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NIH Brain Grant


Optogenetics has emerged as a powerful tool for studyingneural circuit function, byusing light to perturb the activity of specific cell types genetically modified to express light-activated microbial opsins,and assessing the consequences of this perturbation on network activity and behavior. While successful in mice, it has been challenging to apply optogenetics to animals with large brains, largely due to the lack of multifunction integrated probes for precision light delivery and electrophysiology acrossmm-to-cm volumesthrough the depth of the cortex. Largevolume manipulations are essential in large brains in order to observe measurable electrophysiological or behavioral effects. We have assembled an interdisciplinary team of PIs to develop and test in vivo integrated penetrating arrays that allow for large-volume, spatiotemporally patterned optogenetic modulation and electrical recording of neural circuits in the large brains.Thisprojectrequires the coordinated effort of 4 teams, including experts in photonic devicesand µLED development for optogenetics, materials and packaging for biocompatible devices, neurophysiology, and pioneers in electrode array design and commercialization.We will initially develop a 4x4 mm penetrating 10x10 optrode array in a format analogous to the well-established Utah Electrical Array (UEA), with each probe serving as a waveguide allowing visible light to reach tissue depths >1.5mm. Following initial optimization of the probe’s shank diameter and tip angle to minimize tissue damage, we will perform proof-of-concept in vivooptogenetic experiments in deep cortical tissue,using broad-area illumination of the entire array.In a second stage, we will develop light coupling via µLEDs, which will be integrated into a single platform and testedinvivo, consisting of aµLED located overeach optical probe. Completion of stage 2 will deliver a functional multioptrode array for large-volume patterned optogeneticstimulation.Parallel engineering efforts will addelectrical recording capability, byutilizing the engineering resources already in place for the UEA, and will generate two types of integrated arrays. The “interleaved” array consists of an optrode array inserted through the back plane of a modified UEA into which a grid of through-backplane holes is made via laser ablation to accommodate the optrodes.For the “hybrid” array, each optrodeshank will be coated withan isolation layer followed by a conductive layer, in order to allow recording while preventing light attenuation and stimulation artifacts.In vivo testing will assess the recording capabilities of both devices and subsequently the ability to perform simultaneous optical stimulation and electrical recordings. This technology will allow for unprecedented optogenetic investigations of mm-to-cm scale neural circuit function in large brained animals, and for a new generation of therapeutic interventions via cell type specific optical neural control prosthetics.

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