (science)Engineering Environment Event Excitatory Synapse Fiber Frequencies Future Goals Heart Hippocampus (Brain)Image In Vitro Inhibitory Synapse Institution Interdisciplinary Study Label Laboratories Lasers Learning Macaca mulatta Medial Mediating Medical Membrane Memory Mental Depression Mental disorders Mentors Mentorship Microscope Microscopic Modeling Mood Disorders Motor Motor Pathways Muscarinic Acetylcholine Receptor Neuroanatomy Neurobiology Neuromodulator Neurons Neurosciences Outcome Pathway interactions Pattern Phase Physiology Positioning Attribute Prefrontal Cortex Preparation Primates Property Publications Recording of previous events Research Resolution Resources Role Scanning Seminal Slice Spinal Structure Synapses System Techniques Testing Tissues Training Universities Work base brain surgery brain tissue career development cholinergic cingulate cortex design entorhinal cortex executive function experience experimental study hippocampal pyramidal neuron induced pluripotent stem cell inhibitory neuron long term memory medical schools nervous system disorder neuroregulation patch clamp postsynaptic programs public health relevance receptor response tissue processing tissue/cell culture

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to understand the cellular pathway basis of prefrontal executive control of memory and motor information, for using past events to guide future action. Due to its strong reciprocal connections with the medial temporal entorhinal (EC) and premotor cortices (PMC), the medial prefrontal anterior cingulate cortex (ACC) is strategically positioned to serve as the interface between 'long-term memory' and 'motor planning' systems. The ACC coordinates activity-thereby gating information flow-within EC and PMC, which have distinctive anatomical circuits with unique network oscillatory dynamics. How the ACC regulates these two areas is largely unknown. While a number of neuromodulators influence cortical network dynamics, this project will focus on acetylcholine (ACh) due to its critical role in learning and memory. The overall hypothesis of this project is tht ACC projection neurons to EC and to PMC possess distinct intrinsic, synaptic, and cholinergic neuromodulatory properties that underlie differential control of their postsynaptic targets. Dr. Medalla will test this hypothesis by combining neuroanatomical tract-tracing with in vitro whole-cell patch-clamp recording and intracellular filling of retrogradely-labeled neurons in slices prepared from adult rhesus monkeys (Macaca mulatta). Structural analyses of neurons from which recordings are obtained will be conducted using high-resolution laser-scanning confocal imaging and electron microscopy of filled dendrites. This project will lead to a better understanding of prefrontal cortical microcircuitry and mechanisms underlying executive control of learning and memory systems, and the misattribution of context and drive for goal-directed action in depression and other mood and anxiety disorders. To date Dr. Medalla's research endeavors have been dedicated to understanding the structural synaptic pathway basis of functional specialization in the primate prefrontal cortex, using tract-tracing and electron microscopic techniques. The proposed project will use Dr. Medalla's experience in neuroanatomy combined with current training in electrophysiological techniques to address some outstanding issues in prefrontal circuitry, under the mentorship of Dr. Jennifer Luebke, one of the few world experts in whole-cell patch clamp in vitro slice recording techniques in primates. The project will also benefit from the support of collaborators, Dr. Alan Peters, a renowned expert in electron microscopy and cortical ultrastructure, and Dr. Douglas Rosene, an expert in primate neuroanatomy. Drs. Michael Hasselmo and Howard Eichenbaum will serve as consultants to this project; their expertise in learning and memory as well as cholinergic modulation of limbic and cortical systems will be invaluable during the implementation of these experiments. In the mentored phase, studies will focus on the intrinsic, firing and resonance properties of ACC projection neurons to EC and PMC, and their modulation by ACh. In the independent phase, studies will address the cholinergic modulation of excitatory and inhibitory synaptic responses and the structure of synapses onto these projection neurons, and the interaction EC and PMC pathways within ACC using dual patch-clamp recording and bi-directional pathway tracing. The work from the proposed studies will provide Dr. Medalla with data for high quality publications as well as preliminary data for formulating a competitive application for an R01, which will be centered on further studies of the structure and function of prefrontal cortical microcircuitry. The work in the proposed studies will be conducted at Boston University, an institution with a rich history of well-established multidisciplinary research in th field of Neuroscience. In particular, the Department of Anatomy and Neurobiology at the School of Medicine is a collaborative scientific environment with a long- standing history of seminal work on the structure and function of the primate brain. The main experiments in this proposal will be conducted in the Luebke Laboratory, located at the heart of the Medical Campus Evans Biomedical Research Center, which is fully equipped for preparation and electrophysiologic recording in acute and organotypic cortical slices and tissue cell cultures. Other aspects of the proposed experiments will be conducted in collaboration with the Rosene Laboratory for primate brain surgery and tissue processing, and the Peters Laboratory for examining tissue under the electron microscope. The confocal imaging for the proposed studies will be conducted in the Biology Imaging Core at the Life Science and Engineering Building, managed by Dr. Todd Blute, equipped with a state-of-the art Zeiss-510 laser-scanning confocal microscope. Through its extensive academic opportunities, resources, and state-of-the art facilities, BU provides an ideal environment for the mentoring and career development of Dr. Medalla, and the execution of the research goals in the proposed project. These resources at BU will facilitate the training of Dr. Medalla to become an expert electrophysiologist and initiate her own independent cutting-edge research program that investigates prefrontal pathway-specific interactions with receptors, channels, and diverse types of inhibitory neurons, using a structure-function framework at the synaptic, cellular and network levels.

