Manganese Dynamics in Mouse Brain After Systemic MnCl2 Administration for Activation-Induced Manganese-Enhanced MRI.

Hiroki Tanihira,Satomi Kikuta,Noriyasu Homma,Makoto Osanai,Tomonori Fujiwara

doi:10.3389/fncir.2021.787692

Abstract

Activation-induced manganese-enhanced MRI (AIM-MRI) is an attractive tool for non-invasively mapping whole brain activities. Manganese ions (Mn2+) enter and accumulate in active neurons via calcium channels. Mn2+ shortens the longitudinal relaxation time (T1) of H+, and the longitudinal relaxation rate R1 (1/T1) is proportional to Mn2+ concentration. Thus, AIM-MRI can map neural activities throughout the brain by assessing the R1 map. However, AIM-MRI is still not widely used, partially due to insufficient information regarding Mn2+ dynamics in the brain. To resolve this issue, we conducted a longitudinal study looking at manganese dynamics after systemic administration of MnCl2 by AIM-MRI with quantitative analysis. In the ventricle, Mn2+ increased rapidly within 1 h, remained high for 3 h, and returned to near control levels by 24 h after administration. Microdialysis showed that extracellular Mn returned to control levels by 4 h after administration, indicating a high concentration of extracellular Mn2+ lasts at least about 3 h after administration. In the brain parenchyma, Mn2+ increased slowly, peaked 24–48 h after administration, and returned to control level by 5 days after a single administration and by 2 weeks after a double administration with a 24-h interval. These time courses suggest that AIM-MRI records neural activity 1–3 h after MnCl2 administration, an appropriate timing of the MRI scan is in the range of 24–48 h following systemic administration, and at least an interval of 5 days or a couple of weeks for single or double administrations, respectively, is needed for a repeat AIM-MRI experiment.

Highlights

The first step in understanding the expression mechanisms of brain functions and pathophysiological mechanisms of neurological disorders is to understand which brain regions are associated with those functions and diseases
Each point represents the R1 values before (n = 20), and 1 (n = 11), 3 (n = 13), 5 (n = 7), 24 (n = 15), 48 (n = 6), 96 (n = 6), and 120 (n = 6) hours after the administration. *P < 0.05, ****P < 0.0001 (Dunnet test, compared with R1 values before MnCl2 administration). These values are shown in Table 1. (C) Time course of the change in Mn concentration ( [Mn]) in the extracellular space of the striatum compared with pre-administration
We aimed to determine (1) when Mn2+ flows into neurons, (2) when Mn2+ in the extracellular space has been cleared while maintaining intracellular Mn2+, and (3) what is the appropriate interval required for repeated measurements

Summary

Introduction

The first step in understanding the expression mechanisms of brain functions and pathophysiological mechanisms of neurological disorders is to understand which brain regions are associated with those functions and diseases. To address this issue, we need methods to measure and analyze neural activities within the entire brain volume. A paramagnetic ion, Mn2+ shortens the longitudinal relaxation time (T1) of protons (H+), and the longitudinal relaxation rate R1 (=1/T1) is proportional to Mn2+ concentration ([Mn2+]; Nordhøy et al, 2003; Aoki et al, 2004; Silva et al, 2004; Tambalo et al, 2009; Kikuta et al, 2015). AIMMRI can use R1 to measure neural activity changes in a freelymoving subject with the advantage of being insensitive to blood hemodynamics (Tambalo et al, 2009)

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Conclusion