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Title: Life-long genetic and functional access to neural circuits
Author: Ciabatti, Ernesto
ISNI:       0000 0004 7229 6699
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2018
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Network dynamics are thought to be the substrate of brain information processing and of mental representations. Moreover, network-wide dysfunctions are recognized to be at the core of several psychiatric and neurodegenerative disorders. Yet, our ability to target specific networks for functional or genetic manipulations remains limited. The development of monosynaptically-restricted Rabies virus, G-deleted Rabies virus (ΔG-Rabies), has greatly facilitated the anatomical investigation of neural circuits, revealing the network synaptic structure upstream of defined neuronal populations. However, the inherent cytotoxicity of the Rabies virus largely restrains its use to the mere structural characterisation of neural networks. To overcome this limitation, I generated novel tools that allow the manipulation of neural networks for the entire life of the animal, without affecting neuronal and circuit properties. I first developed a viral system obtained by engineering the Rabies virus genome to eliminate its cytotoxicity. This led to the generation of a Self-inactivating Rabies virus (SiR) that transcriptionally disappears from the infected neurons while leaving permanent genetic access to the traced network. I showed that SiR provides a virtually unlimited temporal window for the functional manipulation of neural circuits in vivo without adverse effects on neuronal physiology. To further expand our ways of intervening on neural networks function I then developed a completely virus-free system, named Genetically-Encoded TransSynaptic Shuttle (GETSS), which is the only specific genetically-encoded transsynaptic tracer to date. In this thesis, I established novel approaches that provide, for the first time, the functional and genetic access to traced network elements in vivo for the lifetime of the animal, with no cytotoxic effects, no changes in the electrophysiological properties of the traced neurons and no adverse effects on network function. This opens new horizons in the functional investigation of neural circuits and potentially represent the first approaches to experimentally monitor neural circuit remodelling in vivo.
Supervisor: Tripodi, Marco Sponsor: MRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Rabies ; transsynaptic ; retrograde ; neural tracing ; neural network ; neural circuits ; SiR virus ; Self-inactivating Rabies ; DG-Rabies ; network manipulation