Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice

Abstract

Always stressed The integrated stress response (ISR) plays a role in proteostasis and is important in the brain for learning and memory. Typically, the pathway is thought to be activated transiently to fulfill these roles but may become persistent in disease states. Helseth et al. developed a reporter to study ISR activation brainwide and found a class of cells that engage ISR for steady-state cell function (see the Perspective by Ingebretson and Lemos). In mice, cholinergic interneurons required the ISR to maintain properties of tonic firing and response to dopamine. Inhibiting the ISR in these cells changed dopamine neuromodulation and enhanced performance in learned tasks. Thus, ISR engagement can play a steady-state role that is independent of cell stress and important in learning. Science , this issue p. eabe1931 ; see also p. 345