Neuromodulatory Control of Intrinsic Multiscale Brain Network Dynamics

Obiettivo

Spontaneous brain activity as assessed with resting-state fMRI (rsfMRI) is increasingly used as an index of interregional brain
communication and functional connectivity in health and disease. However, the physiological underpinnings of brain-wide rsfMRI
coupling, and the neural effectors of its dynamic reconfiguration, remain undetermined. Recent investigations, including my own
work, have crucially shown that rsfMRI large-scale activity in the mammalian brain is critically shaped by a limited set of recurrent
wave-like spatiotemporal patterns. Further investigations by us and others point at a putative link between global patterns of brain
activity and fluctuations in internal states linked to arousal. These observations suggest that the dynamics and specific spatial
topography of rsfMRI network dynamics could be critically shaped by the intrinsic activity of ascending neuromodulatory systems like
Acetylcholine (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 imaging
of genetically-encoded ACh and NA fluorescent sensors in the awake mouse brain. To causally link these two phenomena, I will
systematically modulate general arousal levels, and probe neurotransmitter specificity via pharmacological and chemogenetic
manipulations. Importantly, dual-color mesoscale calcium and ACh or NE imaging will be coupled to rsfMRI mapping to disentangle
the tripartite relationship between local and global neuromodulatory tone, neural activity, and network dynamics. These studies will
shed light on the neural drivers and functional significance of rsfMRI signal, with important implications for the use of this method to
map functional connectivity in health and disease.