Investigating neuropeptide signals that slow cognitive aging in C. elegans

研究减缓秀丽隐杆线虫认知衰老的神经肽信号

• 批准号: 10751383
• 负责人: Emily Jean Leptich
• 金额: $ 4.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2026-08-06
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751383
• 关键词: Address; Afferent Neurons; Age; Age-associated memory impairment; Aging; Animals; Association Learning; Behavior; Behavioral Assay; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chemotaxis; Cognition; Cognitive; Cognitive aging; Complex; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Data; Genes; Genetic Transcription; Goals; Health; Healthcare; Homologous Gene; Human; Impaired cognition; Individual; Interneurons; Investigation; Knowledge; Learning; Life Expectancy; Longevity; Memory; Modeling; Molecular; Nematoda; Neurons; Neuropeptide Gene; Neuropeptide Receptor; Neuropeptides; Organism; Pathway interactions; Peptide Signal Sequences; Peptides; Phenotype; Quality of life; RNA Interference; RNA interference screen; Reporter; Research; Role; Sensory; Signal Transduction; Site; Testing; Transgenic Organisms; Visual; age related; aged; aging population; druggable target; effective therapy; egg; gain of function mutation; hatching; healthspan; improved; insight; knock-down; learned behavior; mutant; neuronal circuitry; new therapeutic target; novel; promoter; protein activation; receptor; therapeutic target; young adult; Address; Afferent Neurons; Age; Age-associated memory impairment; Aging; Animals; Association Learning; Behavior; Behavioral Assay; Caenorhabditis elegans; Candidate Disease Gene; Cells; Chemotaxis; Cognition; Cognitive; Cognitive aging; Complex; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Data; Genes; Genetic Transcription; Goals; Health; Healthcare; Homologous Gene; Human; Impaired cognition; Individual; Interneurons; Investigation; Knowledge; Learning; Life Expectancy; Longevity; Memory; Modeling; Molecular; Nematoda; Neurons; Neuropeptide Gene; Neuropeptide Receptor; Neuropeptides; Organism; Pathway interactions; Peptide Signal Sequences; Peptides; Phenotype; Quality of life; RNA Interference; RNA interference screen; Reporter; Research; Role; Sensory; Signal Transduction; Site; Testing; Transgenic Organisms; Visual; age related; aged; aging population; druggable target; effective therapy; egg; gain of function mutation; hatching; healthspan; improved; insight; knock-down; learned behavior; mutant; neuronal circuitry; new therapeutic target; novel; promoter; protein activation; receptor; therapeutic target; young adult

ABSTRACT The average life expectancy has nearly doubled in the last century, leading to increased rates of cognitive decline in aged populations. Therefore, it is critical to identify mechanisms that restore memory function with age. One such mechanism is activation of cAMP response element-binding protein (CREB), which is a highly conserved transcriptional regulator of long-term associative memory (LTAM). Across species, increased CREB activity is associated with enhanced memory with age, but the mechanisms underlying this phenomenon are not well- understood. Recent research in C. elegans suggests that enhanced neuropeptide signaling from a single sensory neuron, the AWC, promotes learning and extends CREB-dependent LTAM in young and aged animals. Specifically, extended memory required 1.) neuropeptide secretion from the AWC and 2.) CREB activity in the AIM interneuron, which is the established site of memory activity in C. elegans. These results indicate that increased AWC neuropeptide signaling may boost cognitive healthspan in C. elegans. However, the memory- promoting neuropeptide(s) and whether their mechanism of action regulates learning or CREB-dependent memory is unknown. Furthermore, AWC neuropeptide signals regulate a variety of neuronal phenotypes that decline with age, including chemotaxis, locomotory behaviors, and egg-laying. Interestingly, we have found that increased AWC peptide release significantly reduces the rate of matricidal egg hatching—a neuronally-regulated phenotype that occurs more frequently in aged animals—suggesting AWC peptide signaling also promotes the healthspan of neuronal circuitry. Although, how AWC peptide signaling regulates the healthspan of other neuronal phenotypes has yet to be investigated. From these findings, we hypothesize that AWC-specific neuropeptide signaling promotes learning and CREB-dependent memory with age and extends neuronal healthspan in C. elegans. We will test this hypothesis by performing a highly targeted RNAi screen to identify AWC neuropeptide signals that promote learning, CREB activity in the AIM, and LTAM. Then, we will identify the corresponding receptors, which are largely conserved, druggable targets that may be tested in higher organisms. Finally, we will perform a battery of AWC-driven behaviors to determine the role of AWC neuropeptide signaling in extending neuronal healthspan phenotypes. Overall, this research will provide insight into the molecular underpinnings of age-related cognitive decline, potentially leading to novel therapeutic targets for cognitive impairment in higher organisms.

抽象的 上个世纪的平均预期寿命几乎翻了一番，导致认知能力下降的速度提高 在老年人中。因此，识别随着年龄恢复内存功能的机制至关重要。一 这种机制是激活CAMP响应元件结合蛋白（CREB），这是一种高度保守的 长期关联记忆（LTAM）的转录调节剂。在整个物种之间，Creb活性增加为 与年龄增强的记忆有关，但是这种现象的基础机制不是很好 理解。秀丽隐杆线虫的最新研究表明，单个感觉的神经肽信号增强 AWC神经元促进学习并扩展了年轻动物和老年动物中CREB依赖的LTAM。 具体而言，需要扩展的内存1.）AWC的神经肽分泌和2.） AIM Interneuron，这是秀丽隐杆线虫中确定的记忆活动的位置。这些结果表明 AWC神经肽信号的增加可能会促进秀丽隐杆线虫中的认知健康范围。但是，内存 - 促进神经肽及其作用机理是调节学习还是依赖CREB 记忆未知。此外，AWC神经肽信号调节了多种神经元表型 随着年龄的增长，包括趋化性，运动行为和卵子上卵。有趣的是，我们发现 AWC果皮释放的增加大大降低了基质卵孵化的速率 - 神经元调节 在老年动物中更频繁地发生的表型 - 探索AWC epeelide信号也促进了 虽然，AWC肽信号如何调节其他人的健康状态 神经元表型尚未研究。从这些发现，我们假设该AWC特定于 神经肽信号传导随着年龄的增长而促进学习和CREB依赖性记忆并扩展神经元 秀丽隐杆线虫中的HealthSpan。我们将通过执行高度靶向的RNAi屏幕来检验该假设以识别 AWC神经肽信号促进学习，目标中的CREB活动和LTAM。然后，我们将确定 相应的受体在很大程度上是保守的，可在较高生物体中进行测试的可药物靶标。 最后，我们将执行一系列AWC驱动的行为，以确定AWC神经肽信号的作用 在扩展神经元健康的表型中。总体而言，这项研究将为分子提供见解 与年龄相关的认知下降的基础，有可能导致新的治疗靶标的认知靶标 较高生物体的损害。