Neuronal sensation of extracellular acidosis relies on acid-sensitive ion channels (ASICs) on the cell membrane surface. Unlike classical voltage- or ligand-gated ion channels, ASICs belong to a novel superfamily of ion channels whose biological functions and operating principles are unclear. In the light of this scientific frontier, our series of new functional, mechanistic and ligand studies suggest that ASICs may constitute new "low toxicity" neuroprotective targets for several major neurological diseases such as stroke and chronic pain. In addition, we have systematically elucidated the relationship between ASIC signaling and neuroplasticity, and resolved the neural circuitry basis and ion channel mechanisms underlying the dynamic regulation of sensory perception, learning and memory, which provides new ideas for understanding the brain cognitive neural network mechanism in normal and disease states.