Significance: In order to advance the understanding of brain function and behaviors, it is critical to be able to monitor and analyze how neural circuis work together to perform computation. Recent advances in optogenetics allow mammalian cells to express photo-sensitive ion channels and pumps called opsins. Neurons that express these opsins can be selectively stimulated by light with the corresponding wavelengths. Optical stimulation of neurons promises more precise neural activity control compared with the conventional electrical stimulation method in terms of spatial and temporal resolution and cell type specificity, and this offers new research directions to map individual neural subcircuits for specific neural computations and behaviors. Although the potential benefits of optogenetics have been generally accepted, optical stimulation has not been widely applicable because of the unmet need for a reliable device to precisely deliver light to the targeted neurons and to record the corresponding neural activity at the same time. This application will develop and validate a multi-shank optical stimulation probe that can provide spatially-confined activation of simultaneously monitored neurons by delivering light precisely above the recording sites in behaving animals. This can be achieved by monolithically integrating multiple LEDs on a lithographically defined probe shank such that the LEDs are hermetic and therefore reliable for long-term chronic studies. The distributed neuron-sized LEDs will enable the co-location of high-density light sources with microelectrodes that also provide the necessary feedback (e.g., tetrodes) such that neuroscientists can fine-tune local neuron recruitment based on their experimental needs. 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 implanted the fabricated probe in a rat and have successfully recorded neural spiking responses to optical stimulation (?=473nm) from the hippocampus CA1 region. For feasibility study of the proposed scheme, we have fabricated neuron-sized LEDs on silicon substrate and successfully demonstrated emission of light.
Specific Aims :
In Specific Aim 1, we will design and fabricate a 4-shank implantable probe with 3 LEDs and 8 recording electrodes monolithically integrated on each shank for emission of light at 460 nm in wavelength for the activation of ChR2. We will perform the reliability test of the fabricated LEDs and recording electrodes by accelerated saline soak tests at elevated temperatures.
In Specific Aim 2, we will validate the fabricated LED optoelectrode. First we will analyze the tissue heating and electrical interference when lighting the integrated LEDs through electrothermal modeling and simulations, followed by experimental validation. We will determine the optimal operating condition of LEDs to minimize the tissue heating and interference within the given thermal budget. Finally, we will test LED control of a few or single unit activities acutely from CA3 pyramidal neurons in the hippocampus. The density of LEDs and microelectrodes this technology platform provides will offer neuroscientists the highest degree of neural circuit control yet available for scientific and clinical investigation.

Public Health Relevance

This project will develop and validate an implantable neural probe capable of simultaneous optical stimulation and electrical recording for chronic animal studies. Our approach can give spatial, temporal control of optical stimulation of target neurons with precise control of locality, by monolithically integrating lighting emitting devices (LEDs) on the probe shank using microfabrication technologies. The density of LEDs and microelectrodes this technology platform provides will offer neuroscientists the highest degree of neural circuit control yet available for scientific and clinical investigation.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Exploratory/Developmental Grants (R21)
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Peng, Grace
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University of Michigan Ann Arbor
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Biomed Engr/Col Engr/Engr Sta
Ann Arbor
United States
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Mendrela, Adam E; Kim, Kanghwan; English, Daniel et al. (2018) A High-Resolution Opto-Electrophysiology System With a Miniature Integrated Headstage. IEEE Trans Biomed Circuits Syst :
Buzsáki, György (2015) Hippocampal sharp wave-ripple: A cognitive biomarker for episodic memory and planning. Hippocampus 25:1073-188
Wu, Fan; Stark, Eran; Ku, Pei-Cheng et al. (2015) Monolithically Integrated ?LEDs on Silicon Neural Probes for High-Resolution Optogenetic Studies in Behaving Animals. Neuron 88:1136-1148
Buzsáki, György; Stark, Eran; Berényi, Antal et al. (2015) Tools for probing local circuits: high-density silicon probes combined with optogenetics. Neuron 86:92-105