Cortical acetylcholine dynamics are predicted by cholinergic axon activity and behavior state

Area of Science:

• Neuroscience
• Systems Neuroscience
• Neurobiology

Background:

• Awake animals exhibit spontaneous shifts in alertness, driven by rapid changes in brain state.
• Neuromodulators, particularly acetylcholine (ACh), are hypothesized to orchestrate these dynamic state transitions.
• Understanding the spatiotemporal dynamics of ACh is crucial for deciphering brain state regulation.

Approach:

• Simultaneous *in vivo* imaging of ACh sensors and GCaMP-expressing axons in the cortex.
• Quantifying the relationship between basal forebrain axon activity and cortical ACh levels.
• Analyzing ACh release dynamics in relation to spontaneous behavioral changes like locomotion and pupil dilation.

Key Points:

• Cortical ACh levels strongly correlate with basal forebrain axon activity during locomotion and pupil dilation.
• ACh exhibits volume transmission, with local concentrations decreasing away from active axons.
• Axon activity serves as a reliable predictor of local ACh levels, validated by sensor fluorescence.
• Rapid ACh clearance is observed, especially during non-locomotion periods.

Conclusions:

• This study provides the first direct evidence linking cortical ACh dynamics to spontaneous brain state transitions.
• Axonal activity is a robust indicator of neuromodulator release and function.
• A predictive model combining pupil size and running speed accurately forecasts ACh fluctuations, enhancing our understanding of brain state control.