Quantitative behavioural phenotyping to investigate anaesthesia induced neurobehavioural impairment

Abstract

Anaesthesia exposure to the developing nervous system causes neuroapoptosis and behavioural impairment in vertebrate models. Mechanistic understanding is limited, and target-based approaches are challenging. High-throughput methods may be an important parallel approach to drug-discovery and mechanistic research. The nematode worm Caenorhabditis elegans is an ideal candidate model. A rich subset of its behaviour can be studied, and hundreds of behavioural features can be quantified, then aggregated to yield a ‘signature’. Perturbation of this behavioural signature may provide a tool that can be used to quantify the effects of anaesthetic regimes, and act as an outcome marker for drug screening and molecular target research. Larval C. elegans were exposed to: isoflurane, ketamine, morphine, dexmedetomidine, and lithium (and combinations). Behaviour was recorded, and videos analysed with automated algorithms to extract behavioural features. Anaesthetic exposure during early development leads to persisting behavioural variation (in total, 125 features across exposure combinations). Higher concentrations, and combinations of isoflurane with ketamine, lead to persistent change in a greater number of features. Morphine and dexmedetomidine do not appear to lead to behavioural impairment. Lithium rescues the neurotoxic phenotype produced by isoflurane. Findings correlate well with vertebrate research: impairment is dependent on agent, is concentration-specific, is more likely with combination therapies, and can potentially be rescued by lithium. These results suggest that C. elegans may be an appropriate model with which to pursue phenotypic screens for drugs that mitigate the neurobehavioural impairment. Some possibilities are suggested for how high-throughput platforms might be organised in service of this field.

The Conscious Nematode: Exploring Hallmarks of Minimal Phenomenal Consciousness in Caenorhabditis Elegans

“…Besides, adult C. elegans response to noxious stimuli becomes delayed due to modulation of premotor neurons, and the chemosensory neurons' response in presence of appetitive stimuli is prolonged (Lawler et al, 2021). Although being unresponsive to propofol, the anesthetic with more evidence in inducing unconsciousness in humans (Forman, 2006), C. elegans responds to volatile ketamine and isoflurane in an agent and concentration-dependent manner, such as it occurs in vertebrates (Nambyiah & Brown, 2021). Whether its neural dynamics are also globally different when under sleep and/or anesthesia is yet to be researched empirically.…”

“…Finally, it is argued that C. elegans have true sleep states, and its behavior changes globally under some anesthetics. Wen et al, 2012;Olivares et al, 2018;Kato et al, 2015;Kaplan et al, 2020;Trojanowski & Raizen, 2016;Nichols et al, 2017;Nambyiah & Brown, 2021…”