Activity-dependent constraints on catecholamine signaling

Catecholamine signaling is thought to modulate cognition in an inverted-U relationship, but the mechanisms are unclear. We measured norepinephrine and dopamine release, postsynaptic calcium responses, and interactions between tonic and phasic firing modes under various stimuli and conditions. High tonic activity in vivo depleted catecholamine stores, desensitized postsynaptic responses, and decreased phasic transmission. Together, these findings provide a more complete understanding of the inverted-U relationship, offering insights into psychiatric disorders and neurodegenerative diseases with impaired catecholamine signaling. [Display omitted] •Activity-dependent catecholamine depletion is shown in vivo using 2nd-generation biosensors•Differing pools of norepinephrine and of dopamine are revealed by repletion kinetics•Phasic norepinephrine release is constrained by the level of tonic release•Stress-induced norepinephrine release causes postsynaptic changes in neuronal firing Li et al. demonstrate activity-dependent catecholamine depletion in vivo using the newer generation of genetically encoded fluorescent norepinephrine and dopamine sensors. Additionally, they identify two pools of the respective catecholamine based on differing repletion kinetics and show an inverse relationship between tonic and phasic catecholamine release.