ABSTRACT
Non-invasive imaging has the potential to play a crucial role in the characterization and translation of experimental animal models to investigate human brain development and disorders, especially when employed to study animal models that more accurately represent features of human neuroanatomy. The purpose of this study was to build and make available MRI and DTI templates and analysis tools for the ferret brain as the ferret is a well-suited species for pre-clinical MRI studies with folded cortical surface, relatively high white matter volume and body dimensions that allow imaging with pre-clinical MRI scanners. Four ferret brain templates were built in this study - in-vivo MRI and DTI and ex-vivo MRI and DTI - using brain images across many ferrets and region of interest (ROI) masks corresponding to established ferret neuroanatomy were generated by semi-automatic and manual segmentation. The templates and ROI masks were used to create a web-based ferret brain viewing software for browsing the MRI and DTI volumes with annotations based on the ROI masks. A second objective of this study was to provide a careful description of the imaging methods used for acquisition, processing, registration and template building and to demonstrate several voxelwise analysis methods including Jacobian analysis of morphometry differences between the female and male brain and bias-free identification of DTI abnormalities in an injured ferret brain. The templates, tools and methodological optimization presented in this study are intended to advance non-invasive imaging approaches for human-similar animal species that will enable the use of pre-clinical MRI studies for understanding and treating brain disorders.
Subject(s)
Brain Mapping/methods , Brain/anatomy & histology , Ferrets/anatomy & histology , White Matter/anatomy & histology , Animals , Atlases as Topic , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging , Image Processing, Computer-Assisted , Male , Signal Processing, Computer-Assisted , SoftwareABSTRACT
Blood-brain barrier (BBB) transcapillary transport was studied after insertion of cannulas and microdialysis probes into the brains of three groups of rats. Quantitative autoradiography was used to measure changes in BBB permeability around the insertion site. In the first group, BBB function was measured with 14C-sucrose at times from immediately, and up to 28 days, after insertion of a microdialysis probe. BBB function was disrupted biphasically: a 19-fold increase in the influx constant (K1) of sucrose occurred immediately after insertion with a second 17-fold increase at 2 days, followed by a slow decline to 5 times normal values at 28 days. In the second group, 14C-dextran (70 kDa) was used to measure BBB transcapillary transport; K1 was increased 90-fold after probe insertion. In the 3rd group, 14C-AIB (alpha-aminoisobutyric acid) was used to evaluate BBB transport after insertion of a 27 gauge cannula, which was used to infuse 1 microliter of saline over 5 min. The K1 of AIB was increased 25 times control values. We conclude that BBB transcapillary transport function is disturbed in response to insertion of brain cannulas and/or microdialysis probes, that BBB dysfunction is maximal at the cannula or probe tip, varies with time after insertion, may persist for at least 28 days after insertion, and occurs over a wide molecular range of solutes. These results suggest caution when using microdialysis as a method to study normal BBB function, and suggest that microdialysis may overestimate the rate of transfer into and out of the brain.
