Investigating neuropeptide signals that slow cognitive aging in C. elegans

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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.