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: 10583467
• 负责人: Roberto Bonasio
• 金额: $ 33.21万
• 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/10583467
• 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; Proliferating; Property; Recombinants; Regulation; Reproduction; Role; Signal Transduction; Social Controls; Social status; Sorting; Testing; Visualization; 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构成了巨大的生物医学挑战。大脑的塑料变化 基础与衰老相关的认知下降和神经退行性，但对神经保护知之甚少 在健康衰老的大脑中阻止这些过程的途径。在哺乳动物中，胶质成分和 属性显示与年龄相关的动态，包括转向更神经保护功能作为大脑 年龄。在果蝇中，神经胶质在调节脑健康和寿命中也实施，强调了深度 神经胶质功能的进化保护。 该提案的目的是确定神经胶质如何对健康的大脑衰老和使用寿命贡献 Harpegnathos盐蚂蚁，一种强大的模型系统，用于研究分子和表观遗传调节的 老化。成人Harpegnathos工人可以通过表型过渡成为皇后区（称为“ Gamergates”） 这导致寿命的延长5倍。 我们在工人向长寿的Gamestergates和 在神经胶质中发现了显着的可塑性。特别是，我们发现开发胶质细胞基本上是 扩展在Gamergate大脑中。有趣的是，Gamesrgates保留了高水平的幽灵 老化，而工人的大脑在一生中迅速消耗了这些细胞。 开发胶质细胞会对损害做出反应，并提供一般的管家和神经保护功能 果蝇，但众所周知，它们会导致健康的大脑衰老和寿命。我们的数据表明 假设扩展的吉尔神经胶质室有助于长时间的寿命 gamergates。 在AIM 1中，我们将确定涉及开发胶质的分子和细胞变化 工人和游戏的差异老化期间的动态。在AIM 2中，我们将研究特定的作用 在开发胶质细胞中表达的受体，可能会直接调节其膨胀 游戏中生殖基因的表达。在AIM 3中，我们将利用原发性蚂蚁神经元文化和 果蝇中的遗传操纵，以确定开发神经胶质与寿命之间的因果关系 它的机制。 我们的工作将阐明1）控制神经胶质可塑性的新分子途径，2）新的生物学作用 用于胶质可塑性和3）通过神经胶质调节健康脑老化的机制。