ABSTRACT Optical imaging holds tremendous promise in our endeavor to understand brain functions. The major challenges for optical brain imaging are depth and speed. Due to strong tissue scattering, the penetration depth and imaging speed of optical microscopy in the mouse brain is very limited. These constraints in depth and speed make large scale, volumetric imaging of mouse brain activity, e.g., functional imaging of an entire mouse cortical column, out of reach of current imaging techniques. Hardware adaptive optics (AO) has proven to be valuable for in vivo brain imaging, and will have even larger impact for deep brain 3-photon microscopy; however, existing AO techniques require iterative optimization using fluorescence signal when imaging deep within scattering mouse brains, which is incompatible with large scale, volumetric imaging over a large range of depth and field of view. In this program, we will leverage the advantages provided by computational adaptive optics (CAO) in optical coherence tomography (OCT), specifically the strong OCT signal (from linear backscattering), which has the potential for parallel computing on a high-end graphics processing unit (GPU), and therefore can provide orders of magnitude speedup for the sensing of aberrations throughout a volume of interest. This information will be utilized to drive a hardware AO system to correct depth-dependent aberrations and significantly increase multiphoton imaging speed. We will demonstrate this approach through the imaging of spontaneous neural activity deep in the intact brain of awake and behaving mice. Successful completion of this program will provide the unprecedented capability of aberration sensing at depths reaching down into the hippocampus (> 1 mm) and dentate gyrus layers (> 1.5 mm), at an update rate of 10 Hz. With its high-speed and deep-tissue aberration sensing capability, with zero additional photobleaching and phototoxicity, our novel method for aberration sensing and correction is ideally positioned to transform our ability for large-scale, volumetric recording of mouse brain activity.