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Rapid brain-wide optogenetic screening with a noninvasive, dynamically programmable in vivo light source

使用无创、动态可编程体内光源进行快速全脑光遗传学筛查

基本信息

批准号：
10401548
负责人：
Kim Butts-Pauly
金额：
$ 180万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10401548
关键词：
Address Amygdaloid structure Animals Behavior Biological Blood Circulation Brain Brain region Cell Nucleus Cerebrum Charge Chemicals Chronic Communities Complex Craniotomy Devices Disease Ensure FOS gene Fiber Focused Ultrasound Half-Life Head Heart Heating Hippocampus (Brain)Image Injections Intravenous Kinetics Light Lighting Location Measures Medial Mediating Memory Methods Modeling Morphine Motor Cortex Mus Neurons Neurosciences Neurosciences Research Opioid Opsin Optics Pathology Pattern Penetration Pharmaceutical Preparations Photometry Photons Prefrontal Cortex Procedures Production Protocols documentation Pump Rapid screening Reporter Resolution Slice Source Specificity Structure Structure of subthalamic nucleus Technology Temperature Testing Time Tissues Training Transducers Transgenic Mice Travel Ultrasonic Transducer Variant Visible Radiation absorption attenuation base biomaterial compatibility biophysical properties brain tissue conditioned place preference cranium design drug seeking behavior excitatory neuron experimental study hemodynamics implantation in vivo interest intravenous injection light emission light intensity millisecond minimally invasive nanoparticle nanophotonic neural circuit neuroregulation optical fiber optical spectra optogenetics photonics preference pressure programs relating to nervous system response sample fixation screening simulation spatiotemporal surface coating tool ultrasound virtual reality

项目摘要

PROJECT SUMMARY/ABSTRACT Optogenetics provides a precise deconstruction of neural circuits by optically manipulating the activity of opsin-expressing neurons with fast temporal responses and neuron-type specificity. A critical challenge of delivering light in the brain for in vivo optogenetics arises from the poor penetration of photons in biological tissue due to the scattering and absorption of light. As a result, in vivo optogenetic stimulation in the deep brain usually requires invasive procedures, such as craniotomy and intracranial implantation of optical fibers. The very invasiveness of these procedures also precludes easy repositioning and volume adjustment of the illuminated region in the same subject. Several strategies have been employed to address the challenges above. Red-shifted and ultrasensitive opsins enable transcranial optogenetics, yet light must travel through all superficial brain tissues with significant power attenuation, heating to other brain structures, potential off-target effects, and an inability to reposition the manipulated brain regions. Tapered optical fibers and reconfigurable nanophotonic circuits enable dynamic illumination across multiple brain regions but still require invasive implantation of photonic devices. Recently the Hong lab demonstrated “sono-optogenetics”, a minimally invasive method for optogenetically manipulating neural activity in vivo via brain-penetrant, focused ultrasound (FUS). Central to this method is mechanoluminescent nanoparticles (MLNPs), which can be delivered intravenously, charged by 400-nm light when passing through superficial vessels, pumped by the heart into cerebral vessels, and then gated by FUS to emit 470-nm light locally for opsin activation, all without exiting the blood circulation. Based on these advances, we propose a rapid brain-wide optogenetic screening approach by producing on-demand light emission at any location or depth in the mouse brain. The long-term objective of this proposal is to noninvasively produce on-demand light emission patterns at any location or depth in the mouse brain for rapid brain-wide optogenetic screening of different brain regions. Specifically, the Hong lab aims to develop a toolbox of MLNPs with distinct emission spectra matching different opsin variants, bright mechanoluminescence, and favorable in-vivo circulation half-life. We will characterize and validate their spectral and biophysical properties by constructing an intravital light source with on-demand emission patterns in the brain of live mice. We then seek to use the FUS-mediated intravital light source to optogenetically stimulate multiple brain regions in the same mouse, thereby fulfilling the dynamic selection of illuminated brain regions. The Butts Pauly lab will facilitate the Hong lab in the design of FUS protocols, ensuring minimal neuromodulatory effects by direct FUS stimulation of the brain. Finally, to demonstrate the unique strengths of this approach in addressing neuroscience challenges, the Hong and Chen labs will screen different brain regions that have been found to store opiate-associated memories in the same mouse brain for dissecting their contributions to the animal’s drug-seeking behavior. The proposed method will provide a valuable tool for the broader neuroscience community to rapidly screen different brain regions underlying a certain behavior or pathology of interest in the same animals.

项目总结/文摘