Label-free biomolecular spectroscopy with vibrational fiber photometry deep in the mouse brain

Optical approaches for in vivo neural monitoring, using genetically encoded molecular reporters, offer a precious window on brain functions and on its mechanisms of development, ageing or disease progression. Nonetheless, the existing methods are still shortsighted with respect to the complex biomolecular alterations that accompany these physiological and pathological dynamics. As a result, our grasp of the multifaceted components of brain activity is still partial. To mitigate this limitation, we propose a fiber photometry method based on spontaneous Raman scattering – which we call vibrational fiber photometry – that allows monitoring the bio-molecular content of arbitrarily deep brain volumes of the mouse brain in vivo without exogenous reporters. To do this, we employed a thin tapered optical fiber (1 µm at its tip) to (i) gather information on the local cytoarchitecture, (ii) to sense molecular alterations linked to circuit dysfunction caused by traumatic brain injury, and (iii) to detect diagnostic markers of brain metastasis with high accuracy. In our view, vibrational fiber photometry offers an opportunity to capture a more comprehensive picture of neural activity in the bio-molecular context of the local micro-environment. This capability, that can be employed alongside traditional fiber photometry or optical approaches, is particularly promising for empowering emerging research on brain-immune1and brain-cancer2 bidirectional dynamics.