Oyarzabal, E. A. | Search bioRxiv

bioRxiv2021

Chemogenetic activation of Locus Coeruleus Noradrenergic Neurons Modulates the Default Mode Network

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

neuroscience↗

bioRxiv2021

Spectral fiber-photometry derives hemoglobin-absorption changes for accurate measurement of fluorescent sensors

Fiber-photometry is an emerging technique for recording fluorescent sensor activity in the brain. However, significant hemoglobin-absorption artifacts in fiber-photometry data may be misinterpreted as sensor activity changes. Because hemoglobin exists in nearly every location in the brain and its concentration varies over time, such artifacts could impede the accuracy of many photometry recording results. Here we present a novel use of spectral photometry technique and propose computational methods to quantify photon absorption effects by using activity-independent fluorescence signals, which can be used to derive oxy- and deoxy-hemoglobin concentration changes. Following time-locked neuronal activation in vivo, we observed that a 20% increase in CBV contributes to about a 4% decrease in green fluorescence signal and a 2% decrease in red fluorescence signal. While these hemoglobin concentration changes are often temporally delayed than the fast-responding fluorescence spikes, we found that erroneous interpretation may occur when examining pharmacology-induced sustained activity changes, and in some cases, hemoglobin-absorption could flip the GCaMP signal polarity. We provided hemoglobin-based correction methods to restore fluorescence signals across spectra and compare our results against the commonly used regression approach. We also demonstrated the utility of spectral fiber-photometry for delineating brain regional differences in hemodynamic response functions. HighlightsO_LIHemoglobin-absorption compromises fiber-photometry recording in vivo C_LIO_LISpectral photometry allows quantification of hemoglobin concentration changes for correction C_LIO_LIThe proposed platform allows measuring regional differences in neurovascular transfer function C_LI

neuroscience↗