Changes in E-S Plasticity in Aging

描述（由申请人提供）：老年人在学习和记忆方面有困难。严重的损伤可能是老年性痴呆的基础。大量的证据表明突触功能的长期增强（LTP）可能是学习和记忆的基础。海马体LTP的破坏与无法获得某些形式的时空学习密切相关。虽然LTP在幼龄动物中很容易诱导，但在老年动物中却越来越困难。这很可能与动物衰老时的一些学习缺陷有关，也可能反映了老年人在记忆获取和维持方面的障碍。尽管许多老年人有轻微的记忆障碍，但学习能力并没有丧失。这就为其他形式的可塑性留下了可能，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，更有效地为老年人学习，以及针对这些形式的可塑性的药物治疗。虽然突触可塑性可能强烈影响突触后神经元动作电位的激发，但一定强度的epsp诱导动作电位的能力也可能被调节。最后一种调制可以定义为E-S塑性。我们发现E-S的可塑性与LTP无关，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，E-S可塑性保持强劲，而LTP随着年龄的增长而减弱。利用不同年龄啮齿动物海马CA1区域的体外片制备，我们将确定E-S可塑性的定义特征及其与LTP的区别，其总体目标是识别随着年龄增长仍可能被刺激快速诱导的不同类型的可塑性。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塑性之间的关系如何随年龄变化；2)判断E-S可塑性是否符合Hebbian协同性、联想性和输入特异性标准；3)阐明E-S可塑性与LTP分子信号通路的差异。虽然测试行为学习范式超出了本提案的范围，但我们最终可以在没有LTP的情况下，使用确定的诱导和阻断E-S可塑性的药理学条件来观察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家老年研究所的目标之一，即“研究整个生命周期中认知衰老的连续性”。

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".