Changes in E-S Plasticity in Aging

老化过程中 E-S 可塑性的变化

• 批准号: 8700297
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700297
• 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; 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; presynaptic; public health relevance; 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方面有困难。严重损害可能是老年性痴呆的基础。大量证据表明突触功能的长时程增强（LTP）可能是学习记忆的基础。海马LTP的中断与无法获得某些形式的时空学习密切相关。虽然LTP在年轻动物中很容易诱导，但在老年动物中变得越来越困难。这可能与随着动物年龄的增长而出现的一些学习缺陷密切相关，也可能反映了老年人记忆获得和维持的障碍。尽管许多老年人有轻度记忆障碍，但学习能力并没有丧失。这为其他形式的可塑性提供了可能性，并且可能不会随着年龄的增长而减少。了解这些形式的可塑性的生理基础可能会导致开发不同的范式，为老年人更有效的学习，以及针对这些形式的可塑性的药物治疗。 虽然突触可塑性可以强烈地影响突触后神经元动作电位放电，但是一定强度的EPSP诱导动作电位的能力也可以被调节。这最后一种类型的调制可以被定义为E-S可塑性。我们有了一个新的发现，即E-S可塑性是独立的LTP，在EPSP强度的变化是不相关的E-S关系产生的单个突触后神经元的变化。我们的初步证据表明，E-S可塑性仍然强劲，而LTP减弱随着年龄的增长。利用不同年龄啮齿动物海马CA 1区的体外切片制备，我们将确定E-S可塑性的定义特征以及它与LTP的不同之处，总体目标是辨别不同类型的可塑性，这些可塑性随着年龄的增长仍然可以通过刺激快速诱导。 为了实现这一目标，我们将研究分为三个目标：1）确定LTP和E-S可塑性之间的关系如何随着年龄的变化; 2）确定E-S可塑性是否遵守Hebbian标准的协同性，关联性和输入特异性; 3）阐明E-S可塑性和LTP之间的分子信号通路的差异。 虽然测试行为学习范式超出了这个建议的范围，但我们最终可以使用在缺乏LTP的情况下诱导和阻断E-S可塑性的药理学条件，看看哪些类型的学习可能与E-S可塑性特别相关。这项研究非常适合国家Agng研究所的目标之一，即“研究整个生命周期中认知老化的连续性”。