Social control of lifespan regulation via glial plasticity in ants

通过蚂蚁的神经胶质可塑性对寿命调节的社会控制

• 批准号: 10197364
• 负责人: Roberto Bonasio
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197364
• 关键词: Adult; Age; Aging; Antibodies; Ants; Apoptosis; Behavior; Biological; Biological Assay; Biological Models; Brain; Brain Injuries; Brain region; Candidate Disease Gene; Castes; Cells; Data; Drosophila genus; Event; Family; Fluorescence Microscopy; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Goals; Homeostasis; Housekeeping; Impaired cognition; In Vitro; Insecta; Life; Ligands; Link; Longevity; Low-Density Lipoproteins; Mammals; Measures; Modeling; Molecular; Nerve Degeneration; Neuroglia; Neuronal Injury; Neurons; Neuropil; Pathway interactions; Phagocytes; Phenotype; Physiology; Play; Population; Process; Property; Recombinants; Regulation; Reproduction; Role; Signal Transduction; Social Controls; Social status; Testing; Time; Vitellogenins; Work; age related; age related neurodegeneration; aged; aging brain; brain health; defined contribution; epigenetic regulation; experimental study; genetic manipulation; healthspan; healthy aging; human old age (65+); in vivo; knock-down; neuroprotection; receptor; reproductive; response; response to brain injury; single-cell RNA sequencing; social; tool

ABSTRACT Age-related neurodegenerative diseases pose an immense biomedical challenge. Plastic changes in the brain underpin aging-related cognitive decline and neurodegeneration but little is known about the neuroprotective pathways that forestall these processes in healthy aging brains. In mammals, glia composition and properties display age-related dynamics including a shift to a more neuroprotective function as the brain ages. In Drosophila, glia are also implicated in regulating brain health and lifespan, underscoring a deep evolutionary conservation of glia function. The goal of this proposal is to determine how glia contribute to healthy brain aging and longevity using Harpegnathos saltator ants, a powerful model system to study the molecular and epigenetic regulation of aging. Adult Harpegnathos workers can become queens (called “gamergates”) via a phenotypic transition that results in a 5-fold extension of lifespan. We performed single-cell RNA-seq before and after the transition of workers to long-lived gamergates and found remarkable plasticity in the glia. Specifically, we found that ensheathing glia cells were substantially expanded in gamergate brains. Interestingly, gamergates retained high levels of ensheathing glia as they aged, whereas worker brains were rapidly depleted of these cells over the course of their life. Ensheathing glia cells respond to damage and provide general housekeeping and neuroprotective functions in Drosophila but they are not known to contribute to healthy brain aging and longevity. Our data suggest the hypothesis that an expanded ensheathing glia compartment contributes to the prolonged lifespan of gamergates. In Aim 1, we will determine the molecular and cellular changes that accompany the ensheathing glia dynamics during differential aging in worker and gamergates. In Aim 2, we will investigate the role of a specific receptor that is expressed in ensheathing glia cells and might directly regulate their expansion in response to the expression of a reproductive gene in gamergates. In Aim 3, we will utilize primary ant neuronal cultures and genetic manipulations in Drosophila to determine the causal link between ensheathing glia and longevity and its mechanism. Together, our work will elucidate 1) new molecular pathways that control glia plasticity, 2) a new biological role for glia plasticity, and 3) mechanisms for the regulation of healthy brain aging by glia.

抽象的 与年龄相关的神经退行性疾病提出了巨大的生物医学挑战。大脑的可塑性变化 是与衰老相关的认知衰退和神经退行性疾病的基础，但人们对神经保护作用知之甚少 在健康衰老的大脑中阻止这些过程的途径。在哺乳动物中，神经胶质的组成和 属性显示与年龄相关的动态，包括向大脑的更多神经保护功能转变 年龄。在果蝇中，神经胶质细胞还与调节大脑健康和寿命有关，强调了深层的 神经胶质细胞功能的进化保守。 该提案的目标是确定神经胶质细胞如何促进健康的大脑老化和长寿 Harpegnathos salator ant，一个强大的模型系统，用于研究蚂蚁的分子和表观遗传调控 老化。成年 Harpegnathos 工人可以通过表型转变成为女王（称为“玩家门”） 从而使寿命延长 5 倍。 我们在工人转变为长寿玩家门之前和之后进行了单细胞 RNA 测序， 发现神经胶质细胞具有显着的可塑性。具体来说，我们发现鞘神经胶质细胞基本上 在玩家门大脑中扩展。有趣的是，玩家门保留了高水平的鞘神经胶质细胞，因为它们 随着年龄的增长，工人们的大脑中的这些细胞在其一生中会迅速耗尽。 鞘神经胶质细胞对损伤做出反应并提供一般的内务管理和神经保护功能 果蝇，但尚不清楚它们是否有助于健康的大脑老化和长寿。我们的数据表明 假设扩大的鞘神经胶质细胞室有助于延长寿命 玩家之门。 在目标 1 中，我们将确定伴随鞘神经胶质细胞发生的分子和细胞变化 工人和玩家门差异老化过程中的动态。在目标 2 中，我们将研究特定角色的作用 在鞘神经胶质细胞中表达的受体，可能直接调节其扩张以响应 玩家门中生殖基因的表达。在目标 3 中，我们将利用原代蚂蚁神经元培养物并 对果蝇进行基因操作以确定鞘神经胶质细胞与长寿之间的因果关系 它的机制。 我们的工作将共同阐明 1) 控制神经胶质可塑性的新分子途径，2) 新的生物学作用 神经胶质细胞的可塑性，以及3）神经胶质细胞调节健康大脑衰老的机制。