The power of positivity: a novel class of voltage indicators for high-fidelity brain activity imaging
积极性的力量:用于高保真大脑活动成像的新型电压指示器
基本信息
- 批准号:10294164
- 负责人:
- 金额:$ 357.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Action PotentialsAddressAffectAmino AcidsAnimalsBenchmarkingBrainBrain DiseasesBrain regionCalciumCellsCommunicationComplexDecision MakingDetectionDevelopmentDiseaseElectrodesEmotionalEquipmentFluorescenceFutureGeneticGoalsHealthHourImageIndividualInterneuronsIon ChannelKineticsMeasurementMembrane PotentialsMembrane ProteinsMethodsModelingMotionMotorMusMutagenesisMutateMutationNatureNeuronsNeurosciences ResearchNeurotransmittersNoiseOutputPatternPerformancePhotonsPhysiologicalPopulationPositioning AttributeProcessProteinsRegulationReportingScanningSchizophreniaSensorySignal TransductionSiteSynapsesSystemTimeValidationVisualWorkbasebrain dysfunctionbrain electrical activitycalcium indicatorcell typecognitive functioncombinatorialexperienceextracellularflyhigh throughput screeningimprovedin vivoin vivo evaluationin vivo imaginginformation processingneuronal cell bodyneuronal circuitryneuroregulationneurotransmitter releasenovelprototyperesponsescreeningsensorsensory inputspatiotemporaltwo-photonvoltage
项目摘要
ABSTRACT
To understand how the brain functions in health, and how sensory, motor, and cognitive functions are affected in disease, it
is crucial to be able to record the activities of large numbers of individual neurons in real time. In the past two decades,
calcium imaging in neuronal cell bodies has provided a conveniently qualitative view of neuronal activity, allowing action
potential firing in specific neuron types or in various brain regions to be correlated with sensory input, decision-making, or
internal representations of emotional or physiological parameters. However, somatic calcium is generally insensitive to
subthreshold activity, i.e. to synaptic inputs that depolarize the membrane potential without eliciting action potentials, and
lacks the temporal precision to determine the timing relationship between action potentials within a circuit.
Our understanding of the brain would beneift greatly from understanding how neuronal circuits use transmembrane voltage
to represent and process information. Outstanding questions include how neuronal types differ in their summatation of
inputs to initiate an action potential output, how neuronal circuits extract salient features or makes a decision based on
complex patterns of input activity, and how experience or neuromodulation or disease affects these processes.
We propose to address this problem by creating a class of high-performance genetically encoded voltage indicators (GEVIs)
to record both subthreshold and spiking activity in large numbers of neurons in living animals. In particular, we find that
positively tuned GEVIs have the potential for detecting spikes with many times greater signal-to-noise ratio than GECIs
while achieving useful discriminability of subthreshold potentials.
We propose an intense effort to develop such positively tuned GEVIs toward ideal performance specifications identified by
quantitative modeling. Aims include (1) comprehensive screening of residues in a prototype positively tuned GEVI to
identify positions modulating voltage tuning and fluorescence responsiveness, followed by deep combinatorial mutagenesis
of identified sites, (2) validation of indicators in vivo in 1-photon and 2-photon imaging in flies and mice, and (3)
development of an ultra-high-throughput single-cell screening system to further accelerate GEVI improvement.
