Significance: A number of scientific questions, especially in local circuit analysis, require manipulating neurons in vivo at multiple sites independently at high spatial and temporal resolutions by perturbing a controlled number and simultaneously recorded neurons. Optogenetic stimulation is cell-type specific which has proven to be the most powerful means of circuit control. Several laboratories have developed solutions to deliver optical stimulation to deep brain structures whilst simultaneously recording neurons. However, stimulation through light sources placed on the surface of the brain or large fibers placed in the brain parenchyma a few hundred “mu”m from the recording sites inevitably activate many un-monitored neurons, making the separation of direct and population-mediated effects impossible. Moreover, the high intensity used for the activation of deep neurons may generate superposition of multiple spike waveforms and considerable light artifacts. There is an unmeet need to provide an adequate tool to enable local circuit stimulation to the level of single neurons and closed-loop interactions with excitation/inhibition patterns. The objective of this application is to develop high-density optoelectrode probes for enabling highly specific neural circuit control. Based upon our previous experience with waveguides, coupling technology, and high-density neural probes, we will implement a fiber-less, multi-channel, multi-wavelength platform for simultaneous, low-noise electrical recording and optical stimulation. Validation of multiple configurations will occur in vivo in rodents against clearly defined benchmarks. Preliminary Data: We have demonstrated the feasibility of the monolithic integration of optical waveguides with Michigan neural probes, delivering light from an aligned optical fiber to the stimulation site. We have also implemented both polymer (SU-8) and oxynitride waveguides in various configurations as optical mixers and splitters to guide light in lithographically-defined patterns. We implanted the fabricated probe in a rat and have successfully recorded neural spiking responses to optical stimulation (lambda=473nm) from the hippocampus CA1 region. Specific Aims: In aim 1, we will develop an efficient coupling scheme from the light source through novel reflector design and high-confinement waveguide implementation. We will optimize the waveguide and reflector efficiency through parametric and free-form optical modeling. In aim 2, we will fabricate and assemble the multi-channel multi-site optoelectrode array to achieve 60-“mu”W output from the low-profile waveguide for simultaneous, low-noise recording and optical stimulation. The tasks include microfabrication, thermal optimization, on-chip driver, low-noise optimization, assembly refinement and verification testing. In aim 3, the fabricated probes will be validated by two in-vivo experiments: one is activating few or single neurons at extremely low power (3-10”mu”W) and the other is closed-loop optogenetic interaction with identified neuron types using multi-color control.

PUBLIC HEALTH RELEVANCE: This project will develop and validate high-density optoelectrode probes for enabling highly specific neural circuit control of a behaving animal. Our approach allows a fiber-less, multi-channel, multi-wavelength platform for simultaneous, low-noise electrical recording and optical stimulation. The target neurons can be perturbed with precise control of locality by monolithically integrating optical waveguides on the probe shank using microfabrication technologies. Our device aims at accelerating the understanding of the roles of specific neurons in behaviors and in complex circuits of the central nervous system, that can be applicable to drug- refractory epilepsies and psychiatric disease.