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Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγ c null Mouse Brain Atlas

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Abstract

Strain specific mouse brain magnetic resonance imaging (MRI) atlases provide coordinate space linked anatomical registration. This allows longitudinal quantitative analyses of neuroanatomical volumes and imaging metrics for assessing the role played by aging and disease to the central nervous system. As NOD/scid-IL-2Rγ c null (NSG) mice allow human cell transplantation to study human disease, these animals are used to assess brain morphology. Manganese enhanced MRI (MEMRI) improves contrasts amongst brain components and as such can greatly help identifying a broad number of structures on MRI. To this end, NSG adult mouse brains were imaged in vivo on a 7.0 Tesla MR scanner at an isotropic resolution of 100 μm. A population averaged brain of 19 mice was generated using an iterative alignment algorithm. MEMRI provided sufficient contrast permitting 41 brain structures to be manually labeled. Volumes of 7 humanized mice brain structures were measured by atlas-based segmentation and compared against non-humanized controls. The humanized NSG mice brain volumes were smaller than controls (p < 0.001). Many brain structures of humanized mice were significantly smaller than controls. We posit that the irradiation and cell grafting involved in the creation of humanized mice were responsible for the morphological differences. Six NSG mice without MnCl2 administration were scanned with high resolution T2-weighted MRI and segmented to test broad utility of the atlas.

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Abbreviations

NSG:

NOD/scid-IL-2Rγ c null

HIV-1:

Human immunodeficiency virus type one

ART:

Antiretroviral therapy

DTI:

Diffusion tensor imaging

PK:

Pharmacokinetics

PD:

Pharmacodynamics

MRI:

Magnetic resonance imaging

MEMRI:

Manganese enhanced MRI

LDDMM:

Large deformation diffeomorphic metric mapping

CH:

Cerebrum

OLF:

Olfactory areas

MOBgl:

Main olfactory bulb, glomerular layer

MOBgr:

Main olfactory bulb, granule layer

AOB:

Accessory olfactory bulb

AON:

Anterior olfactory nucleus

PIR:

Piriform area

HPF:

Hippocampal formation

CA1_CA2_SUB:

Field CA1 + Field CA2 + Subiculum

CA3:

Field CA3 of hippocampus

DG-mo:

Dentate gyrus_molecular layer

DG-(po + sg):

Dentate gyrus_(polymorph layer + granular cell layer)

STR:

Striatum

CP:

Caudoputamen

STRv:

Striatum ventral region

LSX:

Lateral septal complex

PAL:

Pallidum

PALc:

Pallidium, caudal region

GP:

Globus pallidus

MS:

Medial septal nucleus

AMY:

Amygdala

FB:

Fiber tracts

cc:

Corpus callosum

opt:

Optic tract

ac:

Anterior commissure

RFB:

Rest of fiber tracts

BS:

Brain stem

TH:

Thalamus

EPI:

Epithalamus

HY:

Hypothalamus

IC:

Inferior colliculus

PAG:

Periaqueductal gray

PRT:

Pretectal region

SN:

Substantia nigra

RMB:

Rest of midbrain

P:

Pons

MY:

Medulla

CB:

Cerebellum

CBXmo:

Cerebellar cortex, molecular layer

CBXgr:

Cerebellar cortex, granular layer

CBwm:

Cerebellar white matter

FN:

Fastigial nucleus

IP:

Interpose nucleus

DN:

Dentate nucleus

VS:

Ventricular system

VL:

Lateral ventricles

V3:

Third ventricle

AQ:

Cerebral aqueduct

V4:

Fourth ventricle.

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Acknowledgments

This work was supported, in part, by the University of Nebraska Foundation which includes individual donations from Carol Swarts and Frances and Louie Blumkin, the Vice Chancellor’s office of the University of Nebraska Medical Center for Core Facility Developments, Shoemaker Award for Neurodegenerative Research, ViiV Healthcare and National Institutes of Health grants K25 MH08985, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P01 NS43985, P30 MH062261 and R01 AG043540. Authors thank Dr. Jorge Rodriguez-Sierra for instructive discussions on mouse brain anatomy.

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Author notes

  1. Biyun Zhou

    Present address: Anesthesiology, Tongji Medical College, Huanzhong University of Science and Technology, Wuhan, China

Authors and Affiliations

  1. Department of Radiology, University of Nebraska Medical Center, 981045 Nebraska Medical Center, Omaha, NE, USA

    Balasrinivasa R. Sajja, Biyun Zhou, Mariano G. Uberti, Michael D. Boska & Yutong Liu

  2. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE, USA

    Aditya N. Bade, Santhi Gorantla, Howard E. Gendelman, Michael D. Boska & Yutong Liu

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  1. Balasrinivasa R. Sajja
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  2. Aditya N. Bade
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Correspondence to Yutong Liu.

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Aditya N. Bade and Biyun Zhou contributed equally to this work.

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Sajja, B.R., Bade, A.N., Zhou, B. et al. Generation and Disease Model Relevance of a Manganese Enhanced Magnetic Resonance Imaging-Based NOD/scid-IL-2Rγ c null Mouse Brain Atlas. J Neuroimmune Pharmacol 11, 133–141 (2016). https://doi.org/10.1007/s11481-015-9635-8

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