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

基本信息

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
项目类别：
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

项目摘要

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，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因此，确定随着年龄的增长恢复记忆功能的机制至关重要。这种机制是激活 cAMP 反应元件结合蛋白 (CREB)，这是一种高度保守的蛋白。长期联想记忆 (LTAM) 的转录调节因子在不同物种中，CREB 活性增加。与记忆力随年龄增长而增强有关，但这种现象背后的机制尚不清楚—— 最近对秀丽隐杆线虫的研究表明，来自单一感觉的神经肽信号传导增强。 AWC 神经元可促进年轻和老年动物的学习并扩展 CREB 依赖性 LTAM。具体来说，扩展记忆需要 1.) AWC 的神经肽分泌和 2.) CREB 活性 AIM 中间神经元，是秀丽隐杆线虫记忆活动的既定部位。这些结果表明： AWC 神经肽信号传导的增加可能会提高线虫的认知健康寿命，但是，记忆力却会下降。促进神经肽及其作用机制是否调节学习或 CREB 依赖性此外，AWC 神经肽信号调节多种神经元表型。随着年龄的增长，包括趋化性、运动行为和产卵能力下降。 AWC 肽释放的增加显着降低了弑母卵的孵化率——一种神经调节的表型在老年动物中更常见——表明 AWC 肽信号传导也促进然而，AWC 肽信号如何调节其他神经回路的健康寿命。神经元表型还有待研究根据这些发现，我们追寻 AWC 特异性。神经肽信号传导随着年龄的增长促进学习和 CREB 依赖性记忆并延长神经元我们将通过进行高度针对性的 RNAi 筛选来验证这一假设。促进学习的 AWC 神经肽信号、AIM 中的 CREB 活动和 LTAM 然后，我们将识别这些信号。相应的受体，它们在很大程度上是保守的、可药物化的靶标，可以在高等生物体中进行测试。最后，我们将执行一系列 AWC 驱动的行为来确定 AWC 神经肽信号传导的作用总的来说，这项研究将提供对分子的深入了解。与年龄相关的认知能力下降的基础，可能导致新的认知治疗靶点高等生物的损害。