Homeostatic plasticity mechanisms support brain function in vivo

稳态可塑性机制支持体内大脑功能

• 批准号: 8804113
• 负责人: Keith B. Hengen
• 金额: $ 8.06万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8804113
• 关键词: Address; Affect; Alzheimer' s Disease; Animals; Arousal; Behavior; Behavioral; Binding Proteins; Boston; Brain; Cells; Chronic; Circadian Rhythms; Clinical; Cognition; Complex; Computational Biology; Computational Technique; Data; Dedications; Defect; Development; Development Plans; Disease; Education; Elements; Environment; Epilepsy; Equilibrium; Experimental Designs; Failure; Gene Transfer; General Population; Goals; Health; Homeostasis; Human; Human Pathology; In Vitro; Individual; International; Intervention; Laboratories; Learning; Link; Mammals; Measures; Mediating; Membrane; Mentors; Methods; Molecular; Molecular Biology; Molecular Biology Techniques; NCOA2 gene; Neurodegenerative Disorders; Neurons; Neurosciences; Pathology; Pattern; Phase; Physiology; Play; Population; Positioning Attribute; Public Health; Regulation; Research; Research Personnel; Rett Syndrome; Role; Scientist; Sensory Deprivation; Sleep; Sleep Deprivation; Slice; Solid; Staging; Supervision; Symptoms; Synapses; Synaptic plasticity; System; Tail; Techniques; Technology; Temperature; Testing; Time; Training; Universities; Viral; Vision; Work; base; brain shape; career; career development; computational neuroscience; expectation; experience; field study; in vivo; insight; meetings; member; nervous system disorder; neurophysiology; new technology; novel; optogenetics; post-doctoral training; public health relevance; research study; response; scale up; synaptic depression; technology development; theories; trafficking; transmission process

 DESCRIPTION (provided by applicant): A "homeostatic" mechanism functions to stabilize a key parameter of a system, much like a thermostat functions to stabilize the temperature in a building. In neurons, homeostatic synaptic plasticity is believed to counteract the destabilizing influence of Hebbian-plasticity mechanisms that underlie the activity-dependent refinement of synaptic connectivity. It is postulated that severe human pathologies arise from impaired mechanisms of neuronal homeostasis, including Alzheimer's disease, epilepsy, and Rett syndrome. A significant barrier to progress in this field is our nearly complete lack of insight ino homeostatic plasticity in the intact brain. I propose to study how homeostatic synaptic plasticity supports brain function and behavior in the freely behaving animal. Research in this proposal will focus on synaptic scaling, one of the best-understood mechanisms of neuronal activity homeostasis in vitro. First, work performed during the mentored (K99) component will define a functional role for synaptic scaling in firing rate homeostasis in vivo. To do this, I will utilizeviral-mediated gene transfer to block synaptic scaling in a subset of cortical neurons and test the homeostatic response to long-term sensory deprivation. Next, work performed during the mentored and independent phases will test the hypothesis that sleep is necessary for the expression of homeostatic plasticity in vivo. This will be achieved in two steps: (i) neuromodulatory state-specific and/or circadian patterns will be examined in the normal expression of homeostatic plasticity, and (ii) modulatory states will be disrupted at key times during the emergence of firing rate homeostasis in the freely behaving animal. Finally, during the independent stage (R00), I will assess the core prediction about homeostatic plasticity: those homeostatic mechanisms serve to offset the inherently destabilizing effects of Hebbian plasticity during experience dependent refinement of networks (i.e. learning and development). In this work, I will determine the role of synaptic scaling in a) the development of information transmission in cortical networks, and b) the development of cortex-dependent behavior. The proposed research will be instrumental for the understanding and treatment of disorders that are theorized to involve dysregulated homeostatic plasticity mechanisms. Further, these data will provide novel insight into the effects of sleep deprivation. Finally, this work will identify parameters necessary for homeostatic plasticity in the healthy brain and provide insight into the role of homeostatic plasticity in higher-level brain functions. Candidate's immediate and long-term career goals my graduate training and postdoctoral experience thus far have provided me with a solid background in the methods and concepts related to the research proposed here. My long-term research goal is to understand the role of dysregulated homeostatic mechanisms in neurological disorders and disease, and to unravel the contributions of homeostatic plasticity to normal brain function. In order to complete this work, I will need additional training in a variet of techniques as well as intellectual, professional, and academic guidance. The environment at Brandeis University combined with the dedication and expertise of my mentor, the members of my scientific and career subcommittee, and collaborators provides a perfect base from which to pursue an academic tenure-track position at a research university. The combined training in in vivo molecular biology, computational neuroscience, behavior, and technology development will provide the final elements necessary for me to begin an independent career investigating the role of homeostatic plasticity in normal brain function and disease. Key elements of the research career development plan. The research described in the mentored phase of this application will be performed at Brandeis University under the supervision of Dr. Gina Turrigiano. The Turrigiano laboratory pioneered the study of synaptic scaling and is a recognized leader in the field of homeostatic plasticity. I have assembled a scientific and career advisory subcommittee that is scientifically diverse and dedicated to my development as an independent scientist. Dr. Stephen Van Hooser will provide expertise in animal vision, computational techniques, and in vivo optogenetic manipulations. Dr. Avital Rodal will provide expertise in molecular biology techniques and oversee the interpretation of AMPAR trafficking manipulations. Dr. Eve Marder will provide expertise in computational neuroscience, experimental design, and theory. In addition to this training, I will spend two months in the laboratory of my collaborator, Dr. Timoth Gardner (Boston University) learning cutting-edge technology fabrication necessary for the advancement of in vivo neuroscience. Finally, I will support these activities with regular attendance of international meetings and research seminars to develop an international presence for myself and continue my education in relevant topics. As I begin my career, my committee will provide ongoing support in early career issues, further supporting my transition to independence.

