Investigating neuropeptide signals that slow cognitive aging in C. elegans

摘要 平均预期寿命在上个世纪几乎翻了一番，导致认知衰退的速度加快 在老年人口中。因此，确定随年龄增长恢复记忆功能的机制至关重要。一 这种机制是激活cAMP反应元件结合蛋白(CREB)，它是一种高度保守的 长时联想记忆转录调节因子(LTAM)跨物种，CREB活性增加是 与随年龄增长的记忆力增强有关，但这种现象背后的机制尚不清楚- 明白了。最近对线虫的研究表明，来自单一感觉的增强神经肽信号 神经元，AWC，在幼年和老年动物中促进学习并延长CREB依赖的LTAM。 具体而言，需要扩展内存1。)AWC和2的神经肽分泌。)CREB在体内的活性 目的中间神经元是线虫记忆活动的既定部位。这些结果表明， 增加AWC神经肽信号可能会提高线虫的认知健康水平。然而，记忆- 促神经肽(S)及其作用机制是调节学习还是依赖CREB 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 增加AWC多肽释放显著降低交配卵孵化率--一种神经调节的 在老年动物中出现频率更高的表型-表明AWC肽信号也促进了 神经回路的健康寿命。虽然，AWC多肽信号如何调节其他生物的健康范围 神经元的表型还有待研究。根据这些发现，我们假设特定于AWC的 神经肽信号转导促进学习和CREB依赖记忆的增龄并延长神经元 线虫的健康寿命。我们将通过进行高度靶向的RNAi筛查来验证这一假设 AWC神经肽信号促进学习，AIM中CREB活性和LTAM。然后，我们将标识 相应的受体，这些受体在很大程度上是保守的、可用药的靶标，可以在高等生物体中进行测试。 最后，我们将执行一组AWC驱动的行为来确定AWC神经肽信号的作用 在延长神经元的健康跨度表型方面。总体而言，这项研究将提供对分子 年龄相关性认知功能下降的基础，可能导致认知功能的新治疗靶点 高等生物体中的损伤。

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.