Determining the neural mechanisms of mechanosensory food perception in DR-mediated longevity

项目总结： 老年学领域已经确定了多种遗传、药物和生活方式干预措施。 可以延年益寿，延缓与年龄有关的疾病的发生。其中研究最多的一个 干预措施是饮食限制(DR)，即减少营养摄入量，而不会导致 营养不良。DR可以延长不同类群的寿命和健康跨度，以及许多基因 DR的机制最初是在线虫秀丽线虫中发现的。 不幸的是，限制饮食并不是预防年龄相关疾病的现实解决方案 人口水平，因为遵循灾难恢复协议对大多数人来说非常困难，而且因为 DR的好处可能会被环境因素削弱。例如，将禁食的动物暴露在 食物气味会降低DR在多种模式生物中的疗效。在线虫中，食物的气味是 由感觉神经元感知，启动回路，导致神经递质从 5-羟色胺能和多巴胺能神经元。来自这些生物胺神经递质的信号最终 通过细胞非自主信号将食物可获得性信息传递到肠道。在 在肠道，这种信号抑制FMO-2的表达，FMO-2是DR介导的长寿所必需的基因。 在为这项提议收集的初步数据中，我们发现食物感知的第二种模式， 食物的机械感官也抑制DR介导的FMO-2诱导和C。 优雅女装。就像食物气味一样，机械感觉抑制DR需要产生 生物胺类神经递质可驱动细胞对外周长寿基因的非自主调节。 该项目将确定细胞非自主信号的关键神经元和信号组件 机械感官食物感知调节衰老的途径。为了绘制这条线路，我将 首次鉴定机械感官食物激活的多巴胺能神经元和酪氨酸能神经元 感知并确定机械感觉是增加还是抑制这些物质的释放 神经递质(目标1)。接下来，我将研究这条路径的下游元素 生物胺能神经元：1)直接测定表达生物胺受体的中间神经元 生物胺能信号下游，以及2)识别神经肽和神经肽受体 通过它将有关食物环境的信息传递到肠道(目标2)。一起， 这些目标将加强我们对不同食物感知模式如何调节衰老的理解 通过保守的信号元件。最终，我们可以使用这些信息来创建 模仿限制饮食的益处的药物，而不考虑环境食品的暗示。

Project Summary: The field of geroscience has identified multiple genetic, pharmaceutical, and lifestyle interventions that promote longevity and delay the onset of age-related disease. One of the most studied of these interventions is Dietary Restriction (DR), or a reduction in nutrient intake that does not cause malnutrition. DR can extend lifespan and healthspan across taxa, and many of the genetic mechanisms of DR were originally discovered in the nematode Caenorhabditis elegans. Unfortunately, dietary restriction is not a realistic solution to prevent age-related disease on a population level because following a DR protocol is very difficult for most people and because the benefits of DR can be blunted by environmental factors. For example, exposing fasted animals to food smells decreases the efficacy of DR in multiple model organisms. In C. elegans, food smells are perceived by sensory neurons that initiate circuits leading to neurotransmitter release from serotonergic and dopaminergic neurons. Signaling from these bioamine neurotransmitters ultimately conveys food availability information to the intestine through cell nonautonomous signaling. In the intestine, this signal suppresses the expression of fmo-2, a gene required for DR-mediated longevity. In the preliminary data collected for this proposal, we found that a second mode of food perception, mechanosensation of food, also suppresses DR-mediated fmo-2 induction and longevity in C. elegans. Much like food smell, mechanosensory suppression of DR requires the production of bioamine neurotransmitters to drive cell nonautonomous regulation of peripheral longevity genes. This project will identify key neurons and signaling components of the cell nonautonomous signaling pathway through which mechanosensory food perception regulates aging. To map this circuit, I will first identify the dopaminergic and tyraminergic neurons activated by mechanosensory food perception and determine whether mechanosensation increases or suppresses release of these neurotransmitters (Aim 1). Next, I will investigate elements of this pathway downstream of bioaminergic neurons by 1) determining the bioamine receptor-expressing interneurons directly downstream of the bioaminergic signal, and 2) identifying neuropeptides and neuropeptide receptors through which information about the food environment is conveyed to the intestine (Aim 2). Together, these aims will enhance our understanding of how different modes of food perception regulate aging through conserved signaling elements. Ultimately, we can use this information to create pharmaceuticals that mimic the benefits of dietary restriction regardless of environmental food cues.