PROJECT 4-NPTX2 and Adaptation to Cognitive Aging

项目 4-NPTX2 和认知衰老的适应

• 批准号: 10412005
• 负责人: PAUL F WORLEY
• 金额: $ 48.53万
• 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/10412005
• 关键词: Adult; Age-associated memory impairment; Aging; Attention; Axon; Behavior; Biochemical; Biology; Brain; Cellular biology; Cognition; Cognitive; Cognitive aging; Collaborations; Confocal Microscopy; Dose; Equilibrium; Excitatory Synapse; Exocytosis; Extracellular Protein; Failure; Female; Genes; Hippocampus (Brain); Homeostasis; Image; Immediate-Early Genes; Impaired cognition; Impairment; Incidence; Injections; Interneurons; Interruption; Label; Lateral; Levetiracetam; Light; Long-Evans Rats; Maintenance; Measures; Mediating; Membrane; Memory; Messenger RNA; Methods; MicroRNAs; Microscopy; Modeling; Modification; Molecular; Neocortex; Neurons; Oligonucleotides; Parvalbumins; Peptide Hydrolases; Periodicity; Phase; Photons; Physiological Processes; Presynaptic Terminals; Process; Protein Analysis; Proteins; Rattus; Regulation; Resolution; Role; Schedule; Site; Sleep; Synapses; System; Testing; Therapeutic; Time; Transgenes; Vesicle; Virus; Work; age effect; age related; aged; base; calmodulin-dependent protein kinase II; cognitive performance; entorhinal cortex; experimental study; gain of function; hippocampal pyramidal neuron; in vivo; innovation; insight; intravenous administration; loss of function; mRNA Transcript Degradation; male; presynaptic; prevent; protein expression; protein function; resilience; success; synaptic function; tool; trafficking; transgene expression; translatable strategy; two-photon

Project 4 examines the role of NPTX2 and homeostatic scaling in age-related cognitive decline. NPTX2 is an immediate early gene expressed by pyramidal neurons and mediates activity-dependent homeostatic strengthening of inhibitory circuits by adaptively strengthening excitatory drive of parvalbumin interneurons (PV-IN). This PPG has examined the effect of aging on cognition using outbred Long-Evans rats and has documented increased pyramidal neuron excitability and reduced PV-IN circuit inhibition that are associated with cognitive decline. Preliminary studies further reveal reduced NPTX2 expression in Aged-Impaired rats and rescue of circuit deficits by NPTX2 transgene expression. Here, we build on these observations and examine the hypothesis that failure of NPTX2 homeostatic mechanisms contribute to age-related cognitive decline. Aim 1 will test the hypotheses that NPTX2 loss-of-function (LOF) accelerates age-related cognitive decline while NPTX2 gain-of-function (GOF) delays or prevents age-related cognitive decline. A conditional NPTX2 LOF model uses a newly developed NPTX2f/f rat together with virus-mediated delivery of Cre to delete NPTX2 at 11 m and together with Core B details the impact on cognitive behavior. In a reciprocal set of experiments, we create NPTX2 GOF models using two distinct approaches that include virus mediated NPTX2 transgene and oligonucleotide mediated NPTX2 mRNA stabilization. The impact of GOF on cognitive behavior is evaluated in collaboration with Core B. Aim 2 examines molecular and cellular mechanisms mediating dynamic targeting of NPTX2 to excitatory synapses. Studies use state-of-the-art proximity labeling methods to identify proteins involved in synaptic NPTX2 exocytosis and shedding. Aim 3 uses in vivo 2-photon imaging to examine the hypothesis that age-related cognitive deficits are associated with disruption of a critical phase of homeostatic scaling that mediates activity-dependent NPTX2 exocytosis and shedding. Analyses examine diurnal changes in synaptic NPTX2 in association with waking behaviors and sleep comparing Young, Aged-Impaired and Aged-Unimpaired rats. We also test the effect of levetiracetam in Aged-Impaired rats. Studies in Aims 1 and 3 include both male and female rats. The Aims are highly synergistic with other Projects and together will reveal fundamental mechanisms of aging, cognitive resilience and cognitive decline.

项目4研究了NPTX2和稳态缩放在与年龄相关的认知下降中的作用。 NPTX2是一个 锥体神经元表达并介导活性依赖性稳态表达的早期基因 通过适应增强白蛋白中间神经元的兴奋性驱动来增强抑制回路 （pv-in）。该PPG检查了使用近代长evans大鼠衰老对认知的影响，并具有 记录了锥体神经元兴奋性的增加，并降低了相关的光伏电路抑制 认知能力下降。初步研究进一步揭示了年龄损坏的大鼠的NPTX2表达降低和 通过NPTX2转基因表达来挽救电路缺陷。在这里，我们以这些观察为基础并检查 NPTX2稳态机制失败导致与年龄相关的认知能力下降的假设。目的 1将检验NPTX2功能丧失（LOF）的假设会加速与年龄相关的认知能力下降 NPTX2功能获得（GOF）延迟或阻止与年龄有关的认知下降。有条件的NPTX2 LOF 模型使用新开发的NPTX2F/F大鼠，以及病毒介导的CRE的递送在11时删除NPTX2 M并与核心B一起详细介绍了对认知行为的影响。在一组相互的实验中，我们 使用包括病毒介导的NPTX2转基因在内的两种不同的方法创建NPTX2 GOF模型 寡核苷酸介导的NPTX2 mRNA稳定。评估了GOF对认知行为的影响 与CoreB的合作B AIM 2研究了介导动态靶向的分子和细胞机制 NPTX2兴奋性突触。研究使用最新的接近标签方法来识别蛋白质 参与突触NPTX2胞吐作用和脱落。 AIM 3在体内2光子成像中使用以检查 假设与年龄相关的认知缺陷与稳态的关键阶段的破坏有关 缩放介导活性依赖性的NPTX2胞吐作用和脱落。分析检查昼夜变化 在突触NPTX2中与醒来的行为和睡眠相关，比较年轻，年龄障碍和 老化的大鼠。我们还测试了左甲乙酰基在老年障碍大鼠中的作用。目标1和3的研究 包括男性和雌性大鼠。目的与其他项目高度协同作用，将共同揭示 衰老，认知弹性和认知能力下降的基本机制。