Chemogenetic Stimulation of Tonic Locus Coeruleus Activity Strengthens the Default Mode Network

Abstract

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.

Neuronal dynamics of the default mode network and anterior insular cortex: Intrinsic properties and modulation by salient stimuli

“…We used an fMRI-compatible, spectrally resolved, fiber-photometry platform (Bao et al, 2020; Chao et al, 2022; Das et al, 2021; Meng et al, 2018; Oyarzabal et al, 2022; Zhang et al, 2022b, 2022a) with four recording fibers ( Figure 1A ) to measure neuronal GCAMP activity in the RSC, Cg, PrL, and AI from rats ( Supplementary Figure 1 ). GCaMP activity was combined with whole-brain fMRI recordings in anesthetized rodents to capture concurrent resting-state signals from both modalities ( Figure 1A ).…”

“…The first goal of our study was to investigate intrinsic neuronal coupling between putative rodent DMN nodes in the resting state condition. While studies using resting-state fMRI have suggested that the rat DMN is comprised of the RSC, Cg, and PrL (Gozzi and Schwarz, 2016;Hsu et al, 2016;Ji et al, 2018;Lee et al, 2021;Liang et al, 2018;Lu et al, 2012;Osmanski et al, 2014;Oyarzabal et al, 2022;Paasonen et al, 2018;Peeters et al, 2020a;Tu et al, 2021bTu et al, , 2021aXu et al, 2022), such coupling…”

“…While studies using resting-state fMRI have suggested that the rat DMN is comprised of the RSC, Cg, and PrL (Gozzi and Schwarz, 2016; Hsu et al, 2016; Ji et al, 2018; Lee et al, 2021; Liang et al, 2018; Lu et al, 2012; Osmanski et al, 2014; Oyarzabal et al, 2022; Paasonen et al, 2018; Peeters et al, 2020a; Tu et al, 2021b, 2021a; Xu et al, 2022), such coupling has not yet been demonstrated at the neuronal scale. Our findings using static time-averaged functional connectivity analysis are in general agreement with prior literature, showing strong coupling between RSC, Cg, and PrL in the anesthetized rat brain (Gozzi and Schwarz, 2016; Hsu et al, 2016; Ji et al, 2018; Lee et al, 2021; Liang et al, 2018; Lu et al, 2012; Osmanski et al, 2014; Oyarzabal et al, 2022; Paasonen et al, 2018; Peeters et al, 2020a; Tu et al, 2021b, 2021a; Xu et al, 2022), as well as anesthetized mouse brains (Belloy et al, 2021; Coletta et al, 2020; Ferrier et al, 2020; Gozzi and Schwarz, 2016; Grandjean et al, 2017, 2020; Gutierrez-Barragan et al, 2019; Liska et al, 2015; Mandino et al, 2022; Stafford et al, 2014; Vanni et al, 2017; Whitesell et al, 2021). Additionally, our analysis revealed that RSC, Cg and PrL exhibit similar time-locked neuronal activity patterns while the AI displays neuronal antagonism with these regions in relation to fMRI-derived DMN activation and deactivation.…”

“…Likewise, chemogenetically enhanced low frequency power of neuronal activity in the PrL strengthens DMN connectivity in mice (Rocchi et al, 2022). Increased neuronal spiking in the Cg has also been associated with strengthened functional connectivity within the frontal DMN nodes, as well as between frontal and association cortex DMN nodes in mice (Oyarzabal et al, 2022).…”

Multiple Intrinsic Membrane Properties are Modulated in a Switch from Single to Dual-Network Activity

“…Neuromodulation is suggested to elicit rapid rhythmic network reconfiguration among larger circuits as well. For example, norepinephrine appears to contribute to rapid changes in synchronization of multiple vertebrate brain regions during switches in attention (Bouret and Sara 2005; Oyarzabal et al 2022; Ramirez et al 2016). Disordered inter-network coordination and decreased flexibility in oscillatory networks can lead to dysphagia, memory and locomotor deficits, and disruption of cognitive processes (Barlow 2009; Moore et al 2014; Rangel et al 2016).…”