Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
基本信息
- 批准号:10468022
- 负责人:
- 金额:$ 58.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-30 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAgeAmericanAnatomyAnimalsAreaAstrocytesBrainCanadaCell CompartmentationCellular MorphologyCellular StructuresCerebrumChronicClinicalComputer ModelsCraniocerebral TraumaCyclic AMPDataDeafferentation procedureDevelopmentDirect CostsElectric StimulationElectrophysiology (science)ElementsEpilepsyEpileptogenesisEquilibriumFacilities and Administrative CostsFelis catusFoundationsGoalsHodgkin-Huxley modelHourHumanIn VitroInstitutesInterventionLaboratoriesLeadLettersLong-Term EffectsMeasurementMethodsModelingMorphologyMusNeocortexNeuronsOutcomePathologicPathologyPathway interactionsPatientsPatternPenetrating WoundsPharmacogeneticsPhysiologicalPreparationPreventionProcessPropertyRecoveryRegulationReportingResearchSeizuresSignal TransductionSliceSynapsesSynaptic PotentialsTNF geneTechniquesTestingTraumaTraumatic Brain InjuryUniversitiesUp-Regulationage relatedbasebiophysical propertiescell typecostdesignexperimental studyin vivointervention effection dynamicsjuvenile animalmature animalmulti-electrode arraysmulti-scale modelingnetwork modelsneuronal excitabilityoptogeneticspreventsimulationtherapy design
项目摘要
Project Summary/Abstract
The goal of this research is to understand why cerebral cortical trauma often leads to seizures and to propose
interventions that may reduce or prevent trauma-induced epileptogenesis. Within 24 hours following head
injury, up to 80% of patients with penetrating wounds display clinical seizures. Such acute seizures often
initiate epileptogenesis―the subthreshold processes that lead to spontaneous, recurring seizures and
ultimately to epilepsy. The primary hypotheses of this project are: 1) Trauma-related chronic blockade of
activity activates homeostatic plasticity mechanisms that upregulate depolarizing influences (such as excitatory
intrinsic and synaptic conductances) and downregulate hyperpolarizing ones (such as inhibitory
conductances); in traumatized cortex, this may create an unstable balance of excitation and inhibition that
leads to paroxysmal seizures; 2) The effect of the pathological homeostatic changes is age dependent with
older animals being more prone to seizures; 3) External interventions designed to prevent decrease of activity
after trauma reduce the likelihood of epileptic seizures. Importantly, rather than focus on the ways to treat
epilepsies after epileptogenesis is complete, this proposal aims to develop new techniques that can interfere
with a process of epileptogenesis itself. Following past experiments with cats in the Timofeev laboratory, a
well-established undercut model of cortical deafferenation will be used to induce seizures in mice experiments
in vivo and in vitro. Measurement will be performed over the medium-term (days) and long-term (weeks).
Interventions will be explored that can prevent epileptogenesis using pharmocogenetic stimulation to block
homeostatic changes. In vivo electrophysiological semichronic and chronic experiments will be performed at
Laval University (Canada). In vitro experiments from deafferented cortical slices will be conducted at Laval
University and UCSD. Necessary data on the astrocyte properties will be provided by the collaborators (Dr.
Nedergaard, Univ of Rochester). Experimental data will be analyzed at The Salk Institute and UCSD and will
be incorporated into large-scale network models of the neocortex, implementing subcellular, circuit and
network level properties, at the Salk Institute and UCSD. The computational models allow the interplay
between all of the changes that occur in the cortex in vivo during epileptogenesis to be simulated to identify the
critical mechanisms and to make predictions for intervention strategies that could prevent epileptogenesis.
