Synaptic Function & Plasticity in CA3 Circuits in the Aging Hippocampus

描述（由申请人提供）：衰老对学习和编码新记忆有深远的影响。衰老领域的进展表明，细胞水平的变化比结构变化更能帮助我们理解与衰老相关的认知缺陷。在这方面，对海马CA1区域突触功能的电生理分析提供了重要的见解，即年龄破坏了突触连接被修改以编码新记忆的机制。这些突触可塑性的变化为理解老年人的学习缺陷提供了概念基础。尽管关注与学习缺陷相关的CA1基因的改变已经取得了丰硕的成果，但最近很明显需要扩大研究范围。首先，人们认识到海马体中的其他回路在记忆编码过程中的作用是不同的，衰老对它们的影响是不同的，在CA3的情况下，这种影响甚至更为显著。此外，尽管平均认知能力随着年龄的增长而下降，但仍有一部分老年人保持着心智能力。因此，虽然最终目标可能是保持通常受年龄影响的细胞过程的完整性，但补充方法是关注自然发生的适应性变化，以响应丧失的功能。我们通过研究海马依赖学习任务中老年大鼠海马切片的突触可塑性来解决这些问题。该项目的目标是：1)了解衰老如何影响CA3中支持学习的突触功能；2)确定允许一些老年人保持认知能力的机制；3)了解改善老年人学习的干预治疗如何影响突触可塑性。我们的研究表明，老年大鼠突触可塑性的一些机制是不可逆的丧失。然而，那些保持认知能力的老年人通过促进其他机制来弥补损失。这些适应性增强的可塑性机制是旨在恢复老年人学习的治疗策略的明显目标。

DESCRIPTION (provided by applicant): Aging has a profound impact on learning and encoding new memories. Advances in the field of aging suggest that changes at the cellular level rather than structural alterations are more relevant for understanding cognitive deficits associated with aging. In this regard, electrophysiological analysis of synaptic function in the CA1 region of the hippocampus has provided the important insights that age disrupts the mechanisms by which the synaptic connectivity is modified to encode new memories. These changes in synaptic plasticity provide a conceptual basis to understand learning deficits in aged individuals. Although focusing on alterations in CA1 associated with learning deficits has been fruitful, recently it has become clear the need to expand the research scope. First is the realization that other circuits in the hippocampus participate differently during memory encoding, and that aging affects them differently, and even more prominently, in the case of CA3. In addition, although on average cognitive abilities decline with age, a recognizable subpopulation of aged individuals maintains mental abilities. Thus, while an ultimate goal could be to preserve the integrity of the cellular processes normally affected by age, a complementary approach is to focus on adaptative changes occuring naturally in response to lost functions. We approach these issues ex vivo, by studying synaptic plasticity in hippocampal slices from aged rats characterized in a hippocampal- dependent learning task. The goals of this project are to 1) understand how aging affects the synaptic functions that support learning in CA3, 2) identify mechanisms that allow some aged individuals to maintain cognitive abilities and 3) understand how intervention treatments that improve learning in aged individuals affect synaptic plasticity. Our research suggests that some mechanisms of synaptic plasticity are irreversibly lost in aged rats. However, those aged individuals that maintained cognitive performance manage to compensate for the lost by boosting other mechanisms. These adaptatively enhanced plasticity mechanisms are an obvious target for therapeutical strategies aimed at restoring learning in aged individuals. PUBLIC HEALTH RELEVANCE: Aging can have a pronounced impact on mental abilities, particularly on learning and memory. Although such decline is widespread enough to be often considered a normal aspect of aging, some older individuals retain strong cognitive abilities. This proposal will investigate the type of neural adaptive changes that are required to maintain cognitive performance at old age.