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

项目 2-行为特征老年大鼠内嗅/齿状回和 CA3 区的网络特性

• 批准号: 10171061
• 负责人: Michela Gallagher
• 金额: $ 62.73万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10171061
• 关键词: Achievement; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Anatomy; Award; Basic Science; Behavioral; Biological Markers; Brain; Cell surface; Cells; Clinical; Clinical Research; Cognition; Cognitive; Data; Dependence; Development; Disease; Dose; Elderly; Equilibrium; Female; Funding; Funding Mechanisms; Hilar; Hippocampal Formation; Hippocampus (Brain); Human; Hyperactivity; Immunochemistry; Immunohistochemistry; Impairment; In Situ Hybridization; Individual; Individual Differences; Interneurons; Intervention; Label; Late Onset Alzheimer Disease; Lead; Levetiracetam; Measures; Medial; Memory; Memory Loss; Memory impairment; Messenger RNA; Methodology; Methods; Modeling; Monkeys; Mus; Neurobiology; Neurocognitive; Neurocognitive Deficit; Neurons; Observational Study; Outcome; Output; Patients; Pattern; Phenotype; Population; Property; Rabies virus; Rattus; Regulation; Research; Research Project Grants; Risk; Role; Side; Signal Transduction; Site; Somatostatin; Structure; System; Temporal Lobe; Testing; Therapeutic; Three-Dimensional Imaging; Tissues; Tracer; Translating; Treatment Efficacy; Work; age effect; age related; aged; aging brain; clinical application; cognitive function; dentate gyrus; efficacy testing; entorhinal cortex; experimental study; gain of function; gamma-Aminobutyric Acid; immunoreactivity; interest; loss of function; male; memory process; nerve supply; neuroimaging; pre-clinical; preservation; programs; receptor; recruit; relating to nervous system; resilience; sex; study population; targeted agent; tool; young adult

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.

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）电路，有助于认知结果的个体差异， 衰老由于年龄增长是阿尔茨海默病（AD）的最大风险因素， 衰老本身的差异可能会带来这种疾病的风险或恢复力，这表明了潜在的相关性， 与年龄相关的认知障碍的限制条件。项目2研究特定于电路的机制 在广泛的记忆系统网络中，这些网络是受损和保存的个体差异的基础。 认知结果，并认为性别是差异脆弱性下降的一个潜在因素。作为第一 在我们的研究中描述了与年龄相关的记忆受损的远交Long-Evans雄性大鼠 (AI)在老年人的临床观察研究中， 个体，在迟发性AD风险更高的aMCI患者中进一步增加。老龄大鼠体内 研究人群中，我们的背景研究表明神经过度活动有助于记忆 通过使用实验性干预疗法，这一发现也转化为 在临床研究中治疗。除了这些成就，越来越多的证据表明， 抑制功能的适应性恢复有益地支持老年人记忆力下降的恢复力。 未受损大鼠（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，在老化的认知功能的保护。在这 在此背景下，项目2将研究稳态调节的机制，以检查AI的功能丧失， Au中函数的潜在增益。项目2将研究这一机制的状况， EC/海马系统与特定回路改变的解剖方法。海马CA 2区 在我们的模型中，子区域已经成为一个额外的高度关注的子区域;功能丧失有助于 过度活动可能导致AI状况，而Au大鼠可能发生更大的募集， 平衡控制在两种晚年结局中的双向作用。项目2还将率先使用 实验工具与潜在的治疗相关性，因为它在过去与Sv 2a剂左乙拉西坦。 项目2目标4下的研究将检测作为GABAA α5受体变构调节剂的药物。 这些受体在哺乳动物脑中具有高度限制的定位，并且可以提供更高的精确度， 针对AI受损的神经生物学条件，并提供功能测试 Au生物标志物的意义，其表明增强抑制以维持兴奋性/抑制性 大脑老化的平衡因此，在当前的应用研究计划中，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。