Regional Specificity of Manganese accumulation and clearance in the mouse brain: implications for manganese-enhanced MRI

Grünecker, B., et al. "Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese‐enhanced MRI." NMR in Biomedicine (2012). Introduction: Similar to what we are trying to do now, this study was done mostly to establish MeMRI as a technique that the authors will now be able to use in order to study the hippocampus. Although the hippocampus is not the brain region we are interested, this study did look at multiple brain regions with the intent of better understanding manganese accumulation, clearance, structural affects, and degradation to the brain. They found similar results to what we are finding in that manganese accumulation and clearance rates can vary from brain region to brain region. These factors are important for multiple reasons when trying to plan out an experimental design in a new brain region, such as the RVLM. Design: • For the accumulation study 90 rats were separated into nine groups. One group was the control group and the rest of the groups received 1 dose of manganese and each group consecutively received an additional dose of manganese, so that group 8 had received 8 daily doses of manganese. Each group receiving a daily dose of 30 mg/kg manganese. Each group was then imaged 24 hours after the final injection. • For the clearance study 50 rats were broken up into five groups. Group one was imaged one week following injections, Group two was imaged two weeks following injections, Group three was imaged four weeks following injections, Group four was imaged eight weeks following injections, and Group five was imaged twelve weeks following injections. • Forty animals were then used to test hippocampus-dependent learning before and after injections of manganese. Animals were broken up into a control group and manganese group, and were tested for contextual and conditioned fear before and after injections. Conclusion: • Based off a logarithmic analysis this study found that manganese accumulation positively correlated with the number of dose injections given. This result is not surprising, however what was surprising was that between day 7 and day 8 injections a significant difference was seen in signal intensities. Meaning that even after 8 days of injections totaling a dose of 240mg/kg saturation of the hippocampus was not seen. Also important, it was seen that different brain regions accumulate manganese at different rates. There seemed to be a correlation between signal intensity and relative location to the brain ventricles. The brainstem was found to have a much slower rate of uptake compared to other regions such as the cerebral cortex. • Efflux rates were found to correlate well with accumulation rates, in that brain regions with faster uptake had faster efflux rates and brain regions with slower uptake had slower efflux rates. Unlike previous studies, the half life of manganese was found to be much shorter in this study. In the brain stem in particular the average half life was seen to be about 7 days. However, with that said, the signal intensities of manganese were not found to drop back to control levels until about 8 weeks post injection. • The learning test performed observing contextual and conditioned fear before and after manganese injections found that there was no significant difference pre versus post injection. This is important because it is evidence that even at doses of 120 mg/kg applied over a four day period the animals were not suffering from any learning disabilities that would insinuate brain damage to the hippocampus. ~JI