P-DOpE probes reveal local amplification of phasic noradrenergic release in the hippocampus

Abstract

Fiber photometry (FP) has become a tool of choice for in vivo monitoring of genetically encoded biosensors. The ability to record and optogenetically manipulate circuits through the same fiber stub is powerful, but limited, as biosensors typically do not sample membrane voltage, leaving the experimenter blind to the direct effects of opsin photoactivation. Here we developed the Photometry Device with Optogenetics and Electrophysiology (P-DOpE) probe, fabricated via a new convergence taper-break (CTB) method that integrates industry-standard silica optical waveguides with low-impedance metal electrodes that can be arranged in experimenter-defined configurations. We demonstrate that chronically implanted P-DOpE probes provide months-long recordings of local field potential, single unit recording, and fiber photometry, with parallel optogenetic circuit perturbation. Conducting fiber photometry with same-site optogenetic stimulation, we identified a robust fluorescence signal that scaled with network activity and survived biosensor antagonism. As this confound could not be eliminated with standard isosbestic controls, we propose a simple correction strategy. As a first application, we used the probe to test a proposed mechanism for focal modulation of noradrenergic signaling in and by cortical circuits receiving afferents from the locus coeruleus. We found that increasing spiking activity in CA1 amplifies noradrenergic signaling evoked by contextual arousal by [~]50%, but does not induce norepinephrine release in the absence of a phasic trigger - thus supporting the central prediction of the glutamate amplifies noradrenergic effects (GANE) hypothesis. The P-DOpE probe thus enables optogenetic manipulation and multimodal readout in a configurable low-cost, scalable, and robust format.