The Garcia Effect: A Translational and Multidisciplinary Approach to Studying This Higher Form of Learning with Deep Evolutionary Roots

Most of us have tried a new food and later felt sick. While factors like improper preparation might be the actual cause, we instinctively ‘blame’ the new food, avoiding it in the future as even the thought evokes nausea. What makes this link between a novel taste and illness so strong that it overrides other experiences? The first clues emerged during World War II when ecologist C.S. Elton observed that rodents, after consuming poisoned bait, avoided it for weeks, even after recovering. This phenomenon, known as “bait-shyness,” was soon used in pest control. In 1951, Dr. John Garcia revealed its broader implications, coining the term "the Garcia effect." His experiments showed that rodents rapidly develop a long-lasting, taste-specific aversion to a new food causing illness, even with a significant delay between ingestion and symptoms. By the 1970s, clinical studies extended these findings to humans, highlighting its role in conditions like chemotherapy-induced nausea. Despite its significance, research into the Garcia effect has declined over the last two decades. Long thought to be exclusive to mammals, we recently demonstrated its existence in an invertebrate, the pond snail (Lymnaea stagnalis). Sickness was induced by injecting snails with the bacterial endotoxin lipopolysaccharide (LPS), leading to a long-lasting, taste-specific Garcia effect. Molecular analyses revealed that LPS significantly upregulated immune-related genes such as Toll-like Receptor 4 (TLR4), consistent with mammalian studies. While LPS alone did not alter neuroplasticity-related gene expression, pairing it with taste conditioning upregulated key genes involved in learning and memory, including glutamate receptor subunits (LymGRIN1, LymGRIN2A, LymGRIN2B) and the transcription factor LymCREB1. Strain-specific differences in long-term memory (LTM) were observed: laboratory-inbred snails exhibited a 24-hour LTM, whereas freshly collected snails and their first-generation offspring formed a 48-hour LTM. Moreover, pre-treatment with aspirin (a non-steroidal anti-inflammatory drug) before LPS injection blocked both the sickness state and the Garcia-like effect at behavioral and molecular levels. These findings pave the way for translational and ecological studies aimed at characterizing the conserved mechanisms underlying this form of learning with deep evolutionary roots, which can be used to address a range of different biological questions.