Slow Outward Currents and Learning In Aging Hippocampus

衰老海马体的缓慢外向电流和学习

基本信息

  • 批准号:
    7800028
  • 负责人:
  • 金额:
    $ 57.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1990
  • 资助国家:
    美国
  • 起止时间:
    1990-03-01 至 2014-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The hippocampus is critically involved in the early stages of declarative learning, a capacity degraded during aging, contributing to age-associated learning impairments. Enlarged Ca2+-dependent postburst afterhyperpolarization (AHP) during aging reduces the intrinsic excitability of CA1 pyramidal neurons as well as the information handling capacity of the CA1 region of the hippocampus and contributes to the age-associated learning impairment. Our preliminary data strongly suggest that the learning- and age-related AHP changes may, in part, be directly due to alterations in Ca2+ itself. Resting Ca2+ and endogenous Ca2+ buffering capacity profoundly influence neuronal function. But are they altered by learning and aging, serving as the mechanism by which the AHP is changed? We will use Ca2+ imaging techniques to understand the potential contribution of change in Ca2+ handling to the overall alterations in the AHP with learning and aging. We will determine the Ca2+ sources for the AHP, determine if sources in dendrites have the same impact on the AHP as sources near the soma, and if these Ca2+ sources are altered by learning trace eyeblink conditioning and aging. Learning hippocampus-dependent tasks require protein synthesis. We have recently shown that the learning-related AHP reduction in young adult rats is mediated in part by protein kinase A (PKA) activity, known to activate CREB and subsequent gene transcription/translation, and reduce the postburst AHP. Systematic learning- & age-related molecular assays for proteins involved in the subcellular cascades that lead to CREB activation and alterations in the AHP with western blot and immunohistochemistry experiments will be continued. If age related learning impairment is truly due to the enlarged postburst AHP, then genetically silencing the expression of a protein to cause AHP reduction (and thus, increase neuronal excitability) should reverse the age-related learning impairment. We will use recombinant adeno-associated viral vectors to silence specific protein expression in the hippocampus during conditioning. We will also compare the biophysical and Ca2+ properties of transfected (tagged with fluorescent indicators) and untransfected CA1 neurons from treated rats to verify that the Ca2+ transient and the postburst AHP are reduced in the transfected neurons. Candidate genes to silence will be determined from the literature and molecular assays done earlier in this research program. The goals are to confirm that the AHP is the key regulator of intrinsic excitability and that targeted molecular methods to reduce the AHP in CA1 neurons in aged subjects will lead to successful learning. Success will indicate that the protein being silenced is a viable candidate to target as a therapeutic intervention point for age-associated learning impairments. PUBLIC HEALTH RELEVANCE: Behavioral, calcium imaging, molecular and biophysical experimental approaches will be used to investigate the role of neuronal calcium processing in control of learning in young and aging rats. The goal is to determine if molecular genetic interventions developed from these approaches reverse age-associated learning impairments in rats. Successful experiments will have direct translatability to humans, as molecular genetic approaches are being developed to treat neurodegeneration in aging humans and the hippocampus dependent eyeblink conditioning task has direct parallels between experimental animals and humans.
描述(由申请人提供):海马体在陈述性学习的早期阶段起关键作用,这种能力在衰老过程中退化,导致与年龄相关的学习障碍。衰老过程中钙离子依赖的爆发后超极化(AHP)的增大降低了CA1区锥体神经元的内在兴奋性,降低了CA1区的信息处理能力,从而导致与年龄相关的学习障碍。我们的初步数据有力地表明,与学习和年龄相关的AHP变化可能在一定程度上直接源于钙离子本身的变化。静息钙和内源性钙缓冲能力深刻地影响着神经元的功能。但是,它们是否会因为学习和衰老而改变,作为改变AHP的机制?我们将使用钙离子成像技术来了解随着学习和衰老,钙处理的变化对AHP整体变化的潜在贡献。我们将确定AHP的钙来源,确定树突中的来源是否与胞体附近的来源具有相同的影响,以及这些钙来源是否通过学习痕迹眨眼条件和衰老而改变。学习依赖于海马体的任务需要蛋白质合成。我们最近发现,幼年大鼠与学习相关的AHP减少部分是由蛋白激酶A(PKA)活性介导的,PKA激活CREB和随后的基因转录/翻译,并减少后爆发的AHP。系统学习--通过免疫印迹和免疫组织化学实验,继续对参与导致CREB激活和AHP改变的亚细胞级联反应的蛋白质进行与年龄相关的分子分析。如果年龄相关性学习障碍真的是由于爆发性后AHP扩大所致,那么通过基因沉默一种蛋白的表达来导致AHP降低(从而增加神经元的兴奋性)应该可以逆转年龄相关性学习障碍。我们将使用重组腺相关病毒载体在条件反射过程中沉默海马区特定蛋白的表达。我们还将比较(用荧光指示剂标记的)转基因和未转基因大鼠CA1神经元的生物物理和钙离子特性,以验证转基因神经元的钙瞬变和突发性AHP减少。沉默的候选基因将从文献和本研究计划早些时候进行的分子分析中确定。我们的目标是确认AHP是内在兴奋性的关键调节因子,并且有针对性的分子方法降低老年受试者CA1神经元中的AHP将导致成功的学习。成功将表明,被沉默的蛋白质是一个可行的候选目标,作为年龄相关学习障碍的治疗干预点。 公共卫生相关性:将使用行为、钙成像、分子和生物物理实验方法来研究神经元钙处理在年轻和老年大鼠学习控制中的作用。目的是确定从这些方法发展出来的分子遗传干预是否逆转了大鼠与年龄相关的学习障碍。成功的实验将对人类具有直接的可译性,因为正在开发分子遗传学方法来治疗老龄化人类的神经退化,而且实验动物和人类之间依赖海马体的眨眼条件反射任务有直接的相似之处。

