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）：为了从机制上理解大脑功能，从而采取有原则的方法来修复受损的大脑，生物医学科学家面临着弥合单细胞的电生理特性和神经元网络的新兴特性之间的差距的艰巨任务。所提出的实验将有助于弥补这一差距，以解决与认知、学习和记忆密切相关的问题：海马体中连贯θ节律的细胞基础。核心假设是，一类特殊的海马抑制性中间神经元，称为腔隙分子 (O-LM) 细胞，在放大体内 θ 节律和产生体外 θ 节律活动方面发挥着至关重要的作用。拟议的脑切片实验依靠最近开发的实时动态钳系统来研究 O-LM 细胞的整合特性，并将活神经元浸入计算机模拟的微电路中。构建这种混合微电路（包含实时交互的生物和模拟神经元的小型大脑电路）可以让人们以前所未有的定量严格性测试微电路功能的精确假设。其他拟议的研究重点关注 O-LM 细胞投射到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 θ 节律的后果。拟议的研究计划有五个目标：（1）研究 O-LM 细胞响应模拟体内状态的人工突触屏障的输入输出特性。 (2) 研究锁相、远端和近端抑制输入如何导致兴奋性锥体细胞锁相稀疏放电。 (3) 研究基于远端 O-LM 的抑制对锥体神经元树突输入的相位依赖性选择的影响。 (4) 研究从东方-腔隙分子（O-LM）中间神经元到锥体细胞和快速尖峰中间神经元的输入如何有助于“闭环”网络中的自组织theta和gamma节律。 (5)研究在反馈输入、来自隔膜的人工节律驱动和其他因素的操纵下O-LM细胞同步对于节律活动的重要性。该研究计划的长期目标是通过定量和机械的严格性来了解海马体和其他皮质区域正常和异常节律行为的机制。这项工作将与理解 theta 和 gamma 节律直接相关。这两种连贯活动模式似乎对正常认知、学习和记忆至关重要，但在癫痫、精神分裂症、帕金森病和阿尔茨海默病等多种疾病中都会受到干扰。由于所提出的方法可以显示特定的膜机制如何促进网络功能，因此它对于识别新的药物靶点特别有用。所提出的方法的另一个好处是，为这些研究开发的动态钳技术可能被证明对于治疗性、反馈控制的大脑电刺激有用。 公共卫生相关性：拟议项目与公共卫生相关有两个原因。首先，拟议的工作允许对已知对认知、学习和记忆很重要的节律性大脑活动进行严格研究。其次，该项目正在开发和使用的电子技术对于神经系统患者大脑结构的基于反馈的电刺激非常有价值。