Genomic mechanisms of firing rate homeostasis

放电率稳态的基因组机制

• 批准号: 10094256
• 负责人: Susan M. Dymecki
• 金额: $ 57.68万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094256
• 关键词: Address; Back; Biological Assay; Brain; Buffers; CaM kinase I activator; Calcium; Cells; Chemicals; Coupled; Coupling; Data; Detection; Dominant-Negative Mutation; Electrodes; Event; Feedback; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomics; High-Throughput Nucleotide Sequencing; Homeostasis; Hour; Individual; Investigation; Kinetics; Knock-out; Knowledge; Lead; Learning; MAP Kinase Gene; Maps; Measurement; Measures; Mediating; Memory; Mental Health; Mental disorders; Messenger RNA; Mission; Molecular; Neurons; Pattern; Pharmacology; Phase; Public Health; Recording of previous events; Recovery; Research; Runaway; Seizures; Serum Response Factor; Signal Transduction; Specific qualifier value; Synapses; Synaptic Receptors; System; Technology; Temperature; Testing; Therapeutic Intervention; Time; Transcription Factor AP-1; Translating; United States National Institutes of Health; Work; base; conditional knockout; design; experimental study; gene induction; genome-wide; high throughput screening; improved; innovation; multi-electrode arrays; optogenetics; prevent; programs; receptor density; sensor; therapeutic development; tool; transcriptome sequencing; Address; Back; Biological Assay; Brain; Buffers; CaM kinase I activator; Calcium; Cells; Chemicals; Coupled; Coupling; Data; Detection; Dominant-Negative Mutation; Electrodes; Event; Feedback; Functional disorder; Gene Expression; Genes; Genetic Transcription; Genomics; High-Throughput Nucleotide Sequencing; Homeostasis; Hour; Individual; Investigation; Kinetics; Knock-out; Knowledge; Lead; Learning; MAP Kinase Gene; Maps; Measurement; Measures; Mediating; Memory; Mental Health; Mental disorders; Messenger RNA; Mission; Molecular; Neurons; Pattern; Pharmacology; Phase; Public Health; Recording of previous events; Recovery; Research; Runaway; Seizures; Serum Response Factor; Signal Transduction; Specific qualifier value; Synapses; Synaptic Receptors; System; Technology; Temperature; Testing; Therapeutic Intervention; Time; Transcription Factor AP-1; Translating; United States National Institutes of Health; Work; base; conditional knockout; design; experimental study; gene induction; genome-wide; high throughput screening; improved; innovation; multi-electrode arrays; optogenetics; prevent; programs; receptor density; sensor; therapeutic development; tool; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Neuronal Firing Rate Homeostasis (FRH) describes the ability of neurons to maintain their average firing rates at precise set points in the long-term, even in the face of changing synaptic inputs. The stability provided by FRH enables learning and memory. Achieving FRH requires an FRH control circuit that is akin to a thermostat that compares desired to actual room temperatures or an autopilot that compares desired to actual trajectories. Identifying this control circuit will require direct measurement of FRH by perturbing firing rates and observing homeostatic recovery, which has rarely been done. A promising candidate FRH control circuit is the neuronal Activity-Regulated Gene (ARG) program, in which activity-dependent increases in calcium lead to transcription of genes whose mRNA levels remain elevated for many hours. The ARG program is a promising candidate because individual activity-regulated genes protect against seizures, and they also regulate homeostatic effector mechanisms like synaptic scaling that may mediate FRH. However, the molecules that comprise the FRH control circuit are unknown. We hypothesize that the ARG program is the core control mechanism of FRH. Our extensive preliminary data reinforce the importance of testing this hypothesis at genome-scale. The genome-scale approach is important not only because of the sheer number of ARGs but also because different ARGs appear to “interpret” firing rate error in very different -- but as yet undefined -- ways. Relying on our extensive knowledge of the ARG program, we will evaluate its contribution to FRH. For ARG induction to be a core mechanism of FRH, it must be specified quantitatively by firing rates. We will therefore map the coupling of firing rates to ARG expression levels, by controlling firing rates optogenetically and detecting gene expression with RNA-Seq. We will also directly assess the functional contribution of ARG induction to FRH by perturbing firing rates pharmacologically in cortical neurons and observing homeostatic recovery using multi- electrode arrays, with or without perturbation of ARGs. Our approach is innovative because it is a genome- wide investigation of the activity-sensing control system for homeostasis rather than the far better-studied homeostatic effector mechanisms. Our work is significant because it will advance basic knowledge of the control circuit mediating FRH and produce tools for manipulating FRH that will help connect this control circuit to candidate homeostatic mechanisms.

项目摘要/摘要 神经元发射率体内平衡（FRH）描述了神经元保持平均点火率的能力 从长期的精确设定点上，即使面对不断变化的突触输入。提供的稳定性 FRH可实现学习和记忆。实现FRH需要一个类似于恒温器的FRH控制电路 这与实际的室温或自动驾驶仪相比，将所需的自动驾驶仪与实际轨迹进行了比较。 识别此控制电路将需要通过扰动射击率和观察来直接测量FRH 稳态恢复，很少完成。承诺的候选FRH控制电路是神经元 活性调节的基因（ARG）程序，其中活性依赖性钙的增加导致转录 mRNA水平保持升高数小时的基因。 ARG计划是承诺的候选人 因为个体活动调节的基因可预防癫痫发作，并且还调节体内平衡 效应器机制，例如突触缩放，可能介导FRH。但是，完成的分子 FRH控制电路未知。我们假设ARG程序是 FRH。我们广泛的初步数据增强了在基因组规模上检验这一假设的重要性。这 基因组规模的方法不仅重要 Args似乎以非常不同的方式“解释”发射速率误差（但尚未定义）。依靠我们 对ARG计划的广泛了解，我们将评估其对FRH的贡献。为了arg归纳 FRH的核心机制，必须通过发射速率进行定量指定。因此，我们将映射耦合 通过控制发射速率和检测基因的发射速率的发射速率到ARG表达水平 用RNA-seq表达。我们还将直接评估ARG归纳对FRH的功能贡献 在皮质神经元中扰动发射速率，并使用多种多数观察体内稳态恢复 电极阵列，有或没有ARG的扰动。我们的方法具有创新性，因为它是一个基因组 - 对稳态的活动感应控制系统的广泛研究，而不是研究得多的人 稳态效应器机制。我们的工作很重要，因为它将提高对 控制电路中介FRH并生产用于操纵FRH的工具，这将有助于连接该控制电路 候选稳态机制。