描述（由申请人提供）：该项目的目标是了解记忆和运动信息的前额叶执行控制的细胞通路基础，以利用过去的事件来指导未来的行动。由于其与内侧颞内嗅皮质 (EC) 和前运动皮质 (PMC) 具有很强的相互联系，内侧前额叶前扣带皮层 (ACC) 被战略性地定位为“长期记忆”和“运动计划”之间的接口系统。 ACC 协调 EC 和 PMC 内的活动，从而控制信息流，EC 和 PMC 具有独特的解剖回路和独特的网络振荡动力学。 ACC 如何监管这两个领域尚不清楚。虽然许多神经调节剂影响皮质网络动态，但该项目将重点关注乙酰胆碱 (ACh)，因为它在学习和记忆中发挥着关键作用。该项目的总体假设是 ACC 投射到 EC 和 PMC 的神经元具有不同的内在、突触和胆碱能神经调节特性，这些特性是其突触后目标的差异控制的基础。 Medalla 博士将通过将神经解剖束追踪与体外全细胞膜片钳记录以及成年恒河猴（Macaca mulatta）切片中逆行标记神经元的细胞内填充相结合来测试这一假设。将使用高分辨率激光扫描共焦成像和填充树突的电子显微镜对获得记录的神经元进行结构分析。该项目将有助于更好地理解前额皮质微电路和学习和记忆系统执行控制的机制，以及抑郁症和其他情绪和焦虑障碍中的背景和目标导向行动的错误归因。迄今为止，Medalla 博士的研究工作一直致力于利用束追踪和电子显微镜技术来了解灵长类动物前额皮质功能特化的结构突触通路基础。拟议的项目将利用 Medalla 博士在神经解剖学方面的经验，结合当前的电生理技术培训，在 Jennifer Luebke 博士的指导下解决前额叶回路中的一些突出问题，Jennifer Luebke 博士是体外全细胞膜片钳领域的少数世界专家之一灵长类动物切片记录技术。该项目还将受益于合作者电子显微镜和皮质超微结构领域的著名专家 Alan Peters 博士和灵长类动物神经解剖学专家 Douglas Rosene 博士的支持。博士。 Michael Hasselmo 和 Howard Eichenbaum 将担任该项目的顾问；他们在学习和记忆以及边缘和皮质系统胆碱能调节方面的专业知识在这些实验的实施过程中将非常宝贵。在指导阶段，研究将集中于 ACC 投射神经元到 EC 和 PMC 的内在、放电和共振特性，以及 ACh 对它们的调节。在独立阶段，研究将使用双膜片钳记录和双向路径追踪来解决兴奋性和抑制性突触反应的胆碱能调节以及这些投射神经元上的突触结构，以及 ACC 内 EC 和 PMC 路径的相互作用。拟议研究的工作将为 Medalla 博士提供高质量出版物的数据以及制定 R01 竞争性应用的初步数据，该应用将集中于前额皮质微电路的结构和功能的进一步研究。拟议研究的工作将在波士顿大学进行，该大学在神经科学领域拥有丰富的多学科研究历史。特别是，医学院的解剖学和神经生物学系是一个协作的科学环境，在灵长类动物大脑的结构和功能方面有着长期的开创性工作历史。该提案中的主要实验将在位于医学园区埃文斯生物医学研究中心中心的吕贝克实验室进行，该实验室设备齐全，可用于急性和器官型皮质切片和组织细胞培养物的准备和电生理记录。拟议实验的其他方面将与用于灵长类脑手术和组织处理的罗森实验室以及用于在电子显微镜下检查组织的彼得斯实验室合作进行。拟议研究的共焦成像将在生命科学与工程大楼的生物成像核心进行，由 Todd Bute 博士管理，配备最先进的 Zeiss-510 激光扫描共焦显微镜。通过其广泛的学术机会、资源和最先进的设施，BU 为 Medalla 博士的指导和职业发展以及拟议项目中研究目标的执行提供了理想的环境。 BU 的这些资源将有助于培训 Medalla 博士成为一名电生理学专家，并启动她自己的独立尖端研究计划，该计划使用以下结构来研究前额叶通路与受体、通道和不同类型抑制性神经元的相互作用：突触、细胞和网络层面的功能框架。