Novel C. elegans associative learning and memory assays reveal that insulin/IGF-1 signaling and dietary restriction pathways differentially maintain age-related memory decline by influencing expression levels of the transcription factor CREB.
Of all the age-related declines, memory loss is one of the most devastating. While conditions that increase longevity have been identified, the effects of these longevity-promoting factors on learning and memory are unknown. Here we show that the C. elegans Insulin/IGF-1 receptor mutant daf-2 improves memory performance early in adulthood and maintains learning ability better with age but, surprisingly, demonstrates no extension in long-term memory with age. By contrast, eat-2 mutants, a model of Dietary Restriction (DR), exhibit impaired long-term memory in young adulthood but maintain this level of memory longer with age. We find that crh-1, the C. elegans homolog of the CREB transcription factor, is required for long-term associative memory, but not for learning or short-term memory. The expression of crh-1 declines with age and differs in the longevity mutants, and CREB expression and activity correlate with memory performance. Our results suggest that specific longevity treatments have acute and long-term effects on cognitive functions that decline with age through their regulation of rate-limiting genes required for learning and memory.
In humans, aging is often associated with a decline in cognitive function. Progress toward an understanding of the molecular mechanisms underlying the initiation and progression of age-related neuronal decline could be hastened by the development of experimental systems that quickly test early and true symptoms (rather than the correlative downstream effects) of neuronal decline and disease. In contrast to muscle degradation, the nervous system of C. elegans is structurally remarkably well-preserved, leaving open the question of how to define age-related changes in neuronal function. To address this problem, we have established a novel system to study associative learning, short-term associative memory, and long-term associative memory in C. elegans. Through chemotaxis assays, we measured worms' ability to learn a positive association of a neutral chemoattractant with food. We found that long-term, but not short-term, associative memory is dependent on crh-1, the C. elegans homolog of the transcription factor CREB. Furthermore, we find that worm learning and long-term associative memory decreases with age and is influenced differently by insulin/IGF-1 and Dietary Restriction longevity pathways. These effects can be largely attributed to changes in expression of crh-1, which correlate with memory performance.