EXCITOTOXICITY IN THE HIPPOCAMPUS AFTER VIRAL INFECTION

病毒感染后海马的兴奋性毒性

基本信息

  • 批准号:
    6139551
  • 负责人:
  • 金额:
    $ 10.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1998
  • 资助国家:
    美国
  • 起止时间:
    1998-01-01 至 2002-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (Applicant's abstract): Abnormalities in brain development has been implicated in several neuropsychiatric disorders including schizophrenia, autism, and temporal lobe epilepsy. Brain imaging studies and neuropathological observations suggest that at least some of these abnormalities occur in the hippocampal formation. While the etiology of these disorders remains elusive, recent studies have suggested the involvement of a perinatal insult such as a viral infection. However, the information which can be gained from human postmortem studies may be limited because a viral infection could insidiously disrupt development and then be cleared from the brain prior to the manifestation of symptoms. Furthermore, because the immune system would likely be immature at the time of infection, the detection of the immunological hallmarks of infection could be problematic. Thus animal studies are needed to investigate the mechanisms by which a transient viral infection affecting the hippocampus during development can lead to neuropathological and functional changes in the adult. The goals of this proposal are to explore the mechanisms by which infection of rats with lymphocytic choriomeningitis virus (LCMV) during development can initiate a neuropathological cascade in the hippocampus resulting in the continued loss of dentate granule cells in the absence of detectable virus. Electrophysiological data in adult rats which have cleared the virus indicate a loss of GABAergic inhibition in the hippocampal dentate gyrus. Preliminary data suggest this disinhibition is due to an early infection and loss of inhibitory interneurons. Thus, disruption of inhibitory circuits during neurodevelopment could lead to excessive glutamatergic input on dentate granule cells, which would then die gradually due to excitotoxic. Alternatively LCMV could be acting through IL-1b and BDNF to retard the maturation of inhibitory circuits during postnatal development, leading to the latent excitotoxic loss of dentate granule cells. Therefore, Aim 1 will test the hypothesis the LCMV infection causes an early derangement of inhibitory circuits and a consequential unleashing of excitotoxic synapses on hippocampal dentate granule cells. Specifically, 4 day old rats will be infected intracranially with LCMV and the infection and loss of hippocampal neurons involved in inhibitory circuits will be measured as the disease progresses between 6 and 180 days post infection. Aim 2 will determine if blocking excitatory amino acids or facilitating inhibitory neurotransmission will ameliorate LCMV-mediated dentate granule cell loss at 90 and 180 days post infection. Aim 3 will determine if LCMV-induced production of IL-1b can decrease BDNF in the developing hippocampus, and thus interrupt the differentiation of BDNF-dependent interneurons. These studies aim to provide clues to the mechanisms by which an early viral infection could be involved in certain neurodevelopmental disorders.
描述(申请人摘要):脑发育中的abbrachial 与几种神经精神疾病有关, 精神分裂症自闭症和颞叶癫痫 脑成像研究 神经病理学观察表明,至少有一些 海马结构出现异常。 虽然病因 这些疾病仍然难以捉摸,最近的研究表明, 涉及围产期损伤,如病毒感染。 但 从人类死后研究中获得的信息可能有限 因为病毒感染可能会暗中破坏发育, 在症状出现之前从大脑中清除。 此外,委员会认为, 因为免疫系统在感染时可能还不成熟, 检测感染的免疫学标志, 有问题 因此,需要动物研究来研究其机制 通过短暂的病毒感染影响海马, 发育可导致神经病理学和功能变化, 成年人了 本提案的目标是探讨各种机制, 淋巴细胞性脉络丛脑膜炎病毒(LCMV)感染大鼠 发育可以在海马体中引发神经病理级联反应 导致齿状颗粒细胞的持续丧失, 可检测的病毒 成年大鼠的电生理数据, 清除病毒表明海马中GABA能抑制的丧失 齿状回 初步数据表明,这种去抑制是由于 早期感染和抑制性中间神经元的丧失。 因此, 神经发育过程中的抑制回路可能会导致过度的 齿状颗粒细胞的突触能输入,然后逐渐死亡 因为兴奋性中毒 或者,LCMV可能通过IL-1b起作用, 脑源性神经营养因子延缓出生后抑制性神经回路的成熟 发育,导致齿状颗粒的潜在兴奋毒性丧失 细胞 因此,目标1将检验LCMV感染引起的假设 抑制回路的早期紊乱以及随之而来的 海马齿状颗粒细胞上的兴奋性毒性突触。 具体地说, 将用LCMV颅内感染4日龄大鼠, 而参与抑制回路的海马神经元的丢失将是 在感染后6至180天之间的疾病进展中测量。 目的2将确定是否阻断兴奋性氨基酸或促进 抑制神经传递将改善LCMV介导齿状颗粒 感染后90和180天的细胞损失。 目标3将确定是否 LCMV诱导的IL-1b的产生可以减少发育中的BDNF 海马,从而中断BDNF依赖的分化 中间神经元 这些研究旨在提供线索的机制, 早期的病毒感染可能会影响某些神经发育, 紊乱

