Title: 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
Main research methods may cover drug administration, neurobehavioural assays, brain morphology and histopathology, various staining techniques (e.g., immunohistochemistry), gene expression analysis (e.g., real-time qPCR), and statistical analysis. Additional methods may cover western blot, Fluorescence- activated cell sorting (FACS), RNA sequencing, and functional brain imaging.
To scrutinize GA-induced neurotoxicity we will monitor post-treatment effects based on an extensive list of sublethal endpoints (e.g., behavioural, physiological, morphological and histological, molecular and cellular, cardiotoxic endpoints) across various factors such as time, dosage, and drug combinations. Correlational studies of different significant endpoints (e.g., behavioural vs. morphological phenotypes) will be carried out to examine potential positive/negative relationships between different variables. Moreover, to enhance the predictive power of the zebrafish model for neurotoxicity, we will apply single differential evaluation of endpoints specific for individually defined treatments.
Potential Relevance Study outcomes of the research project may shed some light on the target- specific anaesthetic neuronal damage and new therapeutic/neuroprotective strategies for minimizing anaesthesia-induced toxicity. By translating these findings, our work has the potential to open new avenues for identifying clinically useful neurotoxicity endpoints and for establishing better and safer anaesthetic management.
References 1) Vutskits et al., Nat Rev Neurosci. 2016; DOI: 10.1038/nrn.2016.128 2) Félix et al., Crit Rev Toxicol. 2019; DOI: 10.1080/10408444.2019.16172 3) Patton et al., Nat Rev Drug Discov. 2021; DOI: 10.1038/s41573-021-00210-8 4) Jevtovic-Todorovic et al., JAMA Pediatr. 2017; DOI: 10.1001/jamapediatrics.2017.3033
Requirements
A team player who possesses a genuine interest in basic science and translational medical research and in acquiring lab skills and experimental techniques. Good knowledge in neurobiology and physiology; knowledge of toxicology and pharmacology and/or experience with animal experimentation would be a plus.
How to apply
Please send a CV, diploma and transcript of records of BSc and MSc courses, a motivation letter with a brief statement of career goals, and 2-3 reference letters and/or names and contact information of the referees to: [email protected] and [email protected]. Candidates will be evaluated starting in January 2023 and until the position is filled. Only short-listed candidates will be further contacted. The PhD thesis can be started upon mutual agreement ( earliest on April 1st, 2023 ). For further information, please contact Melody Ying-Yu Hedinger.
Contact details of supervisor Melody Ying-Yu Hedinger, [email protected], +41 31 632 08 26 Department for BioMedical Research University Bern
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