Cortical Pathophysiology in Mouse Models of Huntington's Disease
亨廷顿病小鼠模型的皮质病理生理学
基本信息
- 批准号:9543575
- 负责人:
- 金额:$ 50.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-15 至 2021-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelAnteriorApplications GrantsAreaAutomobile DrivingBasal GangliaBehavioralCalciumCell CommunicationCell NucleusCellsCerebral cortexCognitive deficitsCollaborationsCommunicationComplexCorpus striatum structureDevelopmentDiseaseDisease ProgressionDisinhibitionDorsalElectrophysiology (science)Emotional DisturbanceEvaluationFunctional disorderGenesGeneticGenetic DiseasesGlutamineGoalsGrantHuntington DiseaseHuntington geneHuntington proteinImageImpaired cognitionIn VitroIndividualInterneuronsJointsLaboratoriesLeadLocomotionMethodologyModelingMorphologyMotorMotor ActivityMotor CortexMovementMusMutationNerve DegenerationNeurodegenerative DisordersNeuronal DysfunctionNeuronsNuclearPathway interactionsPatientsPhenotypePlayPopulationPublicationsRestRoleSensorySignal TransductionSiliconSliceSomatosensory CortexSymptomsSynapsesSynaptic TransmissionTechniquesTechnologyTestingThalamic NucleiThalamic structureTherapeuticTrinucleotide RepeatsVacuumVentroposterior Medial Nucleus of the ThalamusVibrissaeawakecalcium indicatordensitydesigndisease phenotypeexperimental studyhippocampal pyramidal neuronin vivoin vivo imaginginsightmotor deficitmotor disordermotor symptommouse modelmutantnervous system disordernew therapeutic targetnoveloptogeneticspatch clampreduce symptomsresponsesensory inputsensory integrationsomatosensory
项目摘要
Abstract
The fatal mutation in Huntington's disease (HD) leads to an expanded glutamine repeat within the huntingtin
protein which causes neuronal dysfunction typically followed by selective neurodegeneration especially within
the striatum and cortex. These dysfunctions in neurons and circuits occur during the development of the
disease phenotype, well before there is significant cell loss. Recent studies in animal models have emphasized
that synaptic cell-cell interactions play a role in the pathophysiology of this disease. For example, removing
mutant huntingtin from the cerebral cortex ameliorates some HD symptoms. The experiments in this
application are designed to understand the functional changes that occur in specific populations of cortical
neurons during the progression of the HD phenotype and to uncover new targets and approaches for
therapies. However, little is known about functional changes in cortical neurons, although these neurons also
degenerate in HD. Before motor symptoms become apparent, sensory, cognitive and emotional disturbances
occur and these seem to depend on aberrant communication in the cortex that probably involves
thalamocortical pathways. These pathways have never been examined in HD. Our overarching hypothesis is
that sensory and motor cortical areas are differentially and asynchronously affected during HD progression.
We propose that sensory thalamocortical pathways are downregulated early leading to faulty integration and
interpretation of sensory signals. In turn, the motor cortex becomes upregulated and disorganized, leading to
altered corticostriatal communication and motor symptoms. In this grant proposal we will use state-of-the-art
techniques in three different laboratories at UCLA. Aim 1 uses optogenetics and slice electrophysiology to
examine mechanistically altered synaptic communication between thalamic sensory and motor nuclei and their
corresponding cortical projection areas. Aim 2 uses high-density silicon microprobes to record firing of
hundreds of neurons simultaneously in sensory and motor cortical areas as well as thalamic nuclei in awake
mice. Aim 3 uses genetically encoded calcium indicators to visualize neuronal activity in sensory and motor
cortical areas in awake mice. Together, the studies will provide new and important mechanistic insights into the
understudied cortical dysfunction and will provide the basis for novel and rational treatments for HD by
delineating more restricted targets spatially and temporally. These studies also will be relevant for
understanding other CAG triplet repeat diseases and neurodegenerative disorders.
