Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese‐enhanced MRI

Abstract

Manganese-enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional-specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl2 , as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl2 . Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half-life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T1 -weighted signal intensities after manganese application, and manganese-induced memory impairment has been suggested, we assessed hippocampus-dependent learning as well as possible manganese-induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn(2+) application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for sufficient clearance of the paramagnetic ion from cerebral tissue.

Manganese-Enhanced Magnetic Resonance Imaging for Detection of Vasoactive Intestinal Peptide Receptor 2 Agonist Therapy in a Model of Parkinson's Disease

“…dose per day for 2 days) were used to control uneven Mn 2+ distribution caused by a variety reasons, including differences in extracellular and intracellular Mn 2+ concentrations, anterograde transport through neurons, and injection variability. This design allows Mn 2+ to reach a stable distribution as previously published by others and our laboratory [28,29]. The period of stable distribution allows for reproducible and even distribution of signal during MRI [28][29][30][31][32][33][34].…”

“…This design allows Mn 2+ to reach a stable distribution as previously published by others and our laboratory [28,29]. The period of stable distribution allows for reproducible and even distribution of signal during MRI [28][29][30][31][32][33][34]. For studies performed 2 days post-MPTP treatment, the first MnCl 2 was injected 4 h after MPTP/DPBS administration.…”

A comparative analysis of mouse and human medial geniculate nucleus connectivity: A DTI and anterograde tracing study

“…Given the growing literature that implicates the auditory thalamic nuclei in disorders as diverse as tinnitus and schizophrenia there is a need to study these pathways and their function. Additionally, excellent work has begun to demonstrate the role of mice in understanding stress related brain structure and function (Golub et al, 2011; Grunecker et al, 2013). Our data provide a precedent for the use of tractography in a comparative and translationally meaningful way with a small animal model.…”

Manganese Toxicity Upon Overexposure: a Decade in Review

“…The half-lives of Mn in these tissues are about 5–7 days, with the longest retention in the periaqueductal gray, amygdala, and entorhinal cortex [77]. The elimination rate from brain tissue is expected to be slower than from either liver or kidney.…”