Neuromodulatory Control of Intrinsic Multiscale Brain Network Dynamics

Objective

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.