Neuromodulatory Control of Intrinsic Multiscale Brain Network Dynamics

Spontaneous brain activity as assessed with resting-state fMRI (rsfMRI) is increasingly used as an index of interregional braincommunication and functional connectivity in health and disease.

However, the physiological underpinnings of brain-wide rsfMRIcoupling, and the neural effectors of its dynamic reconfiguration, remain undetermined.

Recent investigations, including my ownwork, have crucially shown that rsfMRI large-scale activity in the mammalian brain is critically shaped by a limited set of recurrentwave-like spatiotemporal patterns.

Further investigations by us and others point at a putative link between global patterns of brainactivity and fluctuations in internal states linked to arousal.

These observations suggest that the dynamics and specific spatialtopography of rsfMRI network dynamics could be critically shaped by the intrinsic activity of ascending neuromodulatory systems likeAcetylcholine (ACh) or Noradrenaline (NA).

This project aims to formally test this hypothesis via a first-of-its-kind multiscale,multimodal investigation of whole-brain rsfMRI activity and intrinsic neurotransmitter function as assessed with mesoscopic imagingof genetically-encoded ACh and NA fluorescent sensors in the awake mouse brain.

To causally link these two phenomena, I willsystematically modulate general arousal levels, and probe neurotransmitter specificity via pharmacological and chemogeneticmanipulations.

Importantly, dual-color mesoscale calcium and ACh or NE imaging will be coupled to rsfMRI mapping to disentanglethe tripartite relationship between local and global neuromodulatory tone, neural activity, and network dynamics.

These studies willshed light on the neural drivers and functional significance of rsfMRI signal, with important implications for the use of this method tomap functional connectivity in health and disease.