Optogenetics through windows on the brain of primates

25 Optogenetics combines optics and genetics to control neuronal activity with cell-type 26 specificity and millisecond temporal precision. Its use in model organisms such as 27 rodents, drosophila, and C. Elegans is now well established. However, application of 28 this technology in non-human primates (NHP) has been slow to develop. One key 29 challenge has been the delivery of viruses and light to the brain through the thick dura 30 mater of NHPs, which can only be penetrated with large-diameter devices that damage 31 the brain. The opacity of the NHP dura prevents visualization of the underlying cortex, 32 limiting the spatial precision of virus injections, electrophysiological recordings and 33 photostimulation. Here we describe a new optogenetics approach in which the native 34 dura is replaced with an optically-transparent artificial dura. This artificial dura can be 35 penetrated with fine glass micropipettes, enabling precisely targeted injections of virus 36 into brain tissue with minimal damage to cortex. The expression of optogenetic agents 37 can be monitored visually over time. Most critically, this optical window permits 38 targeted, non-invasive photostimulation and concomitant measurements of neuronal 39 activity via intrinsic signal imaging and electrophysiological recordings. We present 40 results from both anesthetized-paralyzed (optical imaging) and awake-behaving NHPs 41 (electrophysiology). The improvements over current methods made possible by the 42 artificial dura should enable the widespread use of optogenetic tools in NHP research, a 43 key step toward the development of therapies for neuropsychiatric and neurological 44 diseases in humans. 45 46 Optogenetics through windows on the brain of primates 3