Minimally invasive multimode optical fiber microendoscope for deep brain fluorescence imaging

A major open challenge in neuroscience is the ability to measure and perturb neural activity in vivo from well defined neural sub-populations at cellular resolution anywhere in the brain. However, limitations posed by scattering and absorption prohibit non-invasive multi-photon approaches for deep (>2mm) structures, while gradient refractive index (GRIN) endoscopes are relatively thick and can cause significant damage upon insertion. Here, we present a novel micro-endoscope design to image neural activity at arbitrary depths via an ultra-thin multi-mode optical fiber (MMF) probe that has 5-10X thinner diameter than commercially available micro-endoscopes. We demonstrate micron-scale resolution, multi-spectral and volumetric imaging. In contrast to previous approaches, we show that this method has an improved acquisition speed that is sufficient to capture rapid neuronal dynamics in-vivo in rodents expressing a genetically encoded calcium indicator (GCaMP). Our results emphasize the potential of this technology in neuroscience applications and open up possibilities for cellular resolution imaging in previously unreachable brain regions.