Noradrenaline and acetylcholine shape functional connectivity organization of NREM substages: An empirical and simulation study
Year: 2025
Type: article
Abstract: Sleep onset is characterized by a departure from arousal, and can be separated into well-differentiated stages: NREM (which encompasses three substages: N1, N2 and N3) and REM (Rapid Eye Movement). Awake brain dynamics are maintained by various wake-promoting mechanisms, particularly the neuromodulators Acetylcholine (ACh) and Noradrenaline (NA), whose levels naturally decrease during the transition to sleep. The combined influence of these neurotransmitters on brain connectivity during sleep remains unclear, as previous models have examined them mostly in isolation or only in deep sleep. In this study, we analyze fMRI data obtained from healthy individuals and employ a whole-brain model to investigate how changes in brain neurochemistry during NREM sleep, specifically involving ACh and NA, affect the Functional Connectivity (FC) of the brain. FC analysis reveals distinct connectivity changes: a decrease in Locus Coeruleus (LC) connectivity with the cortex during N2 and N3, and a decrease in Basal Forebrain (BF) connectivity with the cortex during N3. Additionally, compared to Wakefulness (W), there is a transition to a more integrated state in N1 and a more segregated state in N3. Using a Wilson-Cowan whole-brain model, informed by an empirical connectome and a heterogeneous receptivity map of neuromodulators, we explored possible mechanisms underlying these dynamics. We fit the model adjusting the coupling and input-output slope of the whole-brain model to account for ACh and NA, respectively, and show that region-specific neurotransmitter effect is key to explain their effects on FC. This work enhances our understanding of neurotransmitters' roles in modulating sleep stages and their significant contribution to brain state transitions between different states of consciousness, both in health and disease.
Source: PLoS Computational Biology
Institutions: Valparaiso University, University of Valparaíso, University of California, San Francisco, Trinity College Dublin, Adolfo Ibáñez University, Global Brain Health Institute, University Hospital Magdeburg, Friedrich Schiller University Jena, Otto-von-Guericke-Universität Magdeburg, Universidad de Buenos Aires
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: G103069192, NEUROVASCULAR PATHWAYS IN AGING AND NEURODEGENERATIVE DISEASES (ND): INTEGRATING CARDIOVASCULAR HEALTH AND BRAIN FUNCTION, Rückkehrstipendium, FUNCTIONAL MAGNETIC RESONANCE SPECTROSCOPY OF LACTATE IN AGING ACROSS AROUSAL AND COGNITIVE DEMAND, ADVANCED CENTER FOR ELECTRICAL AND ELECTRONIC ENGINEERING, G334976590, G4156359210, G5915980936, EMERGENCE OF COLLECTIVE BEHAVIOR IN LEARNING NEURONAL NETWORKS., MAPPING AND MODELING THE HEALTHY AND PATHOLOGICAL AGING TRAJECTORIES OF THE HUMAN BRAIN
OpenAlex ID: W4415624380