Brain Canada in conjunction with the Azrieli Foundation has provided us with funding, in the form of a platform support grant, for further investigation of Neurodevelopmental disorders in the Mouse. They have provided funding for scanning just over 1000 mice per year from fellow Canadian researchers.
So what does this mean? It means we want to scan your mice using high-field MRI! Below you will find additional information about mouse imaging in general and what it can provide you as well as information about the Mouse Imaging Centre (MICe) here in Toronto.
Mouse Imaging - General Information
You've created a new mouse model, either genetic or environmental, now what?
Historically, a given researcher has a hypothesis on their model, a certain area of the brain that is of interest based on the task or the known genetics, and such that is where they investigate or focus their attention. This is done often using histology, electrophysiology, RNA analysis or some other method. But what if you don't know where to look? Or what if there is more to the story than your area of interest.
(Additionally we are working on getting our systems up and running for imaging in the rat, and while imaging in the rat at our centre is still in its infancy, it is something to keep in mind going forward.)
That's where we come in ...
We want to examine your mouse. We want to find differences you weren't aware of and help you learn more about your model. We want to inform you where in the brain you should be looking for differences by highlighting regions of interest throughout the whole brain.
Magnetic resonance imaging is highly sensitive to differences in the brain at the mesoscopic level. This allows for a better targeted future work to understand the underlying cellular changes. In fact, our preparation protocol for the ex vivo scanning has been carefully designed to allow additional histological examination after the initial scanning performed here in an effort to determine the exact mechanism that is causing the difference found with out technique.
If you are interested in collaborating, please send us a paragraph describing your mouse model and any interventions of interest. Our emails are:
Jacob Ellegood - firstname.lastname@example.org, Jason Lerch - email@example.com
We have a several high-throughput whole brain imaging techniques that can be used to tell you accurately what is different in the brain of your mouse. A couple of those scans are listed here highlighting example papers.
Additionally, we have currently scanned over 75 different mouse models related to neurodevelopmental disorders and can compare your model with others that we have currently scanned to identify related genes or environmental conditions that are similar in phenotype to your model, which may be unexpected. We can also link your findings against the Allen connectivity or gene expression atlases to help generate further hypotheses.
An example paper where we have done this in the past examined 26 different mouse models related to autism:
Ellegood J, Anagnostou E, Babineau BA, Crawley JN, Lin L, Genestine M, DiCicco-Bloom E, Lai JK, Foster JA, Peñagarikano O, Geschwind DH, Pacey LK, Hampson DR, Laliberté CL, Mills AA, Tam E, Osborne LR, Kouser M, Espinosa-Becerra F, Xuan Z, Powell CM, Raznahan A, Robins DM, Nakai N, Nakatani J, Takumi T, van Eede MC, Kerr TM, Muller C, Blakely RD, Veenstra-VanderWeele J, Henkelman RM, Lerch JP. Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity. Mol Psychiatry. 2015 Feb;20(1):118-25.
Anatomical Imaging - MRI
Ex vivo brain samples are provided by the collaborator including samples from both the genetic mouse model of interest and a corresponding wild-type control. Details about preparation of the samples and shipping etc. are listed here -> Collaboration Information.
After scanning we will provide you with high resolution (40 um isotropic) images detailing the findings throughout the brain of your model. Additionally we will provide you with a detailed outline of the regional volume differences between your model and the control for 159 different regions.
Example - Arhgef6(-/y)
Recent papers of published using this technique:
Ellegood J, Nakai N, Nakatani J, Henkelman M, Takumi T, Lerch J. Neuroanatomical Phenotypes Are Consistent With Autism-Like Behavioral Phenotypes in the 15q11-13 Duplication Mouse Model. Autism Res. 2015 Oct;8(5):545-55
Belinson H, Nakatani J, Babineau BA, Birnbaum RY, Ellegood J, Bershteyn M, McEvilly RJ, Long JM, Willert K, Klein OD, Ahituv N, Lerch JP, Rosenfeld MG, Wynshaw-Boris A. Prenatal ?-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors. Mol Psychiatry. 2016 Feb 2.
