HE ERC Consolidator Grant 2025-2029

Neuromodulatory control of brain network dynamics

Abstract: Spontaneous brain activity, the most expensive metabolic process of the human brain, is highly dynamic and continually evolves over timescales of seconds. Human neuroimaging has made it possible to map dynamic patterns of spontaneous network activity with increasing precision. However, our understanding of the origin, function and organization of this phenomenon remains alarmingly limited. This project aims to elucidate the physiological mechanisms and operational principles that govern spontaneous network dynamics (termed here "brain network dynamics" - BND). To achieve these goals, I will establish an integrated research platform that combines advanced manipulations and recordings of BND in the awake mouse brain. To comprehensively probe the mechanisms that operate BND, I will carry out two complementary sets of causal manipulations that are conceptualized as exogenous or endogenous neuromodulation, depending on whether they encompass synthetic (optogenetically generated, Aim 1) or intrinsic (neurotransmitter related, Aim 2) modulatory mechanisms, respectively. Using this approach, I will (a) uncover the rhythms that causally sustain BND, and establish how BND causally responds to (and can be controlled by) mechanistically-precise exogenous neuromodulation; (b) empirically test the hypothesis that cholinergic and noradrenergic transmission cooperatively control the intrinsic organization of BND, as well the selective engagement of higher-order cortical systems relevant for attention and cognition. Crucially, multiscale network activity will be theoretically linked to dynamical regimes (brain states) of translational relevance via quantitative analyses. This research will address fundamental questions regarding the neural mechanisms governing BND and the possibility of controlling its organization via targeted exogenous modulation, with important implications for basic, theoretical and translational neuroscience.

Total budget: 1.791.875,00€

Total contribution: 1.791.875,00€

H2020 ERC - Starting Grant 2019-2024

Neural drivers of functional disconnectivity in brain disorders

Abstract: A rapidly expanding approach to understanding neural organization is to map patterns of spontaneous neural activity as an index of functional communication and connectivity across brain regions. Fostered by the advent of neuroimaging methods like resting-state fMRI (rsfMRI), this approach has revealed that functional connectivity is almost invariably disrupted in severe psychiatric disorders, such as autism or schizophrenia. However, the neural basis of such functional disconnectivity remains mysterious. What drives brain-wide functional synchronization? And are there shared pathophysiological mechanisms leading to impaired large-scale neural coupling? This project aims to elucidate the neural drivers of macroscale functional connectivity, as well as its breakdown in brain connectopathies. To achieve this goal, I propose a multi-scale perturbational approach to establish causal relationships between specific neural events and brain-wide functional connectivity via a novel combination of rsfMRI and advanced neural manipulations and recordings in the awake mouse. By directionally silencing functional hubs as well as more peripheral cortical regions, I will provide a hierarchical description of spontaneous network organization that will uncover regional substrates vulnerable to network disruption. I will also manipulate physiologically-distinct excitatory or inhibitory populations to probe a unifying mechanistic link between excitatory/inhibitory imbalances and aberrant functional connectivity. Finally, to account for the hallmark co-occurrence of synaptic deficits and functional disconnectivity in developmental disorders, I will link cellular mechanisms of synaptic plasticity and learning to the generation of canonical and aberrant spontaneous activity patterns. These studies will pave the way to a back-translation of aberrant functional connectivity into interpretable neurophysiological events and models that can help understand, diagnose or treat brain disorders.

Total budget: 1.498.125,00€

Total contribution: 1.498.125,00€