Protein lactylation induced by neural excitation

Lactate has diverse roles in the brain at the molecular and behavioral levels under both physiological and pathophysiological conditions. It is unknown whether a novel post-translational modification called lysine lactylation (Kla), recently discovered in macrophages, occurs in brain cells and if it does, whether Kla is induced by the stimuli that accompany changes in lactate levels. Herein, we reveal that Kla in brain cells is regulated by neural excitation and social stress, paralleled with changes in lactate levels. These stimuli increased Kla, which were associated with expression of neuronal activity marker c-Fos, as well as with decrease of social behavior and increase of anxiety-like behavior in the stress model. Further, we identified 63 candidate lysine-lactylated proteins and found that the stress preferentially increased histone H1 Kla. This study may open up an avenue for exploration of a novel role of neuronal activity-induced lactate mediated by protein lactylation in the brain.