项目摘要/摘要
这项研究的目的是了解为什么大脑皮层损伤经常导致癫痫发作,并提出
可减少或防止外伤性癫痫发生的干预措施。在事故发生后24小时内
在穿透伤患者中,高达80%的患者表现为临床癫痫发作。这种急性癫痫发作经常
引发癫痫-阈值以下的过程,导致自发性、复发性癫痫发作和
最终导致癫痫。该项目的主要假设是:1)创伤相关的慢性阻断
活动激活体内平衡可塑性机制,从而上调去极化影响(如兴奋性
内源性和突触电导)和下调超极化(如抑制性
电导);在受创伤的皮层,这可能会造成兴奋和抑制的不稳定平衡,
导致阵发性癫痫发作;2)病理内稳态改变的影响与年龄有关
年龄较大的动物更容易癫痫发作;3)旨在防止活动减少的外部干预
创伤后减少癫痫发作的可能性。重要的是,不要把注意力集中在治疗的方法上
在癫痫发生完成后,这项提议旨在开发新的技术,可以干预
伴随着癫痫发生本身的过程。继过去在蒂莫费耶夫实验室进行的猫实验后,
已建立的皮层去传入的下切模型将被用来在小鼠实验中诱导癫痫发作
在体内和体外。将在中期(天)和长期(周)进行测量。
将探索可利用致病刺激阻断癫痫发生的干预措施。
动态平衡的变化。在活体电生理学、半时间和慢性实验将在
拉瓦尔大学(加拿大)。去传入皮层脑片的体外实验将在拉瓦尔进行
大学和加州大学圣迭戈分校。合作者将提供有关星形胶质细胞特性的必要数据(Dr。
内德加德,罗切斯特大学)。实验数据将在索尔克研究所和加州大学洛杉矶分校进行分析,并将
结合到新大脑皮层的大规模网络模型中,实现亚细胞、电路和
索尔克研究所和加州大学圣迭戈分校的网络级属性。计算模型允许相互作用
在癫痫发生期间体内皮层发生的所有变化之间进行模拟,以确定
关键机制,并对可防止癫痫发生的干预策略作出预测。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Characterizing Concentration-Dependent Neural Dynamics of 4-Aminopyridine-Induced Epileptiform Activity.
表征 4-氨基吡啶诱导的癫痫样活动的浓度依赖性神经动力学。
- DOI:10.4172/2472-0895.1000128
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Myers,TimothyL;Gonzalez,OscarC;Stein,JacobB;Bazhenov,Maxim
- 通讯作者:Bazhenov,Maxim
Projections from the nucleus accumbens shell to the ventral pallidum are involved in the control of sucrose intake in adult female rats.
- DOI:10.1007/s00429-020-02161-z
- 发表时间:2020-12
- 期刊:
- 影响因子:3.1
- 作者:Chometton S;Guèvremont G;Seigneur J;Timofeeva E;Timofeev I
- 通讯作者:Timofeev I
Respiration organizes gamma synchrony in the prefronto-thalamic network.
呼吸组织在前面 - 丘脑网络中组织伽马同步。
- DOI:10.1038/s41598-023-35516-7
- 发表时间:2023-05-26
- 期刊:
- 影响因子:4.6
- 作者:Basha, Diellor;Chauvette, Sylvain;Sheroziya, Maxim;Timofeev, Igor
- 通讯作者:Timofeev, Igor
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{{ truncateString('TERRENCE J SEJNOWSKI', 18)}}的其他基金
DDALAB: Identifying Latent States from Neural Recordings with Nonlinear Causal Analysis
DDALAB:通过非线性因果分析从神经记录中识别潜在状态
- 批准号:
10643212 - 财政年份:2023
- 资助金额:
$ 58.89万 - 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
- 批准号:
10229375 - 财政年份:2018
- 资助金额:
$ 58.89万 - 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
- 批准号:
9789979 - 财政年份:2018
- 资助金额:
$ 58.89万 - 项目类别:
Multiscale modeling and large-scale recordings of trauma-induced epileptogenesis
创伤诱发癫痫发生的多尺度建模和大规模记录
- 批准号:
9597206 - 财政年份:2018
- 资助金额:
$ 58.89万 - 项目类别:
SIMULATION NEUROTRANSMITTER DIFFUSION IN CEREBELLAR GLOMERULI
模拟小脑肾小球中的神经递质扩散
- 批准号:
7956214 - 财政年份:2009
- 资助金额:
$ 58.89万 - 项目类别:
Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma
皮质创伤引发癫痫发生的内在机制和突触机制
- 批准号:
8318223 - 财政年份:2009
- 资助金额:
$ 58.89万 - 项目类别:
Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma
皮质创伤引发癫痫发生的内在机制和突触机制
- 批准号:
8144893 - 财政年份:2009
- 资助金额:
$ 58.89万 - 项目类别:
Intrinsic and synaptic mechanisms of epileptogenesis triggered by cortical trauma
皮质创伤引发癫痫发生的内在机制和突触机制
- 批准号:
7654250 - 财政年份:2009
- 资助金额:
$ 58.89万 - 项目类别:
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