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

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.

摘要 在上个世纪，平均预期寿命几乎翻了一番，导致认知能力下降的速度加快 在老年人群中。因此，确定随着年龄的增长恢复记忆功能的机制至关重要。一 这种机制是cAMP反应元件结合蛋白（CREB）的激活，CREB是一种高度保守的 长期关联记忆（LTAM）的转录调节因子。在不同物种中，CREB活性的增加是 随着年龄的增长，记忆力增强，但这种现象背后的机制并不好- 明白C. elegans认为，增强的神经肽信号从一个单一的感觉 神经元，AWC，促进学习和延长CREB依赖性LTAM在年轻和老年动物。 具体来说，扩展内存需要1.）从AWC分泌神经肽和2.）CREB活性 AIM中间神经元是C.优雅的这些结果表明 增加AWC神经肽信号可能会提高C.优雅的但是，记忆- 促进神经肽及其作用机制是否调节学习或CREB依赖性 记忆是未知的。此外，AWC神经肽信号调节多种神经元表型， 随着年龄的增长而下降，包括趋化性，运动行为和产卵。有趣的是，我们发现， AWC肽释放的增加显著降低了杀母卵孵化的速率， 表型，更频繁地发生在老年动物-这表明AWC肽信号也促进了 神经回路的健康寿命。虽然，AWC肽信号传导如何调节其他人的健康寿命， 神经元表型还有待研究。根据这些发现，我们假设AWC特异性 神经肽信号传导促进学习和CREB依赖的记忆随着年龄的增长， C.的健康寿命优雅的我们将通过进行高度靶向的RNAi筛选来验证这一假设， AWC神经肽信号，促进学习，CREB活性的目的，和LTAM。然后，我们将确定 相应的受体，它们在很大程度上是保守的，可在高等生物体中测试的药物靶标。 最后，我们将进行一系列AWC驱动的行为，以确定AWC神经肽信号传导的作用 in extending延长neuronal神经元healthspan健康phenotypes表型.总的来说，这项研究将提供深入了解分子 年龄相关的认知能力下降的基础，可能导致新的治疗目标， 在高等生物中的损伤。