Whole Murine Brain Imaging Based on Optical Elastic Scattering

Abstract

Imaging whole brains is one of the central efforts of biophotonics. While the established imaging modalities used in radiology, such as MRI and CT, have enabled in vivo investigations of various cognitive and affective processes, the prevailing resolution of one-cubic-millimeter has limited their use in studying the “ground-truth” of neuronal activities. On the other hand, electron microscopy (EM) visualizes the finest anatomic structures at a resolution of around 30 nm. However, the extensive tissue preparation process and the required large-scale morphological reconstruction restrict this method to small sample volumes. Light microscopy (LM) has the potential to bridge the above two spatial scales, with a resolution ranging from a few hundred nanometers to a few micrometers. Recent advances in tissue clearing have paved the way for optical investigation of large intact tissue volumes. However, most of these LM studies rely on fluorescence—a nonlinear optical process to provide contrast. This chapter introduces an alternative type of LM that is solely based on a linear optical process—elastic scattering, which has some unique advantages over conventional LM methods for the investigation of large-scale biological systems, such as intact murine brains. Here, we will first lay out the background and the motivation of developing this scattering-based method. Then, the basic principle of this approach will be introduced, including controlling tissue scattering and coherent imaging. Next, we explore current implementation and practical considerations. Up-to-date results and the utility of this method will also be demonstrated. Finally, we discuss current limitations and future directions in this promising field.