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

Journal Article (Journal Article)

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 brainwide imaging of ISR state with cellular resolution. Unexpectedly, we found a class of neurons in mouse brain, 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 noncanonical, steady-state mode of ISR activation is found in CINs, revealing a neuromodulatory role for the ISR in learning.

Full Text

Duke Authors

Cited Authors

  • Helseth, AR; Hernandez-Martinez, R; Hall, VL; Oliver, ML; Turner, BD; Caffall, ZF; Rittiner, JE; Shipman, MK; King, CS; Gradinaru, V; Gerfen, C; Costa-Mattioli, M; Calakos, N

Published Date

  • April 23, 2021

Published In

Volume / Issue

  • 372 / 6540

PubMed ID

  • 33888613

Pubmed Central ID

  • PMC8457366

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.abe1931


  • eng

Conference Location

  • United States