The inability to acquire clean high-resolution (HR) electron microscopy (EM) images over a large brain tissue volume hampers many neuroscience studies. To address this challenge, we propose a deep-learning-based image super-resolution (SR) approach to computationally reconstruct clean HR 3D-EM with a large field of view (FoV) from noisy low-resolution (LR) acquisition. Our contributions are I) Investigating training with no-clean references for $\ell_2$ and $\ell_1$ loss functions; II) Introducing a novel network architecture, named EMSR, for enhancing the resolution of LR EM images while reducing inherent noise; and, III) Comparing different training strategies including using acquired LR and HR image pairs, i.e., real pairs with no-clean references contaminated with real corruptions, the pairs of synthetic LR and acquired HR, as well as acquired LR and denoised HR pairs. Experiments with nine brain datasets showed that training with real pairs can produce high-quality super-resolved results, demonstrating the feasibility of training with non-clean references for both loss functions. Additionally, comparable results were observed, both visually and numerically, when employing denoised and noisy references for training. Moreover, utilizing the network trained with synthetically generated LR images from HR counterparts proved effective in yielding satisfactory SR results, even in certain cases, outperforming training with real pairs. The proposed SR network was compared quantitatively and qualitatively with several established SR techniques, showcasing either the superiority or competitiveness of the proposed method in mitigating noise while recovering fine details.

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