Wei-Ting Zhang

The default mode network (DMN) is critical for self-referential mental processes, and its dysfunction is implicated in many neuropsychiatric disorders. However, the neurophysiological properties and task-based functional organization of the rodent DMN are poorly understood, limiting its translational utility. Here, we combine fiber photometry with functional magnetic resonance imaging (fMRI) and computational modeling to characterize dynamics of putative rat DMN nodes and their interactions with the anterior insular cortex (AI) of the salience network. Our analysis revealed neuronal activity changes in AI and DMN nodes preceding fMRI-derived DMN activations and cyclical transitions between brain network states. Furthermore, we demonstrate that salient oddball stimuli suppress the DMN and enhance AI neuronal activity and that the AI causally inhibits the retrosplenial cortex, a prominent DMN node. These findings elucidate the neurophysiological foundations of the rodent DMN, its spatiotemporal dynamical properties, and modulation by salient stimuli, paving the way for future translational studies.

The default mode network (DMN) of the brain is functionally associated with a wide range of behaviors. 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 mouse DMN. Chemogenetic-induced tonic LC 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 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.

Our interpretation of functional MRI data is built on the assumption that neuronal and vascular responses are tightly coupled.^1,2 The process by which changes in local neural activity lead to changes in cerebral blood flow (CBF) and blood volume³ is often termed neurovascular coupling and this relationship can be described mathematically with a hemodynamic response function (HRF). Early fMRI studies typically assigned a single canonical human HRF across brain regions (hereafter as canonical HRF), derived from two gamma functions.⁴ However, emerging evidence shows that neurovascular coupling can be substantially different between species, brain regions, and physiological conditions.^{5 – 10} Thus, use of the canonical HRF could lead to inaccurate interpretation of fMRI data, especially in preclinical studies that often utilize anesthetized non-human species. Some recent fMRI studies have adapted to use empirically derived HRFs (hereafter as empirical HRFs), but these current approaches have notable limitations (to be discussed in the next paragraph), and a majority of studies still rely on the canonical HRF.^{11 – 13} Therefore, the development of techniques to acquire flexible, accessible, brain-region specific HRF is paramount as the number of hemodynamic animal studies continues to grow.