摘要
项目成果
期刊论文数量(0)
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Michael Z. Lin其他文献
Synaptic basis of feature selectivity in hippocampal neurons
海马神经元特征选择性的突触基础
- DOI:
10.1038/s41586-024-08325-9 - 发表时间:
2024-12-18 - 期刊:
- 影响因子:48.500
- 作者:
Kevin C. Gonzalez;Adrian Negrean;Zhenrui Liao;Satoshi Terada;Guofeng Zhang;Sungmoo Lee;Katalin Ócsai;Balázs J. Rózsa;Michael Z. Lin;Franck Polleux;Attila Losonczy - 通讯作者:
Attila Losonczy
An optimized luciferin formulation for NanoLuc-based in vivo bioluminescence imaging
用于基于 NanoLuc 的体内生物发光成像的优化荧光素制剂
- DOI:
10.1038/s41598-025-97366-9 - 发表时间:
2025-04-15 - 期刊:
- 影响因子:3.900
- 作者:
Chao Gao;Yan Wu;Connor Fitzgerald;Hui Wang;Tim Ugo;Tetsuo Uyeda;Wenhui Zhou;Yichi Su;Thomas A. Kirkland;Michael Z. Lin - 通讯作者:
Michael Z. Lin
Functional and Structural Characterization of A New Monomeric Far-Red Fluorescent Protein
- DOI:
10.1016/j.bpj.2009.12.1158 - 发表时间:
2010-01-01 - 期刊:
- 影响因子:
- 作者:
Michael Z. Lin;Michael R. McKeown;Ho Leung Ng;Tom Alber;Roger Y. Tsien - 通讯作者:
Roger Y. Tsien
On the cutting edge: protease-based methods for sensing and controlling cell biology
处于前沿:基于蛋白酶的细胞生物学传感与控制方法
- DOI:
10.1038/s41592-020-0891-z - 发表时间:
2020-07-13 - 期刊:
- 影响因子:32.100
- 作者:
H. Kay Chung;Michael Z. Lin - 通讯作者:
Michael Z. Lin
Pharmacodynamics of Akt drugs revealed by a kinase-modulated bioluminescent indicator
一种激酶调节的生物发光指示剂揭示的 Akt 药物的药效学
- DOI:
10.1038/s41589-025-01846-y - 发表时间:
2025-02-11 - 期刊:
- 影响因子:13.700
- 作者:
Yan Wu;Chenzhou Hao;Chao Gao;Matt Hageman;Sungmoo Lee;Thomas A. Kirkland;Nathanael S. Gray;Yichi Su;Michael Z. Lin - 通讯作者:
Michael Z. Lin
Michael Z. Lin的其他文献
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{{ truncateString('Michael Z. Lin', 18)}}的其他基金
Development of selective and potent protease inhibitors for corona and other pandemic viruses
开发针对冠状病毒和其他大流行病毒的选择性有效蛋白酶抑制剂
- 批准号:
10514273 - 财政年份:2022
- 资助金额:
$ 357.9万 - 项目类别:
Chemogenetic control of kinase and phosphatase activity by modulating autoinhibition
通过调节自抑制对激酶和磷酸酶活性进行化学遗传学控制
- 批准号:
10195182 - 财政年份:2021
- 资助金额:
$ 357.9万 - 项目类别:
Bioluminescent indicators for noninvasive imaging of acetylcholine release
用于乙酰胆碱释放无创成像的生物发光指示器
- 批准号:
10196839 - 财政年份:2021
- 资助金额:
$ 357.9万 - 项目类别:
Chemogenetic control of kinase and phosphatase activity by modulating autoinhibition
通过调节自抑制对激酶和磷酸酶活性进行化学遗传学控制
- 批准号:
10371123 - 财政年份:2021
- 资助金额:
$ 357.9万 - 项目类别:
Noninvasive bioluminescent imaging of neuronal activity in freely behaving animals
自由行为动物神经元活动的无创生物发光成像
- 批准号:
9906190 - 财政年份:2019
- 资助金额:
$ 357.9万 - 项目类别:
Protein voltage sensors: kilohertz imaging of neural dynamics in behaving animals
蛋白质电压传感器:行为动物神经动力学的千赫兹成像
- 批准号:
8827201 - 财政年份:2014
- 资助金额:
$ 357.9万 - 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
- 批准号:
8896827 - 财政年份:2013
- 资助金额:
$ 357.9万 - 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
- 批准号:
9132820 - 财政年份:2013
- 资助金额:
$ 357.9万 - 项目类别:
Optogenetics for all: A general method for optical control of protein activity
所有人的光遗传学:蛋白质活性光学控制的通用方法
- 批准号:
8564060 - 财政年份:2013
- 资助金额:
$ 357.9万 - 项目类别:
A Molecular Tag for Drug-Regulated Synthesis of Specific Proteins
用于药物调控合成特定蛋白质的分子标签
- 批准号:
8733708 - 财政年份:2011
- 资助金额:
$ 357.9万 - 项目类别:
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