Abstract
This study quantified eight small-molecule neurotransmitters collected simultaneously from prefrontal cortex of C57BL/6J mice (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 (means ± SD). Relative to wakefulness, acetylcholine concentration was lower during isoflurane anesthesia (1.254 ± 1.118 vs. 0.401 ± 0.134, P = 0.009), and concentrations of adenosine (29.456 ± 29.756 vs. 101.321 ± 38.603, P < 0.001), dopamine (0.0578 ± 0.0384 vs. 0.113 ± 0.084, P = 0.036), and norepinephrine (0.126 ± 0.080 vs. 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.NEW & NOTEWORTHY This study discovered that interactions between neurotransmitters in mouse prefrontal cortex were altered during isoflurane anesthesia relative to wakefulness. Machine learning further demonstrated that, relative to wakefulness, higher order interactions among neurotransmitters were disrupted during isoflurane administration. These findings extend to the neurochemical domain the concept that anesthetic-induced loss of wakefulness results from a disruption of neural network connectivity.
Highlights
Anesthetics once were thought to cause loss of wakefulness via a generalized inhibition of brain activity (Perouansky 2012)
The results show that concentrations of norepinephrine, adenosine, and dopamine in the dialysis samples were significantly greater during isoflurane anesthesia than during wakefulness
The state of isoflurane anesthesia was predicted by concentrations of adenosine, norepinephrine, and acetylcholine
Summary
Anesthetics once were thought to cause loss of wakefulness via a generalized inhibition of brain activity (Perouansky 2012). Current theories concerning the mechanisms by which anesthetics cause loss of wakefulness focus on functional disconnection among brain regions (Alkire et al 2008), loss of effective cortical connectivity (Hashmi et al 2017), loss of coherence in the cortical electroencephalogram (Akeju et al 2016), and a breakdown of information integration (Tononi et al 2016). The foregoing findings have clinical relevance for intraoperative neurophysiological monitoring (Smith 2018), efforts to minimize the potential toxic effects of volatile anesthetics (Iqbal et al 2019), and for their potential to address questions concerning the brain mechanisms generating states of consciousness (Baria et al 2018; Kennedy and Norman 2005). Electrophysiology and neuroimaging provide important insights concerning altered network connectivity during general anesthesia, yet achieving a functional connectomics perspective of the brain (Fornito et al 2015) must incorporate neurotransmitter data
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