GABA Receptors and Hilar Neuron Survival in Epilepsy
GABA Receptors and Hilar Neuron Survival in Epilepsy
批准号:
8413046
负责人:
CAROLYN R HOUSER
金额:
$32.51万
依托单位国家:
美国
项目类别:
财政年份:
2012
资助国家:
美国
项目状态:
已结题
起止时间:
2012-02-01 至 2016-12-31
关键词:
Animal ModelAnimalsBiological PreservationBrainCell surfaceCellsCerebellumConfocal MicroscopyD CellsElectron MicroscopyElectronsEpilepsyExhibitsGABA ReceptorGene ExpressionGlutamatesGoalsHilarHippocampal FormationHippocampus (Brain)HumanIn VitroInterneuronsIschemiaLabelLeadLightLocationMapsMediatingMediator of activation proteinMethodsMicroscopicModelingMusNeuronsPatternPilocarpinePlayPredispositionProcessProteinsPublic HealthReagentRelative (related person)ResearchRoleSeizuresSiteSomatostatinStatus EpilepticusSubgroupSuggestionTemporal Lobe EpilepsyTestingTraumatic Brain InjuryViral Genesadeno-associated viral vectorbasecell typedentate gyrusgranule cellin vivointerestneuron lossneuronal excitabilityneuroprotectionnew technologyoptogeneticsreceptorrecombinaseresponse
中文摘要
项目概要
齿状回门神经元的丢失是最一致的形态学发现之一
患有颞叶癫痫和相关获得性癫痫模型的人。肺门的两个主要组
神经元、GABA能生长抑素中间神经元和谷氨酸能苔藓细胞经常受损。
尽管多年来人们对肺门神经元很感兴趣,但重要的问题仍然存在。为什么神经元如此脆弱
兴奋性毒性损伤?他们怎样才能得到保护?损失和损失的功能影响是什么?
这些神经元亚群的保存?一系列新技术、试剂和小鼠现在将允许
以令人兴奋的新方式探讨这些问题。拟议的研究将使用带有 Cre 重组酶的小鼠
这些神经元中的表达,通过 Cre 激活的病毒基因表达选择性地操纵它们。一个
光和电子显微镜免疫组织化学方法的结合将用于评估
变化和功能相关性将通过电生理学方法确定。广泛的目标是
以确定增加这些神经元中的强直性 GABA 能抑制是否可以起到神经保护作用,并且
一组单独的研究,以绘制在操纵任一苔藓后激活的功能电路
正常和易癫痫动物体内的细胞或生长抑素神经元。具体目标 1 将测试
假设两组肺门神经元均缺乏 GABAA 受体 ¿ 亚基的大量表达
(GABAAR) 并具有低水平的强直抑制作用。具体目标 2 将检验以下假设:
外源性 GABAAR 亚基通常参与小脑的强直抑制,会导致
功能性 GABAA 受体的形成并增加两组肺门神经元的强直抑制。具体
目标 3 将检验以下假设:增加肺门神经元的强直抑制将保护它们免受损伤
癫痫持续状态后。具体目标 4 将使用以下方法检查体内肺门神经元的功能回路:
光遗传学方法选择性地操纵神经元,然后通过 Fos 识别激活的神经元
标签。将比较正常动物和易癫痫动物的激活模式以测试
假设刺激剩余的苔藓细胞或沉默体内剩余的生长抑素中间神经元将
导致癫痫小鼠的颗粒细胞活化增加。通过允许选择性地操纵肺门
完整大脑中的神经元,这些研究将为它们在正常和改变的情况下的功能提供独特的观点
神经元回路。
英文摘要
Project Summary
Loss of neurons in the hilus of the dentate gyrus is one of the most consistent morphological findings in
humans with temporal lobe epilepsy and related models of acquired epilepsy. Two major groups of hilar
neurons are frequently damaged, GABAergic somatostatin interneurons and glutamatergic mossy cells.
