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

• DOI: 10.1126/science.abe1931
• Publication Date: 2021-04-22T19:18:34Z
• Authors: Ashley R. Helseth; Ricardo Hernandez...; Victoria L. Hall; Matthew L. Oliver; Brandon D. Turner; Zachary F. Caffall; Joseph E. Rittiner; Miranda K. Shipman; Connor S. King; Viviana Gradinaru; Charles Gerfen; Mauro Costa-Mattioli; Nicole Calakos
• Keywords: Neuromodulation

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