Chemogenetic modulation of fMRI connectivity
Creators: name: Rocchi, Federico
Publisher: name: Universit� degli studi di Trento
Year: 2022

description: Resting-state fMRI (rsfMRI) has been widely used to map intrinsic brain network organization of the human brain both in health and in pathological conditions. However, the neural underpinnings and dynamic rules governing brain-wide rsfMRI coupling remain unclear. Filling this knowledge gap is of crucial importance, given our current inability to decode and reverse-engineer clinical signatures of aberrant connectivity into interpretable neurophysiological events that can help understand or diagnose brain disorders. Toward this goal, here we combined chemogenetics, rsfMRI, and in vivo electrophysiology in the mouse to investigate how regional manipulations of brain activity (i.e. neural inhibition, or excitation) causally contribute to whole-brain fMRI network organization. In a first set of proof of concept investigations, we empirically probed the widely held notion that neural inhibition of a cortical node would result in reduced fMRI coupling of the silenced area and its long-range terminals. Surprisingly, we found that chronic inhibition of the mouse medial prefrontal cortex (PFC) via viral overexpression of a potassium channel paradoxically increased fMRI connectivity between the inhibited area and its direct thalamo-cortical targets. Notably, acute chemogenetic inhibition of the PFC reproduced analogous patterns of fMRI overconnectivity. Using in vivo electrophysiology, we found 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 ? 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, with important implications for neural modeling and interpretation of fMRI overconnectivity in brain disorders. Importantly, our observation that neural inhibition of the PFC results in fMRI overconnectivity allowed us to predict that neural activation of the same area might produce opposite results, i.e. fMRI underconnectivity and neural desynchronization. To test this hypothesis, we used chemogenetics to increase local excitatory-inhibitory (E/I) balance in the PFC. As predicted, chemogenetic stimulation of CamkII-expressing neurons, or inhibition of fast-spiking parvalbumin-expressing neurons, produced similar rsfMRI signatures of rsfMRI underconnectivity. Both manipulations produced analogous electrophysiological signatures characterized by increased firing activity and a robust LFP power shift towards higher (i.e. ?) frequencies, effectively reversing the corresponding neural signature observed in DREADD inhibition studies. Importantly, the same E/I affecting perturbations were also associated with socio-communicative deficits in behaving mice hence underscoring the behavioral relevance of the employed manipulations. These results show that excitatory/inhibitory balance critically biases brain-wide fMRI coupling, pointing at a possible unifying mechanistic link between E/I imbalance and rsfMRI connectivity disruption in developmental disorders. More broadly, these investigations reveal a set of fundamental rules linking regional brain activity to macroscale functional connectivity, offering opportunities to physiologically interpret rsfMRI signatures of functional dysconnectivity in human brain disorders.