Noradrenaline and acetylcholine shape functional connectivity organization of NREM substages: An empirical and simulation study
Fernando Lehue, Carlos Coronel‐Oliveros, Vicente Medel, Thomas Liebe, Jörn Kaufmann, Sebastián Orellana, Diego Becerra, Enzo Tagliazucchi, Patricio Orio
PLoS Computational Biology October 28, 2025 DOI: 10.1371/journal.pcbi.1012852 via OpenAlex
Summary
During sleep, brain dynamics shift from wakefulness through NREM stages N1, N2, and N3, driven partly by decreases in the neuromodulators acetylcholine (ACh) and noradrenaline (NA). Analyzing fMRI data from healthy individuals and using a whole-brain model, the study shows that functional connectivity (FC) changes distinctly: locus coeruleus connectivity with the cortex decreases during N2 and N3, while basal forebrain connectivity with the cortex decreases during N3. Compared to wakefulness, the brain becomes more integrated in N1 and more segregated in N3. Region-specific neurotransmitter effects are key to explaining these FC changes, advancing understanding of how neurochemistry modulates sleep stages and consciousness transitions.
Study at a glance
| Characteristics | Observational study with computational modeling Peer reviewed |
|---|---|
| Population | Healthy individuals |
| Keywords | Wakefulness Basal forebrain Locus coeruleus Acetylcholine Functional connectivity |
| Citations | 1 |
| Key finding | Functional connectivity changes during NREM sleep involve decreased locus coeruleus–cortex connectivity in N2 and N3, decreased basal forebrain–cortex connectivity in N3, and a shift toward integration in N1 and segregation in N3, with region-specific effects of acetylcholine and noradrenaline. |
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.