A chemogenetic approach for dopamine imaging with tunable sensitivity
Marie A. Labouesse, Maria Wilhelm, Zacharoula Kagiampaki, Andrew G. Yee, Raphaëlle Denis, Masaya Harada, Andrea Gresch, A Marinescu, Kanako Otomo, Sebastiano Curreli, Laia Serratosa Capdevila, Xuehan Zhou, Reto B. Cola, Luca Ravotto, Chaim Glück, Stanislav M. Cherepanov, Bruno Weber, Xin Zhou, Jason Katner, Kjell Svensson, Tommaso Fellin, Louis‐Éric Trudeau, Christopher Ford, Yaroslav Sych, Tommaso Patriarchi
Abstract
Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.