Developing REACH: Rabies Engineered Anterograde Connectomics using HSV-1

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Developing REACH: Rabies Engineered Anterograde Connectomics using HSV-1

Thompson, Simon Laurie; (2023) Developing REACH: Rabies Engineered Anterograde Connectomics using HSV-1. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

The development of efficient and accessible anterograde monosynaptic tracing tools holds immense potential for shaping the future of neuroscience research. However, no such tool currently exists. In this study, we introduced a novel pseudotyping strategy, termed REACH, which replaces the native rabies glycoprotein responsible for retrograde infectivity with three glycoproteins derived from herpes simplex virus (HSV) that facilitate anterograde infectivity. We demonstrated the production of infectious virions in vitro using a plaque assay and further showed transsynaptic infectivity in a wild-type in vivo model. To investigate the nature of this transfer, we employed a Cre-recombinase model, which provided strong evidence for selective anterograde transsynaptic transfer. Subsequently, we examined the interplay between this strategy and observed tissue toxicity. This exploration led to the development of potential strategies for reducing toxicity and enhancing transfer efficiency. Additionally, this study has contributed to a deeper understanding of the potential of pseudotyping across viral families, which may inform the rational design of next-generation tracing tools. In conclusion, this study presents the neuroscience community with a promising new approach for investigating the nervous system through anterograde monosynaptic tracing.

Type:	Thesis (Doctoral)
Qualification:	Ph.D
Title:	Developing REACH: Rabies Engineered Anterograde Connectomics using HSV-1
Open access status:	An open access version is available from UCL Discovery
Language:	English
Additional information:	CC BY-NC: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
Keywords:	Rabies, Tracing, Anterograde
UCL classification:	UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre
URI:	https://discovery.ucl.ac.uk/id/eprint/10179033