The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that responds to proteostasis defects and stress conditions by tuning protein synthesis rates. While it has been long recognized that long-term memory formation requires new protein synthesis, our understanding of the central translational control mechanisms that regulate memory formation has advanced vastly. Indeed, novel causal and convergent evidence across different species and model systems shows that the ISR serves as a universal regulator of long-term memory formation. This chapter discusses the evidence explaining how inhibition of the ISR enhances long-term memory formation while activation of the ISR prevents it. In addition, it highlights the role of the ISR in different forms of long-lasting synaptic plasticity in the brain. Finally, the chapter addresses how dysregulated ISR signaling contributes to the pathogenesis of a wide range of cognitive and neurodegenerative disorders and discusses the future prospects for therapeutically targeting the ISR for the treatment of cognitive disorders.
Critical Time-Window for NO–cGMP-Dependent Long-Term Memory Formation after One-Trial Appetitive Conditioning