The tryptophan metabolite kynurenic acid is a neuromodulator mediating learning, brain aging, and neurodegeneration

The ability to change behaviors based on past experience is one of the most important and complex functions of the brain. Elucidating how activity of molecules, cells, and circuits all ultimately control learning and memory is difficult, and the simplicity of the nematode C. elegans offers an opportunity to connect these lower-level changes to full-scale changes in behavior. This allows for a depth of understanding of the brain’s biology that is largely impossible in other model organisms. Here we show that the tryptophan metabolite kynurenic acid (KYNA) functions as an inhibitory neuromodulator, communicating information about peripheral physiology to the nervous system to alter behavior. We have found that dietary restriction and many pathways involved in the body’s responses to dietary restriction – long known to affect brain function – enhance learning in C. elegans because they reduce production of KYNA, releasing KYNA-induced inhibition of neuronal activity in a specific pair of interneurons required for learning. In contrast, KYNA production increases with age, accounting for a significant portion of the decline in learning that occurs as animals get older. Furthermore, a C. elegans model of neurodegeneration may also increase KYNA production to impair learning. These studies demonstrate that metabolism can regulate brain function, having profound effects on cellular activity, learning, and memory. They establish that KYNA production is a crucial physiological indicator of peripheral status to the nervous system, offering insight into how the brain integrates information to direct behavior