Memory has been widely studied for its crucial role in learning and its diverse range of expression. Although the means of acquisition differ, it is generally accepted that memory goes through three encoding stages: sensory, short-term and long-term memory. The retention of memory is important as it enables us to act with the wisdom of past experience. However, although one could not survive without memory, remembering everything is also devastating. In fact, forgetting is an important cognitive feature that allows us to adapt to the constantly changing environments. Despite its importance for cognition, little is known about the molecular nature of forgetting. Here, we investigated the genes behind forgetting by studying an olfactory memory in the nematode C. elegans. Like human, worms can modify their behavior upon acquiring unpleasant experience – their movement towards preferred odor is significantly reduced after prolonged exposure to the odor during starvation. Upon returning to food (e. coli OP50), the odor attraction slowly returns to the worms within 3-4 hours, indicating a diminishing impact of the starvation experience. By contrast, the forgetting process was significantly accelerated by 1-2 hours, when worms were cultivated on pathogenic bacteria, pseudomonas aeruginosa PA14. Our genetic studies showed that a null mutation to the daf-16 gene restored recovery time to 3-4 hours, despite of the exposure to PA14. These data indicate that daf-16 plays a positive role in accelerated memory loss upon pathogen ingestion. Because DAF-16 is involved in innate immunity and stress response, our results provide a potential connection that couples the memory to environmental stressors.

Learning and forgetting are two key processes that keep our memories in balance. In the past few decades, we have learned a great deal about mechanisms associated with memory formation and consolidation. However, little is known about the molecular mechanisms of forgetting, despite its importance in human health. Here, we take advantage of the nematode C. elegans – a living animal with a simple nervous system of 302 neurons – to explore the mechanisms behind forgetting. In particular, we focus on the decay of associative olfactory learning and the regulation of this decay after experience of pathogenic bacteria. Previous studies have shown that worms acquire an associative memory linking starvation experience and the olfactory response. After prolonged exposure to a preferred odor during starvation, worms exhibit a diminished response towards the preferred odor. However, upon returning to a food source, the attractive response toward the preferred odor recovers within 3-4 hours, indicating the loss of the associative olfactory memory. We found that the rate of memory loss, quantified by measuring the time course of recovery of the olfactory response, depends on the type of food source (bacterial strain) that worms experience. Specifically, exposing worms to pathogenic bacteria PA14, compared to the regular food source OP50, leads to a quicker loss of the associative olfactory memory. Our results further show that the acceleration of memory loss is mediated by a conserved transcription factor DAF-16/FOXO, as daf-16 mutants exhibited similar rates of memory loss regardless of OP50 or PA14 experience. Together, these findings demonstrate an unexpected role of DAF-16/FOXO in memory decay induced by exposure to pathogens.