PhD Position in Anaesthesiology

University of Bern Department for BioMedical Research

PhD position in Anaesthesiology

Proposal for a PhD's Thesis Project

Establishing high-throughput behaviour-based screening assays for testing established and widely used anaesthetic and sedative compounds in a zebrafish in vivo model

Background

Over the past decade, compelling evidence from studies in laboratory animals and humans has demonstrated developmental neurotoxic effects of general anaesthetics and sedatives. Such study outcomes have raised considerable concerns about administering anaesthetic agents during pregnancy and in early infancy, and significant limitations have arisen in the translation of preclinical observations into clinical practice.

Anaesthesia-induced postoperative cognitive dysfunction (POCD) is well described among older patients (>60yrs), but largely unknown in younger ones (<3yrs).It is of critical importance to establish a robust preclinical model that can help identify valid clinical endpoints. Any consequential exposure to neuroactive compounds that alters the normal activity of the nervous system, from low-level sensorimotor to high-level cognitive functions, may compromise, diminish, reverse, or even enhance the neural circuit functionality, and especially its ability to learn.

We hypothesize that zebrafish can serve as a promising alternative in vivo model for assessment of anaesthetic-related neurotoxicity in the developing and ageing brain. Such interference with signal transmission and processing of the neural network may be attributed to underlying neuron disruption or death and/or altered molecular and cellular events.
 
Aim

The overarching goal of this research project is to facilitate clinical anaesthesiology studies by providing an efficient preclinical screening platform for anaesthetic compounds, in compliance with the 3R (Replace, Reduce, Refine) concepts.

Research work, methods

Research work and main methods may cover:
  • Drug administration: animal exposures to specific anesthetic compounds at different developmental stages.
  • Neurobehavioural assays (e.g., photomotor response, visual motor response, hypo- or hyperactivity measurement, startle or escape responses, stress responses, etc.)
  • Brain morphology and histopathology
  • Various staining techniques (e.g., immunohistochemistry and RNA in situ hybridization)
  • Gene expression analysis (e.g., real-time qPCR)
  • Statistical analysis
Potential Relevance

A zebrafish model could help identify POCD among other post-anaesthesia complications, determine teratogenic risks in humans, develop potential anaesthetic adjuvants, and discover novel target-specific neuroprotective agents, contributing to better and safer anaesthetic management.

References

1) Jevtovic-Todorovic V. Anesthetics and Cognitive Impairments in Developing Children: What Is Our Responsibility? JAMA Pediatr. 2017 ;171(12):1135-1136.
2) d'Amora M, Giordani S. The Utility of Zebrafish as a Model for Screening Developmental Neurotoxicity. Front Neurosci. 2018 ;12:976.
3) Patton EE, Zon LI, Langenau DM. Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials. Nat Rev Drug Discov. 2021. doi: 10.1038/s41573-021-00210-8.
4) Vutskits L, Xie Z. Lasting impact of general anaesthesia on the brain: mechanisms and relevance. Nat Rev Neurosci. 2016;17(11):705-717.
5) Félix L, Coimbra AM, Valentim AM, Antunes L. Review on the use of zebrafish embryos to study the effects of anesthetics during early development. Crit Rev Toxicol. 2019;49(4):357-370.

Requirements

Team player; good knowledge in biomedical sciences; willing to learn and interested in molecular and developmental biology; knowledge of neurobiology or immunology and/or experience with animal experimentation would be a plus.

Contact details of supervisor

Melody Ying-Yu Hedinger, ying-yu.hedinger@dbmr.unibe.ch, +41 31 632 08 26

Please submit to Frank.Stueber@insel.ch and ying-yu.hedinger@dbmr.unibe.ch