Synchronous Activity in Hybrid Neuronal Microcircuits

混合神经元微电路中的同步活动

• 批准号: 7888024
• 负责人: John A. White
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-26 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7888024
• 关键词: Agonist; Alzheimer' s Disease; Animals; Apical; Behavior; Biological; Brain; Brain Injuries; Cells; Cognition; Computers; Data; Dendrites; Distal; Drug Delivery Systems; Electrical Stimulation of the Brain; Electronics; Epilepsy; Face; Feedback; Fire - disasters; Frequencies; Glutamates; Goals; Hippocampus (Brain); Hybrids; In Vitro; Interneurons; Lead; Learning; Life; Location; Membrane; Memory; Methods; Modeling; Neurologic; Neurons; Output; Pacemakers; Parkinson Disease; Patients; Pattern; Perforant Pathway; Phase; Play; Population; Property; Public Health; Pyramidal Cells; Relative (related person); Research; Role; Schizophrenia; Shapes; Signal Transduction; Simulate; Slice; Source; Structure; Synapses; System; Technology; Testing; Therapeutic; Theta Rhythm; Time; Work; base; biomedical scientist; cholinergic; hippocampal pyramidal neuron; in vitro activity; in vivo; postsynaptic; programs; public health relevance; repaired; research study; response; simulation

DESCRIPTION (provided by applicant): To understand brain function mechanistically, and thus to take principled approaches in repairing damaged brains, biomedical scientists face the daunting task of bridging the gap between the electrophysiological properties of single cells and the emergent properties of neuronal networks. The proposed experiments will help bridge this gap for a problem of great relevance in cognition and learning and memory: the cellular bases of the coherent theta rhythm in the hippocampus. The central hypothesis is that a particular class of hippocampal inhibitory interneurons, called oriens lacunosum-moleculare (O-LM) cells, plays a crucial role in amplifying the theta rhythm in vivo and generating theta-rhythmic activity in vitro. Proposed brain-slice experiments rely upon a recently developed real-time dynamic clamp system to study the integrative properties of O-LM cells and to immerse living neurons in computer-simulated microcircuits. Building such hybrid microcircuits-small brain circuits containing biological and simulated neurons that interact in real time- allows one to test precise hypotheses of microcircuit function with unprecedented quantitative rigor. Additional proposed studies focus on the consequences of O-LM-cell projections to the distal dendrites of pyramidal cells, as well as the consequences of O-LM-cell loss for the theta rhythm in vivo and in vitro. The proposed research program has five aims: (1) To study the input-output properties of O-LM cells in response to artificial synaptic barrages that mimic the in vivo state. (2) To study how phase-locked, distal and proximal inhibitory inputs can lead to phase-locked sparse firing in excitatory pyramidal cells. (3) To study the effects of distal O-LM-based inhibition on phase-dependent selection of dendritic inputs to pyramidal neurons. (4) To study how input from oriens-lacunosum moleculare (O-LM) interneurons to pyramidal cells and fast- spiking interneurons contributes to self-organized theta and gamma rhythms in "closed-loop" networks. (5) To study the importance of synchronization of O-LM cells for rhythmic activity under manipulation of feedback input, artificial rhythmic drive from the septum, and other factors. The long-term goal of this research program is to understand, with quantitative and mechanistic rigor, the mechanisms by which both normal and abnormal rhythmic behaviors emerge in the hippocampus and other cortical regions. The work will be immediately relevant to understanding the theta and gamma rhythms. These two patterns of coherent activity seem crucial for normal cognition and learning and memory, and are disrupted in a broad range of conditions including epilepsy, schizophrenia, Parkinson's disease, and Alzheimer's disease. Because the proposed approach can show how specific membrane mechanisms contribute to network function, it is particularly useful for identifying new drug targets. An added bonus of the proposed approach is that the dynamic clamp technology developed for these studies may prove useful for therapeutic, feedback-controlled electrical stimulation of the brain. PUBLIC HEALTH RELEVANCE: The proposed project is relevant to public health for two reasons. First, the proposed work allows rigorous study of rhythmic brain activity known to be important for cognition and learning and memory. Second, electronic technology being developed and used for this project will be valuable for feedback-based electrical stimulation of brain structures in neurological patients.

描述（由申请人提供）：为了机械理解大脑功能，因此要采取原则方法来修复受损的大脑，生物医学科学家面临着艰巨的任务，即弥合单个细胞的电生理特性与神经元网络的新兴特性之间的差距。提出的实验将有助于弥合这一差距，以解决认知，学习和记忆中非常相关的问题：海马中相干theta节奏的细胞基础。中心假设是，一类特定的海马抑制性中间神经元称为Oriens lacunosum-Moleculare（O-LM）细胞，在体内扩增theta节律并在体外产生theta-Rylythmic Attive在体外产生了theta节律至关重要。拟议的脑部片段实验依靠最近开发的实时动态夹具系统来研究O-LM细胞的整合性特性，并将活的神经元沉浸在计算机模拟的微电路中。构建这种混合微电路，可在实时相互作用的生物学和模拟神经元的脑电路 - 允许一个人以前所未有的定量严格性测试微电路功能的精确假设。其他提出的研究集中于O-LM细胞投影对锥体细胞远端树突的后果，以及O-LM细胞损失对体内和体外theta节律的后果。拟议的研究计划有五个目的：（1）研究响应于模仿体内状态的人工突触弹幕，研究O-LM细胞的输入输出特性。 （2）研究如何在兴奋性金字塔细胞中导致相锁，远端和近端抑制性输入如何导致相锁定的稀疏点火。 （3）研究基于O-LM的远端抑制对锥体神经元的树突状输入相关选择的影响。 （4）研究来自oriens- lacunosum分子（O-LM）中间神经元的输入如何到锥体细胞和快速尖峰中间神经元中的输入，在“封闭环”网络中有助于自组织的theta和gamma节律。 （5）研究O-LM细胞同步在操纵反馈输入，人工节奏驱动器以及其他因素的情况下对节奏活性的重要性。该研究计划的长期目标是通过定量和机械性严格理解正常和异常的节奏行为在海马和其他皮质区域中出现的机制。这项工作将立即与理解theta和伽玛的节奏有关。这两种相干活动的模式对于正常的认知，学习和记忆似乎至关重要，并且在包括癫痫，精神分裂症，帕金森氏病和阿尔茨海默氏病在内的广泛疾病中受到破坏。由于所提出的方法可以显示特定的膜机制如何对网络功能有效，因此对于识别新药物靶标特别有用。提出的方法的另一个好处是，为这些研究开发的动态夹具技术可能对大脑的治疗，反馈控制的电刺激有用。 公共卫生相关性：拟议项目与公共卫生有关，原因有两个。首先，拟议的工作允许对有节奏的大脑活动进行严格的研究，这对于认知，学习和记忆很重要。其次，为该项目开发和使用的电子技术对于基于反馈的神经系统患者的大脑结构的电刺激将是有价值的。