Increased fMRI connectivity upon chemogenetic inhibition of the mouse prefrontal cortex

Federico Rocchi,Alberto Galbusera,Carola Canella,Alexia Stuefer,Alessandro Gozzi,Massimo Pasqualetti,Stefano Vassanelli,Ludovico Coletta,Shahryar Noei,Daniel Gutierrez-Barragan,Giuliano Iurilli,Stefano Panzeri

doi:10.1038/s41467-022-28591-3

Abstract

While shaped and constrained by axonal connections, fMRI-based functional connectivity reorganizes in response to varying interareal input or pathological perturbations. However, the causal contribution of regional brain activity to whole-brain fMRI network organization remains unclear. Here we combine neural manipulations, resting-state fMRI and in vivo electrophysiology to probe how inactivation of a cortical node causally affects brain-wide fMRI coupling in the mouse. We find that chronic inhibition of the medial prefrontal cortex (PFC) via overexpression of a potassium channel increases fMRI connectivity between the inhibited area and its direct thalamo-cortical targets. Acute chemogenetic inhibition of the PFC produces analogous patterns of fMRI overconnectivity. Using in vivo electrophysiology, we find that chemogenetic inhibition of the PFC enhances low frequency (0.1–4 Hz) oscillatory power via suppression of neural firing not phase-locked to slow rhythms, resulting in increased slow and δ band coherence between areas that exhibit fMRI overconnectivity. These results provide causal evidence that cortical inactivation can counterintuitively increase fMRI connectivity via enhanced, less-localized slow oscillatory processes.

Highlights

1,5, Giuliano Iurilli[6], While shaped and constrained by axonal connections, fMRI-based functional connectivity reorganizes in response to varying interareal input or pathological perturbations
To test this prediction and more broadly investigate how resting state” fMRI (rsfMRI) dynamically reconfigures in response to local neural suppression, we carried out rsfMRI measurements in a cohort of mice in which neuronal activity in prefrontal cortex (PFC) was chronically inhibited via bilateral viral transduction of the inward rectifying potassium channel Kir2.1 (Fig. 1a)
Our interest in the PFC was motivated by its translational relevance as a key component of the mouse default mode network (DMN), a major phylogenetically conserved rsfMRI network that in rodents is composed of three hubs, namely the PFC, the retrosplenial cortex, and the medial thalamus[4]

Summary

Introduction

1,5, Giuliano Iurilli[6], While shaped and constrained by axonal connections, fMRI-based functional connectivity reorganizes in response to varying interareal input or pathological perturbations. Growing experimental evidence suggests that, while tightly constrained by underlying anatomy, rsfMRI connectivity may only partially reflect direct interactions between areas, as widespread BOLD signal modulation might arise via subcortical connections, whether through the thalamus via long-range loops[11], or as a result of diffuse neuromodulation mediated by brainstem nuclei[12,13] This notion is epitomized by the observation of intact rsfMRI coupling among brain regions not directly structurally connected as in the case of acallosal humans, primates, and rodents[7,14,15]. Neurological disorders such as Parkinson’s disease, stroke, and Alzheimer’s disease have been often found to be associated with unexpectedly increased interareal rsfMRI connectivity despite the loss of cortical function characterizing these conditions[18,19] Taken together, these observations point at a complex relationship between interareal brain activity and rsfMRI coupling, and call for a deeper investigation of the neural mechanisms underlying the reconfiguration of rsfMRI connectivity in response to varying interareal input or pathological perturbations. These findings reveal a highly dynamic, non-monotonic relationship between regional cortical activity and network-wide rsfMRI connectivity, and provide an interpretative framework for the observation of counterintuitively increased rsfMRI connectivity in pathological conditions characterized by impaired cortical function

Methods

Results

Conclusion