Pathway-selective manipulation of primate neural networks by means of modified viral vectors
Nonhuman primates have widely and critically been utilized as animal models for understanding various higher brain functions and neurological disorders by virtue of their behavioral actions that mimic both normal and disease states in humans. To understand how such behavioral actions emerge from functions/dysfunctions of complex neural networks, it is essential to define the role of a particular pathway or neuron type constituting these networks.
Recently, we established two experimental systems based on genetic and optogenetic manipulation, that allows discrete targeting of functionally specific neural pathways. Briefly, one of our techniques based on the tetracycline-regulated gene expression was applied for the blockade of nigro-striatal dopamine transmission. We injected the pseudotyped lentiviral vector carrying a gene encoding modified tetanus toxin, downstream of a tetracycline-responsive element into the striatum, for retrograde gene-transfer. This was followed by injection of AAV vector carrying a tetracycline reverse-transactivator gene into the nigra. We observed that parkinsonian-like motor deficits were induced by doxycycline administration in the monkeys injected with the vectors.
In our other system, we applied pathway-selective optogenetics to macaque monkeys for stimulating the pathway from the frontal eye field (FEF) to the superior colliculus (SC). We found that the optogenetic stimulation of the FEF-SC pathway, not only activated SC neuronal activity, but also evoked saccadic eye movements toward the response field corresponding to the stimulation site. Thus, stimulating the FEF-SC pathway, among the complex oculomotor network, is sufficient to initiate oculomotor behavior. Our study demonstrates the power of pathway-selective manipulation using viral vectors for elucidating neural network functions in the primate brain.