项目成果

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JOHN F DISTERHOFT其他文献

JOHN F DISTERHOFT的其他文献

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{{ truncateString('JOHN F DISTERHOFT', 18)}}的其他基金

Mechanisms of hippocampal network-targeted stimulation to rescue memory impairment due to Alzheimer's disease
海马网络靶向刺激挽救阿尔茨海默氏病记忆障碍的机制
  • 批准号:
    10294112
  • 财政年份:
    2021
  • 资助金额:
    $ 57.18万
  • 项目类别:
Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation
脑刺激产生海马网络神经可塑性的细胞机制
  • 批准号:
    10025187
  • 财政年份:
    2019
  • 资助金额:
    $ 57.18万
  • 项目类别:
Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation
脑刺激产生海马网络神经可塑性的细胞机制
  • 批准号:
    10688285
  • 财政年份:
    2019
  • 资助金额:
    $ 57.18万
  • 项目类别:
Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation
脑刺激产生海马网络神经可塑性的细胞机制
  • 批准号:
    10247773
  • 财政年份:
    2019
  • 资助金额:
    $ 57.18万
  • 项目类别:
Cellular mechanisms of hippocampal network neuroplasticity generated by brain stimulation
脑刺激产生海马网络神经可塑性的细胞机制
  • 批准号:
    10472719
  • 财政年份:
    2019
  • 资助金额:
    $ 57.18万
  • 项目类别:
Northwestern University Postbaccalaureate Research Education Program
西北大学学士后研究教育计划
  • 批准号:
    10621170
  • 财政年份:
    2017
  • 资助金额:
    $ 57.18万
  • 项目类别:
Northwestern University Interdepartmental Neuroscience Postbaccalaureate Research Education Program
西北大学跨系神经科学学士后研究教育计划
  • 批准号:
    10152609
  • 财政年份:
    2017
  • 资助金额:
    $ 57.18万
  • 项目类别:
Northwestern University Interdepartmental Neuroscience Postbaccalaureate Research Education Program
西北大学跨系神经科学学士后研究教育计划
  • 批准号:
    9923702
  • 财政年份:
    2017
  • 资助金额:
    $ 57.18万
  • 项目类别:
Synaptic substrates of age-dependent memory deficits
年龄依赖性记忆缺陷的突触基质
  • 批准号:
    9285190
  • 财政年份:
    2016
  • 资助金额:
    $ 57.18万
  • 项目类别:
Synaptic substrates of age-dependent memory deficits
年龄依赖性记忆缺陷的突触基质
  • 批准号:
    9031276
  • 财政年份:
    2016
  • 资助金额:
    $ 57.18万
  • 项目类别:

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