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Abstract

Manganese-enhanced MRI (MEMRI) is a new tool for in vivo brain imaging. The
technique is based on the fact that Mn2+ ions reduce the longitudinal (i.e. spinlattice)
relaxation times, T1, of water protons. Consequently T1-weighted MR images show enhanced signal intensity at the locations where Mn2+ ions accumulate. When administered systemically, Mn2+ reaches the brain and enters the cells via voltagegated calcium channels. Therefore, Mn2+ accumulation in the brain is proportional to the neural activity, allowing in vivo visualization of functional maps. However, the technique presents several drawbacks that can challenge its applicability, the most important being the potential toxicity of the ion in the tissue, leading to neuronal death when applied in high doses or motor disorders after chronic exposure. The toxic effects of MnCl2 on motor activity and learning were evaluated in Sprague-Dawley rats. Two ways of MnCl2 administration were compared. In Exp.1, naïve rats were given access to a running wheel (3h/day; 6 days). On day 7, MnCl2 (0.1, 0.2, and 0.5 mmol/kg) was injected (s.c.) 3h prior the running test. Control rats received saline injection. A significant dose-dependent decrease of motor activity was
observed for all doses. In Exp.2, rats were first implanted (i.p.) with osmotic pumps
loaded with MnCl2 (0.5 mmol/kg; 1.0 \u03bcl per hour; 7 days) or saline and then
given access to the running wheels. The motor activity did not differ between the two
groups. In Exp.3, rats were trained to perform a T-maze alternation task and after
reaching an asymptote performance the effect of acute s.c. injections of MnCl2 (0.1
and 0.5 mmol/kg) was tested. Manganese did not affect the choice accuracy, however, the highest dose resulted in increased response latency, as expected from Ex! p.1 results. In Exp.4 rats with implanted Mn- or saline-loaded pumps were trained on the same T-maze alternation task. We found no differences in any of the learning parameters studied, between the two groups. We conclude that most common
protocols of functional MEMRI produce undesirable behavioral effects that can be
avoided by the gradual release of MnCl2 via osmotic pump delivery. The reported protocol represents an appropriate alternative for longitudinal studies using this very important technique.