Intracranial Surface-Enhanced Raman Scattering Endoscopy for In Vivo Protein Quantification under Physiological Stimulation

Surface-enhanced Raman scattering (SERS) endoscopes hold great promise for minimally invasive, high-spatial-resolution in vivo protein detection in deep regions of the central nervous system, such as the brainstem. We developed an intracranial SERS endoscope using 70 μm optical fibers decorated with gold nanoparticles and functionalized with the anti-S100β antibody for in vivo monitoring of S100β, an astrocytic protein, across different brain regions. Here, we report that the SERS endoscope can detect varying levels of protein release across multiple brain regions, corresponding to different levels of brain activity. Using optogenetic stimulation of the cortical masticatory area (CMA) to induce rhythmic jaw movements (RJMs) in awake mice, we observed a significant increase in S100β concentration in the trigeminal main sensory nucleus (NVsnpr) located in the brainstem. Notably, the mild stimulation of the CMA, which did not evoke RJMs, resulted in lower, yet detectable, levels of S100β release. Additionally, SERS endoscopes inserted across different locations of the somatosensory cortex of anesthetized mice revealed S100β levels that matched the known activation profiles across cortical hemispheres in response to tactile stimulation of the hindpaw. Overall, these results demonstrate intracranial SERS endoscopy for in vivo protein monitoring in awake animals.