NuMorph: Tools for cortical cellular phenotyping in tissue-cleared whole-brain images

Oleh Krupa; Giulia Fragola; Ellie Hadden-Ford; Jessica T Mory; Tianyi Liu; Zachary Humphrey; Benjamin W Rees; Ashok Krishnamurthy; William D Snider; Mark J Zylka; Guorong Wu; Lei Xing; Jason L Stein

doi:10.1016/j.celrep.2021.109802

NuMorph: Tools for cortical cellular phenotyping in tissue-cleared whole-brain images

Cell Rep. 2021 Oct 12;37(2):109802. doi: 10.1016/j.celrep.2021.109802.

Authors

Affiliations

¹ Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27514, USA; UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Renaissance Computing Institute, Chapel Hill, NC 27517, USA; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁷ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
⁸ Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
⁹ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: lxing@email.unc.edu.
¹⁰ UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: jason_stein@med.unc.edu.

Abstract

Tissue-clearing methods allow every cell in the mouse brain to be imaged without physical sectioning. However, the computational tools currently available for cell quantification in cleared tissue images have been limited to counting sparse cell populations in stereotypical mice. Here, we introduce NuMorph, a group of analysis tools to quantify all nuclei and nuclear markers within the mouse cortex after clearing and imaging by light-sheet microscopy. We apply NuMorph to investigate two distinct mouse models: a Topoisomerase 1 (Top1) model with severe neurodegenerative deficits and a Neurofibromin 1 (Nf1) model with a more subtle brain overgrowth phenotype. In each case, we identify differential effects of gene deletion on individual cell-type counts and distribution across cortical regions that manifest as alterations of gross brain morphology. These results underline the value of whole-brain imaging approaches, and the tools are widely applicable for studying brain structure phenotypes at cellular resolution.

Keywords: image analysis; neurofibromatosis; tissue clearing; whole-brain imaging.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Video-Audio Media

MeSH terms

Animals
Cell Nucleus / metabolism
Cell Nucleus / pathology*
Cerebral Cortex / metabolism
Cerebral Cortex / pathology*
DNA Topoisomerases, Type I / deficiency
DNA Topoisomerases, Type I / genetics
Gene Deletion
Genes, Neurofibromatosis 1
Histocytological Preparation Techniques*
Image Processing, Computer-Assisted
Mice
Mice, Knockout
Nerve Degeneration*
Neuroglia / metabolism
Neuroglia / pathology*
Neuroimaging*
Neurons / metabolism
Neurons / pathology*
Phenotype
Support Vector Machine

Substances

DNA Topoisomerases, Type I

Abstract

Publication types

MeSH terms

Substances

Grants and funding