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Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies
阐明产前大麻素暴露的分子机制:确定靶点和治疗方法
批准号:
10343805
负责人:
Miranda Nicole Reed
金额:
$35.62万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-04-15 至 2023-02-28

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中文摘要
翻译
项目摘要 大麻是怀孕期间使用最多的非法药物之一,随着合法化的增加, 怀孕期间,预计将上升。临床研究表明,产前大麻素暴露(PCE)的结果 在后代中残留的认知缺陷。尽管PCE有所上升,但人们对 与PCE相关的学习和记忆缺陷的综合机制途径。我们 长期目标是了解PCE如何影响认知,本提案的目标是剖析 与PCE相关的记忆和突触可塑性缺陷的分子机制。我们的初步数据 证明PCE动物中的海马依赖性记忆障碍伴随着突触 以降低的长时程增强(LTP)和增强的长时程抑制(LTD)的形式存在缺陷。 此外,我们已经证明了聚唾液酸化-NCAM(PSA-NCAM)的减少,这是 神经发生、神经元寻路以及学习和记忆。我们先前已经确定, PSA-NCAM可通过调节GluN 2B-Ras-GRF 1-p38 MAPK信号通路, 改变含GluN 2A和GluN 2B的NMDA受体的信号平衡。我们的初步数据, PCE还表明GluN 2A受体表达和信号传导减少,而GluN 2B受体表达和信号传导没有变化。 表达,表明信号的不平衡。根据我们的初步和已发表的数据,我们假设 PSA-NCAM介导的GluN 2A-和GluN 2B-信号通路的改变是导致 PCE导致的突触可塑性改变和记忆缺陷。这项提案的目的是剖析 PCE诱导突触可塑性和认知缺陷的分子机制。我们将使用一个 多学科方法,包括行为学、电化学、电生理学、细胞和分子 方法来测试我们的假设。我们提出了三个相互关联,但顺序独立的具体 目的:(1)探讨大鼠海马神经元行为和突触可塑性损伤的分子机制。 PCE,(2)研究PSA-NCAM如何通过调节NMDA改变突触传递和可塑性 PCE动物中受体介导的信号传导,以及(3)确定应用PSA的功能结果 含有GluN 2A和GluN 2B的NMDA受体对PCE诱导的突触可塑性的模拟和调节 和记忆缺陷我们研究的数据不仅指向了一种特定的机制, PCE相关的缺陷,但也将全面评估突触分子发挥的不同作用, 负责与认知密切相关的可塑性机制。
英文摘要
Project Abstract Cannabis is one of the most illicit drugs used during pregnancy, and with increased legalization, use during pregnancy is expected to rise. Clinical studies have shown prenatal cannabinoid exposure (PCE) results in residual cognitive deficits in offspring. Despite the rise in PCE, there is little understanding of a comprehensive mechanistic pathway responsible for learning and memory deficits associated with PCE. Our long-range goal is to understand how PCE affects cognition, and the goal of this proposal is to dissect the molecular mechanisms of memory and synaptic plasticity deficits associated with PCE. Our preliminary data demonstrate hippocampal-dependent memory impairments in PCE animals are concomitant with synaptic deficits in the form of decreased long-term potentiation (LTP) and enhanced long-term depression (LTD). Furthermore, we have demonstrated reductions in polysialylated-NCAM (PSA-NCAM), which is required for neurogenesis, neuronal pathfinding, and learning and memory. We have previously established that decreased PSA-NCAM can lead to deficits in LTP by modulating GluN2B-Ras-GRF1-p38 MAPK signaling pathway and altering the signaling balance of GluN2A- and GluN2B- containing NMDA receptors. Our preliminary data with PCE also indicates a decrease in GluN2A receptor expression and signaling with no change in GluN2B expression, indicating an imbalance in signaling. Based on our preliminary and published data, we hypothesize that PSA-NCAM mediated alterations in GluN2A- and GluN2B- signaling pathways are responsible for the altered synaptic plasticity and memory deficits resulting from PCE. The objective of this proposal is to dissect the molecular mechanisms by which PCE induces synaptic plasticity and cognitive deficits. We will use a multidisciplinary approach including behavioral, electrochemical, electrophysiological, cellular and molecular methodologies to test our hypotheses. We propose three interrelated but sequentially independent specific aims: (1) Investigate the molecular mechanisms of behavioral and synaptic plasticity deficits resulting from PCE, (2) Investigate how PSA-NCAM modifies synaptic transmission and plasticity by regulating NMDA receptor-mediated signaling in PCE animals, and (3) Determine the functional outcomes of application of a PSA mimetic & modulation of GluN2A- and GluN2B- containing NMDA receptors on PCE-induced synaptic plasticity and memory deficits. The data from our study not only points toward a specific mechanism responsible for PCE-related deficits but will also comprehensively assess the different roles played by synaptic molecules responsible for plasticity mechanisms closely associated with cognition.
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Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies
  • 批准号:
    9917391
  • 项目类别:
  • 资助金额:
    $35.28万
  • 财政年份:
    2020
  • 负责人:
    Miranda Nicole Reed
  • 依托单位:
Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies.
  • 批准号:
    10828602
  • 项目类别:
  • 资助金额:
    $30.69万
  • 财政年份:
    2020
  • 负责人:
    Miranda Nicole Reed
  • 依托单位:
Determining the Roles of Aging and Extrasynaptic NMDARs in Tau Pathology.
  • 批准号:
    8878717
  • 项目类别:
  • 资助金额:
    $35.52万
  • 财政年份:
    2015
  • 负责人:
    Miranda Nicole Reed
  • 依托单位:
海外基金