Aging-dependent and -independent modulation of associative learning behavior by insulin/insulin-like growth factor-1 signal in Caenorhabditis elegans.

Mutations in the insulin/IGF-1 neuroendocrine pathway extend lifespan and affect development, metabolism, and other biological processes in Caenorhabditis elegans and in other species. In addition, they may play a role in learning and memory. Investigation of the insulin/IGF-1 pathway may provide clues for the prevention of age-related declines in cognitive functions. Here, we examined the effects of the life-extending (Age) mutations, such as the age-1 (phosphatidylinositol 3-OH kinase) and daf-2 (insulin/IGF-1 receptor) mutations, on associative learning behavior called isothermal tracking. This thermotaxis learning behavior associates paired stimuli, temperature, and food. The age-1 mutation delayed the age-related decline of isothermal tracking, resulting in a 210% extension of the period that ensures it. The effect is dramatic compared with the extension of other physiological health spans. In addition, young adults of various Age mutants (age-1, daf-2, clk-1, and eat-2) showed increased consistency of temperature-food association, which may be caused by a common feature of the mutants, such as the secondary effects of life extension (i.e., enhanced maintenance of neural mechanisms). The age-1 and daf-2 mutants but not the other Age mutants showed an increase in temperature-starvation association through a different mechanism. Increased temperature-food association of the daf-2 mutant was dependent on neuronal Ca2+-sensor ncs-1, which modulates isothermal tracking in the AIY interneuron. Interestingly, mutations in the daf-7 TGFbeta gene, which functions in parallel to the insulin/IGF-1 pathway, caused deficits in acquisition of temperature-food and temperature-starvation association. This study highlights roles of the Age mutations in modulation of certain behavioral plasticity.