Manganese-Enhanced Magnetic Resonance Imaging And Its Applications In Brain Activities And Neuronal Tract Tracing In Rats

Calcium ion (Ca²⁺) is an important substrate for neurotransmission, which plays an essential role in neural function. Biologically divalent manganese ion (Mn²⁺) is an analog to Ca²⁺, which can enter neurons via voltage-gated Ca²⁺ channels and be transported through neuronal microtubule system. In addition, Mn²⁺ is paramagnetic and can be used as contrast agent in magnetic resonance imaging (MRI). Taking advantage of these properties of Mn²⁺, Lin and Koretsky developed manganese-enhanced magnetic resonance imaging (MEMRI) in 1997. Using Mn²⁺ as the tracer for Ca²⁺, they showed that, serving as the surrogate for neuronal activities, the intracellular and trans-synaptic transport of Mn²⁺ in the central nervous system could be monitored and recorded by MRI. Nowadays, this method has found wide applications in studying brain and heart activities, neuronal tracts tracing and delineation of fine cerebral neuroarchitecture etc.In this dissertation, three basic questions in MEMRI were addressed. First, which manganese compound is the most suitable for MEMRI? Based on experimental evidence and taking into account the availability, water solubility, redox properties, toxicity and relaxitivity of the manganese compounds, MnCl2 were selected for use in MEMRI. Secondly, at which concentration and dosage, intracerebrally injected MnCl2 will not cause significant toxicity to neurons near the injection site? The experiments showed that injecting 100 nL of 400mM MnCl2 solution into brain result in significant neuronal loss, but injection of the same amount of 200mM MnCl2 solution is safe. Thirdly, how should exogenous Mn²⁺ be administered into the subjects? The results showed that oral administration, though safe and less stressful, results in only minimal manganese deposition in the brain. Intraperitonially injected Mn²⁺ rapidly enters cerebral ventricles via choroid plexus in mice, but the transportation to brain parenchyma is slow due to the limited ability of Mn²⁺ to cross blood brain barrier (BBB) even when it is partly damaged by (S)-3-chloro-1,2-propanediol. In comparison, intraventricularlly injected Mn²⁺ can enter brain parenchyma more rapidly, and deposit selectively in the hippocampus and ventral globus pallidus. These studies suggest that in MEMRI one should choose the...