EAGER: Neuromodulation in the second near-infrared window

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Understanding the full complexity of the brain requires precisely manipulating the activity of specific neurons and observing their responses. One approach to manipulate neurons, which is termed “optogenetics”, uses visible light to activate light-sensitive ion channels on the cell membrane of neurons. Since visible light does not penetrate deep into the brain, this approach usually requires the invasive implantation of an optical fiber, which delivers light of desired wavelengths into the brain. The aim of this EArly-concept Grant for Exploratory Research (EAGER) project is to improve the penetration depth of light for manipulating specific neurons in the brain, thus eliminating the need of an optical fiber and allowing the subject animal to behave freely. The results obtained from this project will enable noninvasive approaches to modulate brain activity through the intact scalp and skull. This project will also include research training opportunities for underrepresented minority (URM) high school students, with efforts to guide their pursuit of careers in STEM-related work.Understanding neural computation requires causal manipulation of neural activity to dissect the complex circuit connections and the relationship between neural activity and certain behaviors. Optogenetics enable precise modulation of neural activity with millisecond temporal resolution and neuron-type specificity. Conventional optogenetics is performed in the visible spectrum; however, the delivery of visible light usually requires invasive implantation of an optical fiber into the brain, due to light attenuation (i.e., scattering and absorption) in cranial bone and brain tissue. This tethered fiber interface usually leads to acute tissue damage, chronic immune responses, and restriction of the subject’s free behavior. To address these challenges, the Investigator aims to investigate the feasibility of in vivo neuromodulation with light up to 1,500 nm in wavelength in the second near-infrared (NIR-II) spectrum. NIR-II light benefits from much reduced scattering and absorption compared to its visible counterpart, and it has been demonstrated to enable deep-brain imaging through the intact scalp and skull in mice. The Research Plan is organized under three objectives: (1) Synthesize biocompatible polymers with NIR-II absorption in the range of 1,000~1,500 nm; (2) Target NIR-light sensitive transient receptor potential vanilloid 1 (TRPV1) ion channels in dorsal root ganglion (DRG) neurons with NIR-II absorbing polymers for in-vitro neuromodulation; and (3) Demonstrate the feasibility of NIR-II neuromodulation in the mouse hippocampus through the intact scalp and skull. The knowledge gained from this project will shed light on the feasibility of optogenetic neuromodulation in the NIR-II window and thus offer more guidance on NIR-II light-based approaches in biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.