Despite years of interest in hilar neurons, important questions persist. Why are the neurons so vulnerable to
excitotoxic damage? How could they be protected? What are the functional effects of both loss and
preservation of subgroups of these neurons? A set of new technologies, reagents and mice will now allow
probing these questions in exciting new ways. The proposed studies will use mice with Cre-recombinase
expression in these neurons to selectively manipulate them through Cre-activated viral gene expression. A
combination of light and electron microscopic immunohistochemical methods will be used to evaluate the
changes, and functional correlates will be determined with electrophysiological methods. The broad goals are
to determine if increasing tonic GABAergic inhibition in these neurons could be neuroprotective and, in a
separate set of studies, to map the functional circuits that are activated following manipulation of either mossy
cells or somatostatin neurons in normal and seizure-prone animals in vivo. Specific Aim 1 will test the
hypothesis that both groups of hilar neurons lack substantial expression of the ¿ subunit of the GABAA receptor
(GABAAR) and have low levels of tonic inhibition. Specific Aim 2 will test the hypothesis that expressing an
exogenous GABAAR subunit, which is normally involved in tonic inhibition in the cerebellum, will lead to the
formation of functional GABAA receptors and increase tonic inhibition in both groups of hilar neurons. Specific
Aim 3 will test the hypothesis that increasing tonic inhibition in hilar neurons will protect them from damage
following status epilepticus. Specific Aim 4 will examine the functional circuitry of hilar neurons in vivo by using
optogenetic methods to manipulate the neurons selectively and then identifying the activated neurons by Fos
labeling. The patterns of activation in normal and seizure-prone animals will be compared to test the
hypotheses that stimulating remaining mossy cells or silencing remaining somatostatin interneurons in vivo will
lead to increased granule cell activation in the epileptic mice. By allowing selective manipulation of hilar
neurons in the intact brain, these studies will provide unique views of their function within normal and altered
neuronal circuits.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Role of Neuronal Loss in Epileptogenesis
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批准号:10364639
-
项目类别:
-
资助金额:$32.18万
-
财政年份:2018
-
负责人:CAROLYN R HOUSER
-
依托单位:
Role of Neuronal Loss in Epileptogenesis
-
批准号:9891119
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项目类别:
-
资助金额:$32.18万
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财政年份:2018
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负责人:CAROLYN R HOUSER
-
依托单位:
2012 Mechanisms of Epilepsy and Neuronal Synchronization Gordon Research Conferen
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批准号:8306407
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项目类别:
-
资助金额:$2.0万
-
财政年份:2012
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负责人:CAROLYN R HOUSER
-
依托单位:
GABA System Alterations and Fragile X Syndrome
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批准号:8234488
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项目类别:
-
资助金额:$31.96万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA System Alterations and Fragile X Syndrome
-
批准号:8606484
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项目类别:
-
资助金额:$31.06万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptors and Hilar Neuron Survival in Epilepsy
-
批准号:8585940
-
项目类别:
-
资助金额:$33.35万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA System Alterations and Fragile X Syndrome
-
批准号:8426129
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项目类别:
-
资助金额:$30.33万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptors and Hilar Neuron Survival in Epilepsy
-
批准号:8293815
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA System Alterations and Fragile X Syndrome
-
批准号:9008056
-
项目类别:
-
资助金额:$31.64万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptors and Hilar Neuron Survival in Epilepsy
-
批准号:8968872
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项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptors and Hilar Neuron Survival in Epilepsy
-
批准号:8773617
-
项目类别:
-
资助金额:$33.69万
-
财政年份:2012
-
负责人:CAROLYN R HOUSER
-
依托单位:
Neuronal Loss and Plasticity in Epilepsy
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批准号:8394616
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
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负责人:CAROLYN R HOUSER
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依托单位:
Neuronal Loss and Plasticity in Epilepsy
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批准号:8259057
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项目类别:
-
资助金额:$0.0万
-
财政年份:2010
-
负责人:CAROLYN R HOUSER
-
依托单位:
Neuronal Loss and Plasticity in Epilepsy
-
批准号:7923622
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项目类别:
-
资助金额:$0.0万
-
财政年份:2010
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负责人:CAROLYN R HOUSER
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依托单位:
Neuronal Loss and Plasticity in Epilepsy
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批准号:8195936
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项目类别:
-
资助金额:$0.0万
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财政年份:2010
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负责人:CAROLYN R HOUSER
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依托单位:
GABA Receptor Subunit Plasticity in Epilepsy
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批准号:7379931
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项目类别:
-
资助金额:$33.59万
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财政年份:2005
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负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptor Subunit Plasticity in Epilepsy
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批准号:8088999
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项目类别:
-
资助金额:$38.5万
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财政年份:2005
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负责人:CAROLYN R HOUSER
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依托单位:
GABA Receptor Subunit Plasticity in Epilepsy
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批准号:6901738
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项目类别:
-
资助金额:$33.57万
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财政年份:2005
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负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptor Subunit Plasticity in Epilepsy
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批准号:7029715
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项目类别:
-
资助金额:$34.59万
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财政年份:2005
-
负责人:CAROLYN R HOUSER
-
依托单位:
GABA Receptor Subunit Plasticity in Epilepsy
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批准号:7217452
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项目类别:
-
资助金额:$33.59万
-
财政年份:2005
-
负责人:CAROLYN R HOUSER
-
依托单位:
海外基金