Life-Long Genetic and Functional Access to Neural Circuits Using Self-Inactivating Rabies Virus

Neural networks are emerging as the fundamental computational unit of the brain and it is becoming progressively clearer that network dysfunction is at the core of a number of psychiatric and neurodegenerative disorders. Yet, our ability to target specific networks for functional or genetic manipulations remains limited. Monosynaptically restricted rabies virus facilitates the anatomical investigation of neural circuits. However, the inherent cytotoxicity of the rabies largely prevents its implementation in long-term functional studies and the genetic manipulation of neural networks. To overcome this limitation, we developed a self-inactivating ΔG-rabies virus (SiR) that transcriptionally disappears from the infected neurons while leaving permanent genetic access to the traced network. SiR provides a virtually unlimited temporal window for the study of network dynamics and for the genetic and functional manipulation of neural circuits in vivo without adverse effects on neuronal physiology and circuit function.