 描述（由申请人提供）：“稳态”机制的作用是稳定系统的关键参数，就像恒温器的作用是稳定建筑物中的温度一样，在神经元中，稳态突触可塑性被认为可以抵消赫布的不稳定影响。 -可塑性机制是突触连接活动依赖性细化的基础，据推测，严重的人类病理是由神经元稳态机制受损引起的，包括阿尔茨海默氏病，在这一领域取得进展的一个重大障碍是我们对完整大脑的稳态可塑性几乎完全缺乏了解，我建议研究稳态突触可塑性如何支持自由行为动物的大脑功能和行为。该提案将重点关注突触建模，这是体外最容易理解的神经活动稳态机制之一。首先，在指导（K99）部分期间进行的工作将定义突触的功能作用。为此，我将利用病毒介导的基因转移来阻断皮质神经元子集的突触缩放，并测试对长期感觉剥夺的稳态反应。独立阶段将检验睡眠对于体内稳态可塑性的表达是必需的这一假设，这将通过两个步骤来实现：（i）将在正常表达中检查神经调节状态特异性和/或昼夜节律模式。稳态可塑性，以及（ii）在自由行为动物的放电率稳态出现期间，调节​​状态将在关键时刻被破坏。最后，在独立阶段（R00），我将评估关于稳态可塑性的核心预测：那些稳态。机制用于抵消赫布可塑性在网络的经验依赖细化（即学习和发展）过程中固有的不稳定效应，我将确定突触缩放在以下方面的作用：皮质网络中信息传输的发展，以及b）皮质依赖性行为的发展将有助于理解和治疗理论上涉及稳态可塑性机制失调的疾病。最后，这项工作将确定健康大脑中稳态可塑性所需的参数，并深入了解稳态可塑性在我的研究生培训中的高级大脑功能中的作用。迄今为止的博士后经验为我提供了与本文提出的研究相关的方法和概念的坚实背景。我的长期研究目标是了解失调的稳态机制在神经系统疾病和疾病中的作用，并阐明其贡献。为了完成这项工作，我需要接受各种技术以及智力、专业和学术指导的额外培训，以及我导师的奉献和专业知识。 ，我的成员科学和职业小组委员会以及合作者为在研究型大学追求学术终身职位提供了完美的基础。体内分子生物学、计算神经科学、行为和技术开发的综合培训将为获得所需的最终要素提供基础。我开始独立的职业生涯，研究稳态可塑性在正常大脑功能和疾病中的作用。本申请的指导阶段描述的研究将在布兰迪斯大学博士的监督下进行。吉娜·图里吉亚诺。 Turrigiano 实验室开创了突触建模研究，是稳态可塑性领域公认的领导者，我组建了一个科学和职业咨询小组委员会，该委员会具有科学多样性，致力于我作为独立科学家的发展。 Avital Rodal 博士将提供分子生物学技术方面的专业知识，并监督 AMPAR 贩运操作的解释。Eve Marder 博士将提供计算方面的专业知识。除了本次培训之外，我还将在蒂莫斯·加德纳博士（波士顿大学）的实验室学习神经科学、实验设计和理论。我将通过定期参加国际会议和研究研讨会来支持这些活动，以发展自己的国际影响力并继续接受相关主题的教育。当我开始我的职业生涯时，我的委员会将在早期职业问题上提供持续的支持，进一步支持我。向独立过渡。