PROJECT 2-Network properties of entorhinal/dentate gyrus and CA3 region in behaviorally-characterized aged rats

我们在这一资助机制下的研究计划为衰老的具体影响提供了证据 内侧颞叶(MTL)环路对认知结果个体差异的影响 衰老。由于年龄增长是阿尔茨海默病(AD)的最大风险因素，个人 衰老本身的差异可能赋予这种疾病的风险或韧性，表明潜在的相关性 年龄相关性认知功能障碍的局限性。项目2研究特定于电路的机制 在广泛的记忆系统网络中，这是受损和保留的个体差异的基础 认知结果，并认为性别是差异易感性下降的潜在因素。作为第一个 在我们的研究中描述了以年龄相关记忆障碍为特征的杂交Long-Evans雄性大鼠 (AI)，MTL中神经过度活动的一种条件，在老年人的临床观察研究中转化为 随着aMCI患者的进一步增加，晚发性AD的风险也更高。在老年大鼠中 研究人群，我们的背景研究表明，神经过度活跃有助于记忆 使用治疗学的实验性干预造成的损害，这一发现也转化为 临床研究中的治疗方法。除了这些成就，越来越多的证据表明 抑制功能的适应性招募有益于支持老年人对记忆衰退的复原力 未损伤大鼠(AU)。项目2中的研究现在将检查抑制的功能意义 招募作为一种潜在的适应机制，在衰老过程中保持认知功能。在那 背景，项目2将调查动态平衡调节的机制，以检查人工智能和 在AU中潜在的功能增益。项目2将研究这一机制在 EC/海马体系统，以解剖学方法进行电路特异性改变。CA2海马区 在我们的模型中，子域已成为另一个高度关注的子域；功能的丧失导致 过度活动可能导致AI状况，而AU大鼠可能发生更大的招募，从而使 动态平衡控制在两种晚年生活结局中的双向作用。项目2还将带头使用 具有潜在治疗相关性的实验工具，就像它过去对SV2A试剂左乙拉西坦所做的那样。 项目2中AIM 4下的研究将测试充当GABA Aα5受体变构调节剂的药物。 这些受体在哺乳动物大脑中的定位高度受限，可能为 针对AI中潜在的神经生物学条件，并提供功能测试 AU生物标志物的意义，它们已表明增强抑制以维持兴奋/抑制 大脑老化中的平衡。因此，在目前应用的研究计划中，项目2保持了较强的 注重基础研究成果与临床应用的相关性。

Our research program under this funding mechanism has provided evidence for specific effects of aging on medial temporal lobe (MTL) circuits that contribute to individual differences in cognitive outcomes in aging. Because advancing age represents the strongest risk factor for Alzheimer’s Disease (AD), individual differences in aging itself may confer risk or resilience for that disease, indicating potential relevance beyond the limited condition of age-related cognitive impairment. Project 2 investigates circuit-specific mechanisms within the broad memory system network that underlie individual differences in both impaired and preserved cognitive outcomes, and considers sex as a potential factor for differential vulnerability to decline. As first described in our research with outbred Long-Evans male rats characterized for age-related impaired memory (AI), a condition of neural overactivity in the MTL translated in clinical observational studies of elderly individuals, with further augmentation in aMCI patients at greater risk for late onset AD. Within the aged rat study population, our background research demonstrated that neural overactivity contributes to memory impairment by using experimental intervention with therapeutics, a finding that has also translated therapeutically in clinical studies. Alongside those achievements, accumulating evidence suggests that adaptive recruitment of inhibitory function beneficially supports resilience to memory decline in aged unimpaired rats (AU). Research in Project 2 will now examine the functional significance of inhibitory recruitment as a potentially adaptive mechanism in the preservation of cognitive function in aging. In that context, Project 2 will investigate a mechanism for homeostatic regulation, to examine loss of function in AI and potential gain of function in AU. Project 2 will study the condition of this mechanism across the EC/hippocampal system with anatomical methods for circuit-specific alterations. The CA2 hippocampal subfield has become an additional subregion of high interest in our model; loss of function contributes to excess activity possibly contributing to the AI condition while greater recruitment may occur in AU rats, giving a bi-directional role for homeostatic control in both late life outcomes. Project 2 will also lead in the use of experimental tools with potential therapeutic relevance, as it has in the past with the Sv2a agent levetiracetam. Studies under Aim 4 in Project 2 will test agents that act as allosteric modulators of GABAA α5 receptors. These receptors have highly restricted localization in the mammalian brain and may offer greater precision for targeting the neurobiological conditions underlying impairment in AI and providing a test for the functional significance of AU biomarkers, which have indicated augmented inhibition to maintain excitatory/inhibitory balance in brain aging. Thus, in the research plans in the current application, Project 2 maintains a strong focus on the relevance of basic research findings for clinical applications.