Brain-wide screen for a neural pacemaker of aging

总结 衰老是一个渐进的过程，导致全身细胞功能的丧失， 导致许多慢性疾病，增加死亡率。阐明精确的 衰老机制对于减少疾病和延长健康寿命至关重要。 然而，几乎身体中的每一个组织都因衰老而改变， 找出老化的主要控制者本提案的目的是确定 大脑是否通过离散的大脑活动模式来调节衰老， 神经网络我们将使用寿命最短的脊椎动物之一， 绿松石鳉，作为一个快速，高通量的老化模型，以揭示基因- 定义了调节细胞代谢和寿命的神经元。雇用大规模 我们将对鳉鱼进行光片成像，可视化全脑钙活动动态， 无偏见地识别对长寿干预做出反应的神经元。我们将描述 通过免疫组织化学， 单细胞和磷酸化核糖体捕获方法。研究是否 这些神经元在控制大脑和其他组织中的整体细胞功能方面发挥着因果作用。 组织，我们将光遗传学激活这些神经元和测量分子 年轻的特征和大脑和外周组织中的体内代谢活动。我们 将监控和操纵神经活动在整个短暂的生命周期中使用 纤维光度测定法来确定这种“神经起搏器”是否决定了衰老的克里思， 年轻人的行为这些方法将扩展到寿命更长的物种- 斑马鱼和老鼠。从这些研究中获得的知识应该是变革性的， 了解调节和同步衰老的基本机制， 中心blog由于年龄是许多疾病的主要风险因素，包括神经退行性疾病， 疾病，这项建议应该提供新的，基于电路的方法来治疗这些疾病， 疾病 !

Summary Aging is a gradual process that results in the loss of cellular function across the body, leading to numerous chronic diseases that promote mortality. Elucidating the precise mechanisms of aging is critical for reducing illness and extending healthy lifespan. However, almost every tissue in the body is modified by aging, making it difficult to pinpoint the principal controller of aging. The goal of this proposal is to determine whether the brain modulates aging through coordinated activity patterns within discrete neuronal networks. We will use one of the shortest-living vertebrates, the African turquoise killifish, as a rapid, high-throughput model of aging to uncover genetically- defined neurons that regulate cellular metabolism and lifespan. Employing large-scale light-sheet imaging in killifish, we will visualize brain-wide calcium activity dynamics to unbiasedly identify neurons that respond to longevity interventions. We will characterize the genetic profiles of the identified neurons via a combination of immunohistochemical, single cell, and phosphorylated ribosome capture approaches. To examine whether these neurons play a causal role to control overall cellular function in the brain and other tissues, we will optogenetically activate these neurons and measure molecular signatures of youth and in vivo metabolic activity in the brain and peripheral tissues. We will monitor and manipulate neural activity throughout the short lifespan of killifish using fiber photometry to determine if this ‘neural pacemaker’ dictates the tempo of aging and youthful behavior. These approaches will then be extended to longer-lived species – zebrafish and mice. Knowledge resulting from these studies should be transformative to understand the fundamental mechanisms that regulate and synchronize aging and longevity. As age is the prime risk factor for many diseases, including neurodegenerative diseases, this proposal should provide new, circuit-based approaches to treat these diseases. !