Mapping the escape from inhibition.
绘制逃离抑制的图谱。
基本信息
- 批准号:8232069
- 负责人:
- 金额:$ 33.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnatomyAnimalsAreaBrainBrain InjuriesCalciumCellsCharacteristicsColorComplexComputer SimulationConvulsantsDataDevelopmentElementsEpilepsyExcitatory SynapseFailureFeedbackFigs - dietaryFinancial compensationFire - disastersFunctional disorderGeneticGlutamatesGrowthHealthHomeostasisHumanImageImageryImaging DeviceIn VitroIndiumIndividualInjuryInterneuronsLabelLasersLocationMapsMediatingMental DepressionMicroscopyModelingMusMyoepithelial cellNeuronsNeurotransmittersOutputParvalbuminsPathogenesisPathway interactionsPatientsPatternProcessPyramidal CellsRecoveryRefractoryRunawayRunningScanningSeizuresSliceSpeedSynapsesTechniquesTestingTherapeutic InterventionTimefluorophoregamma-Aminobutyric Acidgraspin vivoinhibitory neuroninsightoptogeneticsphotoactivationpreventratiometricresponsesimulationsynaptic depressiontheoriestool
项目摘要
DESCRIPTION (provided by applicant): Feedback inhibition is the process by which activity in principal neurons stimulates interneurons to release the inhibitory neurotransmitter GABA onto the active principal neurons to prevent runaway excitation. Failure of feedback inhibition is thus a critical element in most theories of the pathogenesis of seizures. However, the functional anatomy of feedback inhibition in the normal brain and epileptic focus is unknown. Recent developments in optogenetics and multiphoton microscopy have made it possible to address this question directly. Here we propose to combine channelrhodopsin-mediated photoactivation of targeted pyramidal cells with high-speed multiphoton imaging of the responses in interneurons expressing the calcium fluorophore yellow chameleon 3.6. These techniques will allow us to define the location of the interneurons that are activated by the target pyramidal cell. After brain injury, the loss of principal neurons and interneurons is compensated by sprouting of new synaptic connections. Our computer modeling suggests that the circuit complexity engendered by this sprouting leaves the interneurons vulnerable to activity-induced synaptic depression that permits runaway excitation and seizures. We hypothesize therefore that epileptic circuits will be defined by characteristic changes in the anatomy of feedback inhibition: more principal neurons will share the same interneuron feedback networks, and individual interneurons will be activated by a wider anatomical range of pyramidal cells, so that the anatomical complexity of local feedback circuits will be increased in epileptic foci. We will test this hypothesis directly with the new optogenetic and microscopy tools in vitro using chronically epileptic organotypic slice cultures, and in vivo using chronically epileptic animals. This data will provide a critical new insight into the pathophysiology of epilepsy that we have not been able to acquire despite wonderfully detailed electrophysiological and classical anatomical studies. Testing for characteristic circuit alterations in epilepsy will make possible new classes of therapeutic interventions including pharmacological manipulation of activity-dependent depression, as well as preemptive activation of critical circuit elements.
描述(由申请人提供):反馈抑制是主神经元中的活动刺激中间神经元将抑制性神经递质GABA释放到活性主神经元上以防止失控兴奋的过程。因此,反馈抑制的失败是癫痫发作发病机制的大多数理论中的关键因素。然而,反馈抑制在正常大脑和癫痫病灶的功能解剖是未知的。光遗传学和多光子显微镜的最新发展使得直接解决这个问题成为可能。在这里,我们建议结合联合收割机通道视紫红质介导的光激活的目标锥体细胞的高速多光子成像的响应在中间神经元表达的钙荧光团黄色变色龙3.6。这些技术将使我们能够确定由目标锥体细胞激活的中间神经元的位置。脑损伤后,主要神经元和中间神经元的损失通过新突触连接的萌芽来补偿。我们的计算机模型表明,这种萌芽产生的电路复杂性使中间神经元容易受到活动诱导的突触抑制,从而导致失控的兴奋和癫痫发作。因此,我们假设癫痫回路将被定义为反馈抑制解剖结构的特征性变化:更多的主神经元将共享相同的中间神经元反馈网络,单个中间神经元将被更广泛的锥体细胞激活,因此癫痫灶中局部反馈回路的解剖复杂性将增加。我们将直接测试这一假设与新的光遗传学和显微镜工具在体外使用慢性癫痫器官型切片培养,并在体内使用慢性癫痫动物。这些数据将为癫痫的病理生理学提供一个重要的新见解,尽管有非常详细的电生理学和经典解剖学研究,我们还没有能够获得。测试癫痫的特征性电路改变将使新的治疗干预措施成为可能,包括活动依赖性抑郁症的药理学操作,以及关键电路元件的抢先激活。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kevin J. Staley其他文献
Expression of LIM Protein Genes Lmo1, Lmo2, andLmo3 in Adult Mouse Hippocampus and Other Forebrain Regions: Differential Regulation by Seizure Activity
LIM 蛋白基因 Lmo1、Lmo2 和 Lmo3 在成年小鼠海马和其他前脑区域的表达:癫痫活动的差异调节
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:5.3
- 作者:
G. L. Hinks;B. Shah;S. J. French;S. J. French;L. S. Campos;L. S. Campos;Kevin J. Staley;J. Hughes;M. Sofroniew;M. Sofroniew - 通讯作者:
M. Sofroniew
Case 28-2008
案例28-2008
- DOI:
10.1056/nejmcpc0804642 - 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Kevin J. Staley;Katherine B. Sims;P. E. Grant;E. T. Hedley - 通讯作者:
E. T. Hedley
Kevin J. Staley的其他文献
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{{ truncateString('Kevin J. Staley', 18)}}的其他基金
Changes in the Ionic Basis of GABAergic Inhibition that Contribute to Post-traumatic Epilepsy
导致创伤后癫痫的 GABA 能抑制离子基础的变化
- 批准号:
10713240 - 财政年份:2023
- 资助金额:
$ 33.55万 - 项目类别:
Neuronal ion and volume shifts after acute brain injury
急性脑损伤后神经元离子和体积变化
- 批准号:
10152689 - 财政年份:2020
- 资助金额:
$ 33.55万 - 项目类别:
Neuronal Ion and Volume Shifts After Acute Brain Injury
急性脑损伤后神经元离子和体积变化
- 批准号:
10611844 - 财政年份:2020
- 资助金额:
$ 33.55万 - 项目类别:
Neuronal ion and volume shifts after acute brain injury
急性脑损伤后神经元离子和体积变化
- 批准号:
10228299 - 财政年份:2020
- 资助金额:
$ 33.55万 - 项目类别:
Neuronal ion and volume shifts after acute brain injury
急性脑损伤后神经元离子和体积变化
- 批准号:
10392372 - 财政年份:2020
- 资助金额:
$ 33.55万 - 项目类别:
Optimizing Organotypic Slices to Study Epileptogenesis
优化器官切片以研究癫痫发生
- 批准号:
8192448 - 财政年份:2011
- 资助金额:
$ 33.55万 - 项目类别:
Mechanisms of neuronal death during epileptogenesis
癫痫发生过程中神经元死亡的机制
- 批准号:
9116953 - 财政年份:2011
- 资助金额:
$ 33.55万 - 项目类别:
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