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.

综合应激反应 (ISR) 通过调节蛋白质合成来维持蛋白质稳态，并且在突触可塑性、学习和记忆中很重要。我们开发了一种报告器 SPOTlight，用于以细胞分辨率对 ISR 状态进行全脑成像。出乎意料的是，我们在小鼠大脑中发现了一类神经元，即纹状体胆碱能中间神经元 (CIN)，其中 ISR 在稳定状态下被激活。遗传和药理学操作表明，ISR 信号在 CIN 中对于正常的 2 型多巴胺受体 (D2R) 调节是必需的。抑制 ISR 会反转 D2R 调制 CIN 放电的信号，并诱发多巴胺释放和技能学习改变。因此，在 CIN 中发现了一种非规范的、稳态的 ISR 激活模式，揭示了 ISR 在学习中的神经调节作用。