A Genetically Encoded Fluorescent Sensor for Rapid and Specific In Vivo Detection of Norepinephrine

Highlights

• GRAB_NE sensors are genetically encoded GPCR activation-based norepinephrine sensors

• GRAB_NE distinguishes norepinephrine from dopamine with 1,000-fold specificity

• The norepinephrine measurements are sensitive, with high spatiotemporal resolution

• Norepinephrine dynamics are observed during stressful behaviors in zebrafish and mice

Summary

Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRAB_NE) sensors with a 230% peak ΔF/F₀ response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral- or transgenic-mediated expression of GRAB_NE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRAB_NE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.

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