项目成果

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BRADLEY D PEARCE其他文献

BRADLEY D PEARCE的其他文献

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{{ truncateString('BRADLEY D PEARCE', 18)}}的其他基金

2/2 Schizophrenia Heterogeneity and Toxoplasma Exposure
2/2 精神分裂症异质性和弓形虫暴露
  • 批准号:
    8367828
  • 财政年份:
    2010
  • 资助金额:
    $ 10.82万
  • 项目类别:
2/2 Schizophrenia Heterogeneity and Toxoplasma Exposure
2/2 精神分裂症异质性和弓形虫暴露
  • 批准号:
    8024600
  • 财政年份:
    2010
  • 资助金额:
    $ 10.82万
  • 项目类别:
2/2 Schizophrenia Heterogeneity and Toxoplasma Exposure
2/2 精神分裂症异质性和弓形虫暴露
  • 批准号:
    8197338
  • 财政年份:
    2010
  • 资助金额:
    $ 10.82万
  • 项目类别:
Schizophrenia biomarkers discerned by cellular networks in DiGeorge syndrome
迪乔治综合征细胞网络识别的精神分裂症生物标志物
  • 批准号:
    7816836
  • 财政年份:
    2009
  • 资助金额:
    $ 10.82万
  • 项目类别:
Schizophrenia biomarkers discerned by cellular networks in DiGeorge syndrome
迪乔治综合征细胞网络识别的精神分裂症生物标志物
  • 批准号:
    7590731
  • 财政年份:
    2009
  • 资助金额:
    $ 10.82万
  • 项目类别:
Neurobiology of MIF in development and disease
MIF 在发育和疾病中的神经生物学
  • 批准号:
    7282669
  • 财政年份:
    2006
  • 资助金额:
    $ 10.82万
  • 项目类别:
Neurobiology of MIF in development and disease
MIF 在发育和疾病中的神经生物学
  • 批准号:
    7143547
  • 财政年份:
    2006
  • 资助金额:
    $ 10.82万
  • 项目类别:
Cytokine-HPA Interactions During Pregnanacy
怀孕期间细胞因子-HPA 相互作用
  • 批准号:
    6876655
  • 财政年份:
    2004
  • 资助金额:
    $ 10.82万
  • 项目类别:
Cytokine-HPA Interactions During Pregnanacy
怀孕期间细胞因子-HPA 相互作用
  • 批准号:
    6674816
  • 财政年份:
    2004
  • 资助金额:
    $ 10.82万
  • 项目类别:
Cytokine-HPA Interactions During Pregnanacy
怀孕期间细胞因子-HPA 相互作用
  • 批准号:
    7020064
  • 财政年份:
    2004
  • 资助金额:
    $ 10.82万
  • 项目类别:

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