Neurotransmitter networks in mouse prefrontal cortex are reconfigured by isoflurane anesthesia.

This study quantified eight, small molecule neurotransmitters collected simultaneously from prefrontal cortex of C57BL/6J mouse (n=23) during wakefulness and during isoflurane anesthesia (1.3%). Using isoflurane anesthesia as an independent variable enabled evaluation of the hypothesis that isoflurane anesthesia differentially alters concentrations of multiple neurotransmitters and their interactions. Machine learning was applied to reveal higher order interactions among neurotransmitters. Using a between-subjects design, microdialysis was performed during wakefulness and during anesthesia. Concentrations (nM) of acetylcholine, adenosine, dopamine, GABA, glutamate, histamine, norepinephrine, and serotonin in the dialysis samples are reported (mean +/- SD). Relative to wakefulness, acetylcholine concentration was lower during isoflurane anesthesia (1.254 +/- 1.118 versus 0.401 +/- 0.134, P=0.009), and concentrations of adenosine (29.456 +/- 29.756 versus 101.321 +/- 38.603, P<0.001), dopamine (0.0578 +/- 0.0384 versus 0.113 +/- 0.084, P=0.036), and norepinephrine (0.126 +/- 0.080 versus 0.219 +/- 0.066, P=0.010) were higher during anesthesia. Isoflurane reconfigured neurotransmitter interactions in prefrontal cortex, and the state of isoflurane anesthesia was reliably predicted by prefrontal cortex concentrations of adenosine, norepinephrine, and acetylcholine. A novel finding to emerge from machine learning analyses is that neurotransmitter concentration profiles in mouse prefrontal cortex undergo functional reconfiguration during isoflurane anesthesia. Adenosine, norepinephrine, and acetylcholine showed high feature importance, supporting the interpretation that interactions among these three transmitters may play a key role in modulating levels of cortical and behavioral arousal.