Changes in E-S Plasticity in Aging

老化过程中 E-S 可塑性的变化

• 批准号: 9084436
• 负责人: Morris J. Benveniste
• 金额: $ 35.38万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9084436
• 关键词: Action Potentials; Adolescent; Adult; Age; Aging; Animals; Behavioral; Behavioral Paradigm; Brain; Characteristics; Chemosensitization; Cognitive aging; Cues; Data; Elderly; Event; Excitatory Postsynaptic Potentials; Exhibits; Familiarity; Family; Functional disorder; Goals; Health; Hippocampus (Brain); Impairment; In Vitro; Individual; Institutes; Knockout Mice; Learning; Life; Long-Term Potentiation; Longevity; Maintenance; Memory; Memory impairment; Molecular; Mus; Neurons; Pathway interactions; Pharmaceutical Preparations; Pharmacological Treatment; Physiological; Play; Preparation; Pyramidal Cells; Rattus; Regulation; Research; Rodent; Role; Senile dementia; Signal Pathway; Slice; Specificity; Stimulus; Synaptic plasticity; Techniques; Testing; aged; base; behavior test; classical conditioning; information processing; inhibitor/antagonist; juvenile animal; memory acquisition; memory recall; novel; postsynaptic; postsynaptic neurons; presynaptic; synaptic function; young adult

DESCRIPTION (provided by applicant): Older adults have difficulties with learning and memory acquisition. Severe impairment may be the basis for senile dementia. A vast accumulation of evidence strongly suggests that long term potentiation of synaptic function (LTP) may underlie learning and memory. Disruption of LTP in the hippocampus is well correlated to the inability to acquire some forms of temporal-spatial learning. While LTP is readily induced in young animals, it becomes increasingly difficult in older animals. This may well correlate with some learning deficits as animals age and may also reflect impairment in memory acquisition and maintenance in the elderly. Despite mild memory impairment in many elderly individuals, the ability to learn is not lost. This leaves open the possibility that other orms of plasticity are possible and may not diminish with age. Understanding the physiological basis for these forms of plasticity may result in developing different paradigms for more efficacious learning for the elderly, as well as targeting these forms of plasticity for pharmacological treatment. Although synaptic plasticity may strongly influence postsynaptic neuronal action potential firing, the ability for EPSPs of a certain strength to induce an action potential may als be modulated. This last type of modulation can be defined as E-S plasticity. We have made a novel discovery that E-S plasticity is independent of LTP, in that changes in EPSP strength are not correlated with changes in the E-S relationship generated for single postsynaptic neurons. Our preliminary evidence suggests that E-S plasticity remains robust while LTP wanes with age. Utilizing the in vitro slice preparation of the CA1 region of the hippocampus from different aged rodents, we will determine the defining characteristics of E-S plasticity and how it differs from LTP, with the overall goal of discerning different types of plasticity that still may be rapidly induced by stimulation as we age. To accomplish this we have delineated the study into three aims: 1) To determine how the relationship between LTP and E-S plasticity changes with age; 2) to determine if E-S plasticity abides by Hebbian criteria of cooperativity, associativity and input specificity; and 3) to elucidate differences in the molecular signaling pathway between E-S plasticity and LTP. Although testing behavioral learning paradigms is beyond the scope of this proposal, we can eventually use pharmacological conditions determined for induction and block of E-S plasticity in the absence of LTP to see which types of learning may be specifically related to E-S plasticity. This study is ideally suited for one of the aims of the National Institute of Agng of to "study the continuum of cognitive aging across the lifespan".

描述（由申请人提供）：老年人在学习和记忆中遇到困难。严重损害可能是老年痴呆症的基础。大量证据积累表明突触功能的长期增强（LTP）可能是学习和记忆的基础。海马中LTP的破坏与无法获得某些形式的颞空间学习相关。虽然LTP很容易在年轻动物中诱导，但在老年动物中它变得越来越困难。随着动物年龄的增长，这很可能与一些学习缺陷有关，并且也可能反映了老年人的记忆习得和维护障碍。尽管许多老年人的记忆力障碍轻度，但学习能力并没有消失。这留下了其他可塑性可能是可能的，并且可能随着年龄的增长而减少的可能性。了解这些形式的可塑性的生理基础可能会导致建立不同的范式，从而为老年人提供更有效的学习，并针对这些形式的可塑性进行药理学治疗。 尽管突触可塑性可能会强烈影响突触后神经元动作电势触发，但具有某种强度诱导动作电位的EPSP的能力可能会受到调节。最后类型的调制可以定义为E-S可塑性。我们已经做出了一个新的发现，即E-S可塑性与LTP无关，因为EPSP强度的变化与单个突触后神经元产生的E-S关系的变化无关。我们的初步证据表明，在LTP随着年龄的增长时，E-S可塑性保持稳健。利用来自不同老年啮齿动物的海马的CA1区域的体外切片制备，我们将确定E-S可塑性的定义特征及其与LTP的差异，其总体目标是辨别不同类型的可塑性，这些可塑性仍然可以随着年龄的增长而被刺激迅速引起。 为了实现这一目标，我们将研究描述为三个目的：1）确定LTP和E-S可塑性之间的关系如何随着年龄的增长而变化； 2）确定E-S可塑性是否符合Hebbian合作，关联性和输入特异性的标准； 3）阐明了E-S可塑性和LTP之间分子信号通路的差异。 尽管测试行为学习范例超出了该提案的范围，但在没有LTP的情况下，我们最终可以使用确定的诱导和E-S可塑性的药理条件，以查看哪些类型的学习可能与E-S可塑性特别相关。这项研究非常适合美国国立Agng研究所的目标之一，即“研究整个生命周期的认知衰老连续性”。