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(申请人提供)：“稳态”机制起到稳定系统关键参数的作用，就像恒温器起到稳定建筑物温度的作用一样。在神经元中，稳态突触可塑性被认为抵消了Hebbian可塑性机制的不稳定影响，Hebbian可塑性机制是突触连接的活性依赖精细化的基础。据推测，严重的人类病理是由神经元稳态机制受损引起的，包括阿尔茨海默病、癫痫和雷特综合征。在这一领域取得进展的一个重要障碍是我们几乎完全缺乏对完整大脑的自我平衡可塑性的洞察力。我打算研究在行为自由的动物中，稳态突触可塑性如何支持大脑功能和行为。这项建议的研究将集中在突触伸缩，这是体外最了解神经元活动动态平衡的机制之一。首先，在指导(K99)组件期间进行的工作将定义突触调节在体内放电速率动态平衡中的功能作用。为了做到这一点，我将利用病毒介导的基因转移来阻止部分皮质神经元中突触的伸缩，并测试长期感觉剥夺后的动态平衡反应。接下来，在指导阶段和独立阶段进行的工作将检验睡眠对于体内内稳态可塑性的表达是必要的这一假设。这将通过两个步骤来实现：(I)神经调节状态特有的和/或昼夜节律模式将在稳态可塑性的正常表达中被检测，以及(Ii)在自由行为动物的放电率稳态出现的关键时刻，调节状态将被破坏。最后，在独立阶段(R00)，我将评估关于稳态可塑性的核心预测：这些稳态机制用于抵消在依赖经验的网络细化(即学习和发展)过程中Hebbian可塑性固有的不稳定影响。在这项工作中，我将确定突触伸缩在a)皮质网络中信息传输的发展中的作用，以及b)皮质依赖行为的发展中的作用。这项拟议的研究将有助于理解和治疗理论上涉及失调的体内平衡可塑性机制的疾病。此外，这些数据将为研究睡眠不足的影响提供新的见解。最后，这项工作将确定健康大脑中平衡可塑性所必需的参数，并提供对平衡可塑性在更高水平大脑功能中的作用的洞察。应聘者的近期和长期职业目标，我的研究生培训和博士后经历，到目前为止为我提供了与这里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疾病和疾病中的作用，并揭示稳态可塑性对正常大脑功能的贡献。为了完成这项工作，我需要在各种技术以及智力，专业和学术指导方面的额外培训。布兰迪斯大学的环境加上我的导师、我的科学和职业小组委员会的成员以及合作者的奉献精神和专业知识，为我在研究型大学寻求终身教职提供了完美的基础。体内分子生物学、计算神经科学、行为学和技术开发方面的综合培训将为我开始独立的职业生涯提供必要的最后要素，研究体内平衡可塑性在正常大脑功能和疾病中的作用。研究职业发展计划的关键要素。在本申请的指导阶段中描述的研究将在Brandeis大学进行，由Gina Turrigiano博士监督。特里加诺实验室是突触伸缩研究的先驱，也是稳态可塑性领域公认的领导者。我已经组建了一个科学和职业咨询小组委员会，该委员会在科学上具有多样性，致力于我作为一名独立科学家的发展。史蒂芬·范·胡瑟博士将提供动物视觉、计算技术和活体光基因操作方面的专业知识。阿维塔尔·罗达尔博士将提供分子生物学技术方面的专业知识，并监督AMPAR贩运操纵的解释。伊夫·马德博士将提供计算神经科学、实验设计和理论方面的专业知识。除了这次培训，我还将在我的合作者Timoth Gardner博士(波士顿大学)的实验室里花两个月的时间学习推进体内神经科学所必需的尖端技术制造。最后，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，以提高我的国际影响力，并继续我在相关主题方面的教育。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的过渡。