Changes in E-S Plasticity in Aging

描述(申请人提供)：老年人在学习和记忆获得方面有困难。严重的损害可能是老年性痴呆的基础。大量证据有力地表明，突触功能的长时程增强可能是学习和记忆的基础。海马区LTP的中断与无法获得某些形式的时空学习有很好的相关性。虽然LTP很容易在幼年动物身上诱导，但在年长的动物身上变得越来越困难。随着动物年龄的增长，这很可能与一些学习缺陷有关，也可能反映了老年人在记忆获取和维护方面的障碍。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。这就留下了一种可能性，即其他的可塑性也是可能的，并且可能不会随着年龄的增长而减弱。了解这些形式的可塑性的生理基础可能会导致为老年人更有效地学习开发不同的范例，以及针对这些形式的可塑性进行药物治疗。尽管突触的可塑性可能强烈影响突触后神经元动作电位的放电，但一定强度的EPSP诱导动作电位的能力也可能受到调节。最后一种调制可以定义为E-S可塑性。我们有了一个新的发现，即E-S可塑性与长时程增强无关，因为EPSP强度的变化与单个突触后神经元产生的E-S关系的变化不相关。我们的初步证据表明，E-S的可塑性保持强劲，而LTP随着年龄的增长而减弱。利用不同年龄啮齿动物海马区CA1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，总体目标是区分随着年龄的增长仍可能通过刺激快速诱导的不同类型的可塑性。为了实现这一目标，我们将研究划分为三个目标：1)确定长时程增强与E-S可塑性之间的关系是如何随年龄变化的；2)确定E-S可塑性是否遵循协作性、关联性和输入专一性的赫比标准；3)阐明E-S可塑性与长时程可塑性在分子信号通路上的差异。虽然测试行为学习范式超出了这一建议的范围，但我们最终可以使用在没有LTP的情况下确定的诱导和阻断E-S可塑性的药理学条件来看看哪些类型的学习可能与E-S可塑性特定相关。这项研究非常适合美国国立爱格研究所的目标之一，即“研究人的一生中认知老化的连续体”。

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".