Molecular mechanisms of memory maintenance and dysfunction in neural circuits

记忆维持和神经回路功能障碍的分子机制

基本信息

  • 批准号:
    10372932
  • 负责人:
  • 金额:
    $ 69.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-06-01 至 2024-03-31
  • 项目状态:
    已结题

项目摘要

How molecular mechanisms modify neuronal networks to maintain long-term memory is a fundamental question in neuroscience, with relevance for disorders of persistent, memory-like dysfunction of brain circuits. Atypical PKCs (aPKC), the persistently active isoform PKMζ and PKCι/λ, are core molecules maintaining late- phase synaptic long-term potentiation (LTP) and several forms of long-term memory. Unlike most PKCs that are active only briefly after stimulation, aPKCs have persistent actions. After strong synaptic stimulation, PKMζ increases by new synthesis, and the persistent increase in the autonomously active isoform enhances synaptic transmission during LTP maintenance and lasts for days to weeks during long-term memory storage. The other aPKC, PKCι/λ, can also maintain LTP and long-term memory, as revealed by PKMζ-knockout (KO) mice. Inhibitors of aPKC disrupt memory even weeks after it is formed and ameliorate persistent symptoms of PTSD, addiction, and chronic neuropathic pain in specific brain circuits in animal models. Conversely, overexpressing PKMζ enhances long-term memory and alleviates persistent deficits in disorders in which decreased PKMζ is implicated. Thus, understanding how aPKCs contribute to maintaining memory by sustaining representations of memory in brain circuits will provide fundamental information to assess their roles in pathological memory. Therefore, our Specific Aims are: Aim 1: Is there a hierarchy of PKCs in memory maintenance that store representations differently in networks of neurons? Spatial memory representations depend on the discharge of hippocampus place cell ensembles. We will examine if the properties of hippocampus place cell ensemble representations of spatial memories differ when maintained by PKMζ or PKCι/λ, and if other PKCs can also maintain spatial memory. Aim 2: How are spatial memory-related place cell ensemble representations modified when memory is erased by inhibiting individual PKCs in wild-type and PKMζ- KO mice? Using novel isoform-selective antagonists and conditional KO (cKO) mice, we will test the necessity of aPKC-mediated enhanced synaptic connectivity for representing spatial memory by examining whether reversing this connectivity concurrently erases memory and destabilizes memory-related place cell ensemble representations. Aim 3: Does persistently increased synthesis of PKMζ maintain very long-term memory? Strong conditioning produces increases in PKMζ in the hippocampus that last a month. We will use PKMζ-antisense and PKMζ-cKOs to determine if these persistent increases are due to persistent increased synthesis and/or decreased degradation. To test sufficiency of PKMζ for maintaining memory and memory- related representations of space, we will use overexpression of PKMζ that prolongs long-term memory to examine if increased PKMζ synthesis also perpetuates memory-related place cell ensemble representations. Our aims will elucidate the persistent molecular mechanisms maintaining long-term memories, causally test their role in memory persistence, and so establish a basis for understanding disorders of pathological memory.
分子机制如何改变神经网络以维持长期记忆是一个基本问题

项目成果

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ANDRE ANTONIO FENTON其他文献

ANDRE ANTONIO FENTON的其他文献

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{{ truncateString('ANDRE ANTONIO FENTON', 18)}}的其他基金

Towards a critical test of the synaptic plasticity and memory hypothesis
对突触可塑性和记忆假说进行关键测试
  • 批准号:
    10681918
  • 财政年份:
    2023
  • 资助金额:
    $ 69.39万
  • 项目类别:
Molecular mechanisms of memory maintenance and dysfunction in neural circuits
记忆维持和神经回路功能障碍的分子机制
  • 批准号:
    9884816
  • 财政年份:
    2018
  • 资助金额:
    $ 69.39万
  • 项目类别:
Neural coordination and discoordination in Fmr1 null mice
Fmr1 缺失小鼠的神经协调和不协调
  • 批准号:
    9903473
  • 财政年份:
    2017
  • 资助金额:
    $ 69.39万
  • 项目类别:
Translation, Synchrony, and Cognition
翻译、同步和认知
  • 批准号:
    9460176
  • 财政年份:
    2017
  • 资助金额:
    $ 69.39万
  • 项目类别:
Neural coordination and discoordination in Fmr1 null mice
Fmr1 缺失小鼠的神经协调和不协调
  • 批准号:
    9472717
  • 财政年份:
    2017
  • 资助金额:
    $ 69.39万
  • 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
  • 批准号:
    9280819
  • 财政年份:
    2013
  • 资助金额:
    $ 69.39万
  • 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
  • 批准号:
    8723046
  • 财政年份:
    2013
  • 资助金额:
    $ 69.39万
  • 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
  • 批准号:
    8506187
  • 财政年份:
    2013
  • 资助金额:
    $ 69.39万
  • 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
  • 批准号:
    9067887
  • 财政年份:
    2013
  • 资助金额:
    $ 69.39万
  • 项目类别:
Hippocampal neurogenesis, pattern separation & age-related cognitive impairments.
海马神经发生,模式分离
  • 批准号:
    8876526
  • 财政年份:
    2013
  • 资助金额:
    $ 69.39万
  • 项目类别:

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年龄相关记忆障碍的遗传学和功能神经解剖学
  • 批准号:
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年龄相关记忆障碍的遗传学和功能神经解剖学
  • 批准号:
    7205360
  • 财政年份:
    2004
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  • 批准号:
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  • 财政年份:
    1999
  • 资助金额:
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CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
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年龄相关记忆障碍(AAMI)生物学特征的研究。
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  • 财政年份:
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    $ 69.39万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C).
CITICOLINE AND AGE ASSOCIATED MEMORY IMPAIRMENT
胞二磷胆碱与年龄相关的记忆障碍
  • 批准号:
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    $ 69.39万
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