PROJECT 3-Synaptic function in behaviorally-characterized aged rats in circuits of the entorhinal cortex and dentate gyrus

项目 3-行为特征老年大鼠内嗅皮层和齿状回回路中的突触功能

• 批准号: 10412004
• 负责人: Alfredo Kirkwood
• 金额: $ 45.86万
• 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/10412004
• 关键词: AMPA Receptors; Abeta synthesis; Ablation; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Area; Behavioral; Brain; Brain region; Cells; Cerebrospinal Fluid; Cognition; Cognitive; Cognitive aging; Data; Deposition; Dominant-Negative Mutation; Elderly; Equilibrium; Extracellular Protein; Functional disorder; Genetic; Hippocampus (Brain); Human; Hyperactivity; Impaired cognition; Impairment; Individual; Interneurons; Intervention; Lateral; Learning; Medial; Mediating; Memory; Memory impairment; Modeling; Mus; Neurons; Output; Parvalbumins; Pathogenicity; Pathway interactions; Performance; Phase; Play; Process; Production; Pyramidal Cells; Rattus; Regulation; Research; Rodent; Rodent Model; Role; Sensory; Simian virus 40; Structure; Synapses; System; Targeted Research; Temporal Lobe; Testing; Theoretical Studies; Toxic effect; Transfection; Viral; Virus; Whole-Cell Recordings; age related; aged; base; calmodulin-dependent protein kinase II; cell age; cognitive function; cognitive performance; comparative; dentate gyrus; entorhinal cortex; excitatory neuron; experience; experimental study; functional status; mossy fiber; neuronal pentraxin; novel; optogenetics; overexpression; postsynaptic; preservation; programs; recruit; relating to nervous system; sensory cortex; synaptic function; tau Proteins; therapeutic target

Aging frequently impairs cognitive functions associated with the medial temporal lobe (MTL), particularly the formation of new memories, and it is also a major risk factor for Alzheimer’s disease (AD). Recent studies in rodent models and humans identified hyperactivity in specific circuits/subregions of the MTL, the lateral entorhinal cortex (LEC) and its downstream target the dentate/CA3 subfields of the hippocampus, as a distinctive feature that associates with impaired memory in aged individuals. A wealth of experimental and theoretical studies indicates that the deleterious consequences of hyperactivity are multiple. Hyperactivity not only compromises normal neural processing and the recruitment of plasticity mechanisms required for encoding new memories, but it can also accelerate activity dependent pathogenic processes, like Aβ production/deposition and spread of tau-hyperphosphorylation/toxicity along neural connections. In multiple brain areas, network activity is dynamically controlled primarily by GABAergic circuits subserved by parvalbumin-positive inhibitory interneurons (PV-INs). Importantly, mounting evidence indicates that dysfunction of these inhibitory circuits is a contributing factor in age-related hyperexcitability, particularly in the earliest phases of AD. In adults, the inhibitory output of the PV-INs is relatively stable, but the excitatory input onto PV-INs is comparatively dynamic and plastic. In this context, a particularly interesting research target for hyperxcitability during aging is Neuronal Pentraxin-2 (NPTX2), an extracellular protein released by excitatory neurons in an activity-dependent manner that is crucial for stabilizing AMPA receptors at synapses on PV-INs. Importantly, the genetic ablation of NPTX2 reduces these excitatory inputs by half in mouse cortex, and in elderly humans low levels of NPTX2 in the cerebral spinal fluid (CSF) correlates with reduced cognitive performance across the spectrum of aging/AD. In this proposal we will examine the novel hypothesis that a reduction in NPTX2- mediated stabilization of the excitatory connectivity onto PV-INs contributes to cognitive impairment during aging. We will directly evaluate the functional status of multiple excitatory inputs onto PV-INs within the MTL in a well-characterized rat model for individual cognitive differences in aging. We will also test whether manipulating NPTX2 affects these inputs as expected from the hypothesis. Testing the causal effect of NPTX2 in age-dependent cognitive impairment in a comprehensive manner in multiple pathways, might help identifying potential therapeutic targets to can alleviate age related cognitive decline.

衰老经常会损害与内侧临时叶有关的认知功能 （MTL），特别是新记忆的形成，也是主要风险因素 阿尔茨海默氏病（AD）。啮齿动物模型和人类的最新研究确定了多动症 在MTL的特定电路/子区域中，侧向肾上腺皮质（LEC）及其下游 针对海马的齿状/CA3子场，作为关联的独特特征 老年人的记忆力受损。丰富的实验和理论研究 表明多动症的删除后果是多重的。不仅活跃 损害正常的神经加工和所需的可塑性机制的募集 用于编码新记忆，但也可以加速活动依赖于活动的致病过程 像Aβ的产生/沉积以及沿神经的tau-hyperphopphosphylation/毒性的扩散 连接。 在多个大脑区域，网络活动主要由GABA能动态控制 白蛋白阳性抑制性中间神经元（PV-INS）均能兑现电路。重要的是， 越来越多的证据表明，这些抑制回路的功能障碍是导致的因素 与年龄相关的过度兴奋性，特别是在AD的最早阶段。在成人中，抑制作用 PV-INS的输出相对稳定，但是PV-INS上的兴奋性输入相对 动态和塑料。在这种情况下，一个特别有趣的研究目标 在衰老过程中是神经元五肽-2（NPTX2），一种兴奋性释放的细胞外蛋白 神经元以活动依赖性方式对于稳定AMPA接收器至关重要 PV-INS上的突触。重要的是，NPTX2的遗传消融降低了这些兴奋性输入 在小鼠皮层中的一半，而在大脑脊柱液中的低水平NPTX2中的一半 （CSF）与衰老/AD范围内的认知性能降低相关。 在该提议中，我们将研究以下新假设：NPTX2-的减少 兴奋连接到PV-IN的介导的稳定性有助于认知 衰老期间的损害。我们将直接评估多个兴奋性的功能状态 在特征良好的大鼠模型中，在MTL中输入PV-INS的单个认知模型 衰老的差异。我们还将测试操纵NPTX2是否会影响这些输入 从假设预期。测试NPTX2在年龄依赖性认知方面的因果关系 以多种途径的全面方式损害可能有助于确定潜力 治疗目标可以减轻与年龄相关的认知下降。