We address the 3D volume reconstruction problem from depth adjacent sub-volumes acquired by a confocal laser scanning microscope (CLSM). Our goal is to align the sub-volumes by estimating a set of optimal global transformations that preserve morphological continuity of medical structures, e.g., blood vessels, in the reconstructed 3D volume. We approach the problem by learning morphological characteristics of structures of interest in each sub-volume to understand global alignment transformations. Based on the observations of morphology, sub-volumes are aligned by connecting the morphological features at the sub-volume boundaries by minimizing morphological discontinuity. To minimize the discontinuity, we introduce three morphological discontinuity metrics: discontinuity magnitude at sub-volume boundary points, and overall and junction discontinuity residuals after polynomial curve fitting to multiple aligned sub-volumes. The proposed techniques have been applied to the problem of alig...