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）：该项目的目的是了解记忆和运动信息前额叶执行控制的蜂窝路径基础，用于使用过去的事件来指导未来的行动。由于其与内侧颞内河（EC）和前皮层（PMC）的牢固相互连接，内侧前额叶前扣带回皮层（ACC）的策略性位置可作为“长期记忆”和“运动计划”系统之间的接口。 ACC协调活性 - 基于门控信息与EC和PMC，它们具有独特的解剖回路，具有独特的网络振荡动力学。 ACC如何调节这两个领域是未知的。尽管许多神经调节剂会影响皮质网络动力学，但由于其在学习和记忆中的关键作用，该项目将重点放在乙酰胆碱（ACH）上。该项目的总体假设是对EC的ACC投影神经元，并且PMC具有独特的内在，突触和胆碱能神经调节特性，是对其突触后靶标的差异控制的基础。 Medalla博士将通过将神经解剖学追踪与体外全细胞斑块钳记录和逆行标记神经元的细胞内填充在成人恒河猴（Macaca Mulatta）中制备的切片中的细胞内填充来检验这一假设。将使用高分辨率激光扫描共聚焦成像和填充树突的电子显微镜进行神经元的结构分析。该项目将使对学习和记忆系统的执行控制的前额叶皮层微电路和机制有更好的了解，以及对抑郁症以及其他情绪和其他情绪和焦虑症的目标行动的错误贡献和动力。迄今为止，Medalla博士的研究工作一直致力于了解灵长类动物前额叶皮层中功能专业化的结构突触途径基础，使用道跟踪和电子显微镜技术。拟议的项目将利用Medalla博士在神经解剖学方面的经验以及当前的电生理技术培训，以解决前额叶电路中的一些杰出问题，在詹妮弗·卢布克（Jennifer Luebke）博士的指导下，詹妮弗·卢布克（Jennifer Luebke）博士是少数几个世界上全细胞斑块夹夹在体外贴片上的专家之一。该项目还将受益于合作者，著名的电子显微镜和皮质超微结构专家Alan Peters博士，以及灵长类神经剖析专家Douglas Rosene博士。博士。 Michael Hasselmo和Howard Eichenbaum将担任该项目的顾问；在实施这些实验期间，它们在边缘和皮质系统的学习和记忆以及对边缘和皮质系统的胆碱能调节方面将是无价的。在指导阶段，研究将重点关注ACC投影神经元对EC和PMC的固有，触发和共振特性及其对ACH的调节。在独立阶段，研究将解决兴奋性和抑制性突触反应的胆碱能调节，以及突触对这些投影神经元的结构，以及使用双贴片钳记录和双向方向途径跟踪ACC中ACC中的相互作用EC和PMC途径。拟议的研究的工作将为Medalla博士提供高质量出版物的数据，以及为R01制定竞争应用的初步数据，该数据将集中于前额叶皮质微环流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，该机构具有悠久的神经科学领域的多学科研究历史。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，具有长期的关于灵长类动物大脑结构和功能的开创性工作的历史。该提案中的主要实验将在位于医疗校园埃文斯生物医学研究中心的Luebke实验室中进行，该研究中心齐全，该研究中心齐全，用于制备和电生理记录，以急性和器官型皮质切片和组织细胞培养。拟议的实验的其他方面将与罗斯纳（Rosene）实验室合作进行灵长类动物脑外科手术和组织加工的实验室，以及在电子显微镜下检查组织的彼得斯实验室。拟议研究的共聚焦成像将在由Todd Blute博士管理的生命科学和工程大楼的生物学成像核心中进行，配备了最先进的Zeiss-510激光扫描共焦显微镜。 BU通过其广泛的学术机会，资源和最先进的设施，为Medalla博士的指导和职业发展提供了理想的环境，并在拟议项目中执行了研究目标。 BU的这些资源将促进Medalla博士成为一名专家电生理学家的培训，并启动自己的独立尖端研究计划，该计划使用在突触，蜂窝和网络水平上使用结构功能框架来研究前额叶途径特异性与受体，通道和各种抑制性神经元的相互作用。