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bioRxiv · 10.1101/2020.08.05.237453

Phasic oxygen dynamics underlies fast choline-sensitive biosensor signals in the brain of behaving rodents

Santos, R. M.·Sirota, A.
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Abstract

Fast time-scale modulation of synaptic and cellular physiology by acetylcholine is critical for many cognitive functions, but direct local measurement of neuromodulator dynamics in freely-moving behaving animals is technically challenging. Recent in vivo brain measurements using choline oxidase (ChOx)-based electrochemical biosensors have reported surprising fast cholinergic transients associated with reward-related behavioral events. However, in vivo recordings with conventional ChOx biosensors could be biased by phasic local field potential and O2-evoked enzymatic responses. Here, we have developed a Tetrode-based Amperometric ChOx (TACO) sensor enabling minimally invasive artifact-free simultaneous measurement of cholinergic activity and O2. Strikingly, the TACO sensor revealed highly-correlated O2 and ChOx transients following spontaneous locomotion and sharp-wave/ripples fluctuations in the hippocampus of behaving rodents. Quantitative analysis of spontaneous activity, in vivo and in vitro exogenous O2 perturbations revealed a directional effect of O2 on ChOx phasic signals. Mathematical modeling of biosensors identified O2-evoked non-steady-state ChOx kinetics as a mechanism underlying artifactual biosensor phasic transients. This phasic O2-dependence of ChOx-based biosensor measurements confounds phasic cholinergic dynamics readout in vivo, challenging previously proposed ACh role in reward-related learning. The discovered mechanism and quantitative modeling is generalizable to any oxidase-based biosensor, entailing rigorous controls and new biosensor designs.

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Santos, R. M., Sirota, A.. 2020-08-06. Phasic oxygen dynamics underlies fast choline-sensitive biosensor signals in the brain of behaving rodents. https://doi.org/10.1101/2020.08.05.237453

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