Image registration plays an important role in comparing images. It is particularly important in analyzing medical images like CT, MRI, PET, etc. to quantify different biological samples, to monitor disease progression and to fuse different modalities to support better diagnosis. The recent emergence of tissue clearing protocols enable us to take images at cellular level resolution. Image registration tools developed for other modalities are currently unable to manage images of such extreme high resolution. The recent popularity of deep learning based methods in the computer vision community justifies a rigorous investigation of deep-learning based methods on tissue cleared images along with their traditional counterparts. In this paper, we investigate and compare the performance of a deep learning based registration method with traditional optimization based methods on samples from tissue-clearing methods. From the comparative results it is found that a deep-learning based method outperforms all traditional registration tools in terms of registration time and has achieved promising registration accuracy.