Diffusion Tensor Imaging - DTI
This sequence can be used to provide the collaborator with a better understanding of the underlying tissue microstructure and possible differences there. It is commonly used to assess differences in the white matter, but can be looked at throughout the brain.
This can be examined in the same exact brains as the above sequence to provide more information about what the cause of the underlying volume difference may be.
Example - BTBR mouse
Example paper published using this technique:
Ellegood J, Babineau BA, Henkelman RM, Lerch JP, Crawley JN. 14. Neuroanatomical analysis of the BTBR mouse model of autism using magnetic resonance imaging and diffusion tensor imaging. Neuroimage. 2013 Apr 15;70:288-300.
Mouse Imaging Centre (MICe)
The Mouse Imaging Centre (MICe) at The Hospital for Sick Children was created as a unique resource and comprehensive imaging facility combining the latest state-of-the-art digital medical imaging technologies for the characterization of mouse functional genomics.
The goals of the Mouse Imaging Centre are:
- To provide a variety of medical imaging technologies adapted to studying genetically modified mice. These technologies include magnetic resonance (MR) imaging, micro computed tomography (micro-CT), ultrasound biomicroscopy (UBM), and optical projection tomography (OPT).
- To screen large numbers of mice for models of human diseases.
- To image an individual mouse over time to observe development, disease progression and responses to experimental treatment.
- To develop an exciting team of investigators with expertise in imaging techniques, computer science, engineering, imaging processing, developmental biology and mouse pathology.
- To work by collaboration with researchers throughout the world.
To achieve these goals, MICe is staffed by an exciting team of about 30 investigators with expertise in imaging techniques, computer science, engineering, imaging processing, developmental biology and mouse pathology.
Here is a list (with links to full-text articles) of some "core" publications from the Mouse Imaging Centre. These references are important because they describe the modalities and techniques that are regularly used in MICe research and provide the rationale behind many of our methodological choices. The list is long, but it (or at least the part of it relevant to your research) is recommended reading for any staff member or student. The references are grouped by topic/modality.
- Importance of 3D imaging: B.J. Nieman, M.D. Wong, R.M. Henkelman. Genes into geometry: imaging for mouse development in 3D. Current Opinion in Genetics & Development. 21(5): 638-646, 2011.
- Image-based phenotyping: R.M. Henkelman. Systems biology through mouse imaging centers: experience and new directions. Annual Review of Biomedical Engineering. 12(1): 143-166, 2010.
Multiple Mouse MRI
- Original idea: N.A. Bock, N.B. Konyer, R.M. Henkelman. Multiple mouse MRI. Magnetic Resonance in Medicine. 49(1): 158-167, 2003.
- Methods (video): J. Dazai, S. Spring, L.S. Cahill, R.M. Henkelman. Multiple mouse neuroanatomical magnetic resonance imaging (video article). Journal of Visualized Experiments (JoVE), 2010.
- In-/ex-vivo multiple mouse MRI: B.J. Nieman, J. Bishop, J. Dazai, N.A. Bock, J.P. Lerch, A. Feintuch, X.J. Chen, J.G. Sled, R.M. Henkelman. MR technology for biological studies in mice. NMR in Biomedicine. 20(3): 291-303, 2007.
- Cylindrical Fast Spin Echo (FSE) MRI: B.J. Nieman, N.A. Bock, J. Bishop, J.G. Sled, X.J. Chen, R.M. Henkelman. Fast spin-echo for multiple mouse magnetic resonance phenotyping. Magnetic Resonance in Medicine. 54(3): 532-537, 2005.
Fixed Brain MRI
- Justification of protocol: L.S. Cahill, C.L. Laliberté, J. Ellegood, S. Spring, J.A. Gleave, M.C. van Eede, J.P. Lerch, R.M. Henkelman, Preparation of fixed mouse brains for MRI, NeuroImage, 60(2):933-939, 2012.
- "Brain-in-a-Basket": J.P. Lerch, J.G. Sled, R.M. Henkelman. MRI phenotyping of genetically altered mice. Methods in Molecular Biology. 711: 349-361, 2011.
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