Various　genetic　mouse　models　have　been　used　to　understand　aspects　of　the　biology　of　the　neurodegenerative　disease.　A　rapid　growth　of　data　collection　from　the　mouse　brain　has　put　image　registration,　a　key　prerequisite　step　for　brain　image　analysis　in　great　focus.　SyN　(symmetric　image　normalization　method)　is　one　of　the　most　performed　diffeomorphic　strategies　which　has　been　widely　used　in　human　brain　mapping.　In　this　study,　we　optimized　the　SyN　strategy　for　tiny　mouse　brain.　The　optimized　protocol　is　able　to　accurately　remove　the　anatomical　variability　between　mouse　brain　MR　microscopy　(MRM)　and　offers　superior　performance　over　the　SyN　protocol　for　human.