P059 Modeling Cholinergic Heterogeneity in Whole-Brain Cortical Dynamics: Bridging Local Circuits to Global State Transitions
Leonardo Dalla Porta*1, Jan Fousek2, Alain Destexhe3, Maria V. Sanchez-Vives1,4
1Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic
3Institute of Neuroscience (NeuroPSI), Paris-Saclay University, Paris, France
4Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
*Email: dallaporta@recerca.clinic.cat
Introduction
The wake-sleep cycle consists of fundamentally distinct brain states, including slow-wave sleep (SWS) and wakefulness. During SWS, the cerebral cortex exhibits large, low-frequency fluctuations that propagate as traveling waves [1]. In contrast, wakefulness is characterized by the suppression of low-frequency activity and the emergence of asynchronous, irregular dynamics. While neurotransmitters such as acetylcholine (ACh) are known to regulate the wake-sleep cycle, the mechanisms by which local neuronal interactions give rise to large-scale brain activity patterns are still an open question [2].
Methods
Here, we integrated local circuit properties [2] with global brain dynamics in a whole-brain model [3], constrained by human tractography and cholinergic gene expression. Using a mean-field model, cortical regions incorporated intrinsic excitatory and inhibitory neuronal properties. Connectivity among different brain regions was determined by structural tractography from the human connectome. Cholinergic heterogeneity was introduced using the Allen Human Brain Atlas [4], which quantifies transcriptional activity for over 20,000 genes. M1 and M2 muscarinic receptors, which are targets of ACh, were incorporated by adjusting local node properties, thus creating a detailed virtual brain landscape.
Results
Our model successfully replicated spontaneous slow oscillation patterns and their wave propagation properties, as well as awake-like dynamics. Heterogeneity influenced cortical properties, modulating excitability, synchrony, and the relationship between functional and structural connectivity. Additionally, we quantified global brain complexity in response to stimulation using the Perturbational Complexity Index (PCI) [5] to differentiate brain states and assess the impact of cholinergic heterogeneity on evoked activity. We observed a significant increase in complexity during awake-like states, which depended on the level of heterogeneity.
Discussion
Building on prior insights into cholinergic modulation in local circuits [2], we developed a whole-brain model constrained by muscarinic receptor distributions, bridging intrinsic neuronal properties to large-scale brain activity. Overall, our findings underscore the impact of cholinergic heterogeneity on global brain dynamics and transitions across brain states, shaping the spatiotemporal complexity of neural patterns and functional interactions across cortical areas. Moreover, our approach also offers a pathway to studying the role of various neuromodulators involved in brain state regulation.
Acknowledgements
EU H2020 No. 945539 (Human Brain Project SGA3); INFRASLOW PID2023-152918OB-I00 funded by MICIU / AEI / 10.13039/501100011033/FEDER, UE; ERC SyG grant NEMESIS 101071900
References
1.https://doi.org/10.1523/jneurosci.1318-04.2004
2.https://doi.org/10.1371/journal.pcbi.1011246
3.https://doi.org/10.3389/fncom.2022.1058957
4.https://doi.org/10.1038/nature11405
5.https://doi.org/10.1126/scitranslmed.3006294
