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

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

项目成果

期刊论文数量(0)
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科研奖励数量(0)
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:
Mouse Genetics Core
小鼠遗传学核心
  • 批准号:
    7119855
  • 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:
Transgenic Mouse Models of Huntington's Disease
亨廷顿病转基因小鼠模型
  • 批准号:
    6640426
  • 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:
    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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