Cholinergic neurons engage the integrated stress response for dopamine modulation and skill learning

The integrated stress response (ISR) maintains proteostasis by modulating protein synthesis and is important in synaptic plasticity, learning and memory. We developed a reporter (SPOTlight) for brain-wide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brains, striatal cholinergic interneurons (CINs), in which the ISR was activated at steady-state. Genetic and pharmacological manipulations revealed that ISR signaling was necessary in CINs for normal type 2 dopamine receptor (D2R) modulation. Inhibiting the ISR inverted the sign of D2R modulation of CIN firing and evoked dopamine release and altered skill learning. Thus, a non-canonical, steady-state mode of ISR activation is found in CINs and the ISR plays a neuromodulatory role in learning. Striatal cholinergic interneurons have high steady-state ISR activation that regulates dopamine modulation and skill learning.