Social control of lifespan regulation via glial plasticity in ants

摘要 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。大脑中的可塑性变化 支持与衰老相关的认知衰退和神经退行性变，但对神经保护作用知之甚少 在健康老化的大脑中阻止这些过程的途径。在哺乳动物中，神经胶质细胞的组成和 属性显示与年龄相关的动态变化，包括向更多神经保护功能的转变，如大脑 年龄。在果蝇中，胶质细胞也与调节大脑健康和寿命有关，这突显了一种深刻的 神经胶质细胞功能的进化保守性。 这项提案的目标是确定神经胶质细胞如何有助于大脑健康衰老和长寿 Harpegnathos saltator ants，一个研究蚂蚁分子和表观遗传调控的强大模式系统 衰老。成年的Harpegnathos工蚁可以通过表型转变成为女王(称为“游戏之门”) 这将导致寿命延长5倍。 我们在工人过渡到长寿配偶门前后进行了单细胞rna-seq和 在胶质细胞中发现了显著的可塑性。具体地说，我们发现成鞘的神经胶质细胞基本上是 在游戏门大脑中扩展。有趣的是，游戏之门保留了高水平的神经鞘胶质细胞，因为他们 而工人的大脑在他们的一生中迅速耗尽了这些细胞。 成鞘胶质细胞对损伤做出反应，并提供一般管家和神经保护功能 果蝇，但它们对健康的大脑衰老和长寿的贡献还不是很清楚。我们的数据表明 一种假说认为，扩大的包膜胶质细胞隔室有助于延长脑膜瘤的寿命 游戏之门。 在目标1中，我们将确定伴随着成鞘的神经胶质细胞的分子和细胞变化。 工人和游戏机门不同衰老过程中的动态变化。在目标2中，我们将调查特定的 在成鞘的神经胶质细胞中表达的一种受体，可能直接调节它们的扩张以响应 生殖基因在配子门中的表达。在目标3中，我们将利用原代蚂蚁神经元培养和 在果蝇中进行基因操作以确定成鞘胶质细胞与寿命和寿命之间的因果联系 它的机制。 我们的工作将共同阐明1)控制胶质细胞可塑性的新分子途径，2)新的生物学作用 对于胶质细胞的可塑性，以及3)胶质细胞调节健康大脑衰老的机制。

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.