Synaptic Silencing with Transactivation of Tetanus Neurotoxin for Pathway-Selective Manipulation

To selectively block specific brain circuits using viral vectors, two main approaches have been developed. The first involves injecting a single viral vector into the cell bodies of target neurons, followed by chemical or optogenetic stimulation at their axon terminals. The second method, known as the intersectional double viral vector technique, uses a retrograde vector injected at the axon terminals and an anterograde vector at the cell bodies of target neurons, along with systemic ligand administration. This chapter focuses on the second approach, which allows for the targeted expression of enhanced tetanus neurotoxin in specific neural pathways. This effectively disrupts their transmission by Tet transactivator system, leading to behavioral deficits in macaque monkeys. Additionally, this chemogenetic blocking technique can be combined with the DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) technique to inhibit multiple pathways within a single animal. This approach has the potential to significantly advance systems neuroscience research.