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

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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.

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