摘要
亨廷顿病(HD)中的致命突变导致亨廷顿蛋白内谷氨酰胺重复序列扩增
一种蛋白质,引起神经元功能障碍,通常随后是选择性神经变性,特别是在
纹状体和皮质这些神经元和回路的功能障碍发生在发育过程中,
疾病表型,以及之前有显着的细胞损失。最近的动物模型研究强调,
突触细胞间的相互作用在这种疾病的病理生理学中起作用。例如移除
来自大脑皮层的突变亨廷顿蛋白改善了某些HD症状。这个实验
应用程序的目的是了解发生在特定人群的皮质功能的变化,
在HD表型的进展过程中的神经元,并发现新的目标和方法,
治疗然而,对皮层神经元的功能变化知之甚少,尽管这些神经元也
在HD中退化。在运动症状变得明显之前,
发生,这些似乎取决于异常的沟通,在皮层,可能涉及
丘脑皮质通路这些途径从未在HD中进行过检查。我们的首要假设是
感觉和运动皮质区在HD进展过程中受到不同和异步的影响。
我们认为,感觉丘脑皮层通路在早期下调,导致错误的整合,
解读感官信号反过来,运动皮层变得上调和混乱,导致
改变皮质纹状体通讯和运动症状。在这个拨款申请中,我们将使用最先进的
加州大学洛杉矶分校的三个不同实验室的技术。AIM1使用光遗传学和切片电生理学,
研究丘脑感觉和运动核团之间的突触通讯机制的改变,
对应的皮质投射区。Aim 2使用高密度硅微探针记录
在清醒状态下,感觉和运动皮质区以及丘脑核团中同时存在数百个神经元,
小鼠AIM3使用遗传编码的钙指标来可视化感觉和运动神经元的活动
清醒小鼠的皮质区。总之,这些研究将提供新的和重要的机械见解,
未充分研究皮质功能障碍,并将为HD的新型合理治疗提供基础,
在空间和时间上描绘出更多受限的目标。这些研究也将与
了解其他CAG三联体重复疾病和神经退行性疾病。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Michael S. Levine其他文献
Structural and physiological analyses of a neural circuit for swimming locomotion of the Ciona intestinalis larva
海鞘幼虫游泳运动神经回路的结构和生理分析
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Takeo Horie;Masamichi Ohkura;Yasunori Sasakura;Takehiro G. Kusakabe;Junichi Nakai;Michael S. Levine;Masashi Nakagawa - 通讯作者:
Masashi Nakagawa
Corticostriatal maldevelopment in the R6/2 mouse model of juvenile Huntington's disease
- DOI:
10.1016/j.nbd.2024.106752 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:
- 作者:
Carlos Cepeda;Sandra M. Holley;Joshua Barry;Katerina D. Oikonomou;Vannah-Wila Yazon;Allison Peng;Deneen Argueta;Michael S. Levine - 通讯作者:
Michael S. Levine
Sensitive and Accurate Proteome Profiling of Embryogenesis Using Real-Time Search and TMTproC Quantification
使用实时搜索和 TMTproC 定量对胚胎发生进行敏感而准确的蛋白质组分析
- DOI:
10.1016/j.mcpro.2024.100899 - 发表时间:
2025-02-01 - 期刊:
- 影响因子:5.500
- 作者:
Alex N.T. Johnson;Jingjing Huang;Argit Marishta;Edward R. Cruz;Andrea Mariossi;William D. Barshop;Jesse D. Canterbury;Rafael Melani;David Bergen;Vlad Zabrouskov;Michael S. Levine;Eric Wieschaus;Graeme C. McAlister;Martin Wühr - 通讯作者:
Martin Wühr
Comprehensive single-cell transcriptome reveals heterogeneity in cancer tissue
综合单细胞转录组揭示癌症组织的异质性
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:0
- 作者:
Takeo Horie;Masamichi Ohkura;Yasunori Sasakura;Takehiro G. Kusakabe;Junichi Nakai;Michael S. Levine;Masashi Nakagawa;Shinichi Hashimoto - 通讯作者:
Shinichi Hashimoto
Ventilatory and Diffusion Abnormalities in Potential Heart Transplant Recipients
- DOI:
10.1378/chest.98.4.816 - 发表时间:
1990-10-01 - 期刊:
- 影响因子:
- 作者:
Robert S. Wright;Michael S. Levine;Paul E. Bellamy;Michael S. Simmons;Poonam Batra;Lynne Warner Stevenson;Julie A. Walden;Hillel Laks;Donald P. Tashkin - 通讯作者:
Donald P. Tashkin
Michael S. Levine的其他文献
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{{ truncateString('Michael S. Levine', 18)}}的其他基金
Cortical Pathophysiology in Mouse Models of Huntington's Disease
亨廷顿病小鼠模型的皮质病理生理学
- 批准号:
9761585 - 财政年份:2017
- 资助金额:
$ 50.37万 - 项目类别:
Optogenetic control of striatal dopamine in Huntington's disease
亨廷顿病纹状体多巴胺的光遗传学控制
- 批准号:
8416342 - 财政年份:2012
- 资助金额:
$ 50.37万 - 项目类别:
Optogenetic control of striatal dopamine in Huntington's disease
亨廷顿病纹状体多巴胺的光遗传学控制
- 批准号:
8284759 - 财政年份:2012
- 资助金额:
$ 50.37万 - 项目类别:
Progression of Electrophysiological Alterations in Mouse Models of PD
PD小鼠模型电生理改变的进展
- 批准号:
7119849 - 财政年份:2006
- 资助金额:
$ 50.37万 - 项目类别:
2005 CAG Triplet Repeat Disorders Gordon Conference
2005 年 CAG 三联重复疾病戈登会议
- 批准号:
6934426 - 财政年份:2005
- 资助金额:
$ 50.37万 - 项目类别:
2003 Gordon Conference on CAG Triplet Repeat Disorders
2003 年关于 CAG 三联体重复疾病的戈登会议
- 批准号:
6597717 - 财政年份:2003
- 资助金额:
$ 50.37万 - 项目类别:
Pathophysiology of Transgenic Mouse Models of Huntington's Disease
亨廷顿病转基因小鼠模型的病理生理学
- 批准号:
8245957 - 财政年份:2002
- 资助金额:
$ 50.37万 - 项目类别:
Pathophysiology of Transgenic Mouse Models of Huntington's Disease
亨廷顿病转基因小鼠模型的病理生理学
- 批准号:
8672693 - 财政年份:2002
- 资助金额:
$ 50.37万 - 项目类别:
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