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

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.

SUBMITTER: Tanihira H

PROVIDER: S-EPMC8722453 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Chronic pain is a major health problem, affecting 10-30% of the population in developed countries. While chronic pain is defined as "a persistent complaint of pain lasting for more than the usual period for recovery," recently accumulated lines of evidence based on human brain imaging have revealed that chronic pain is not simply a sustained state of nociception, but rather an allostatic state established through gradually progressing plastic changes in the central nervous system. To visualize the brain activity associated with spontaneously occurring pain during the shift from acute to chronic pain under anesthetic-free conditions, we used manganese-enhanced magnetic resonance imaging (MEMRI) with a 9.4-T scanner to visualize neural activity-dependent accumulation of manganese in the brains of mice with hind paw inflammation. Time-differential analysis between 2- and 6-h after formalin injection to the left hind paw revealed a significantly increased MEMRI signal in various brain areas, including the right insular cortex, right nucleus accumbens, right globus pallidus, bilateral caudate putamen, right primary/secondary somatosensory cortex, bilateral thalamus, right amygdala, bilateral substantial nigra, and left ventral tegmental area. To analyze the role of the right amygdala in these post-formalin MEMRI signals, we repeatedly inhibited right amygdala neurons during this 2-6-h period using the "designer receptors exclusively activated by designer drugs" (DREADD) technique. Pharmacological activation of inhibitory DREADDs expressed in the right amygdala significantly attenuated MEMRI signals in the bilateral infralimbic cortex, bilateral nucleus accumbens, bilateral caudate putamen, right globus pallidus, bilateral ventral tegmental area, and bilateral substantia nigra, suggesting that the inflammatory pain-associated activation of these structures depends on the activity of the right amygdala and DREADD-expressing adjacent structures. In summary, the combined use of DREADD and MEMRI is a promising approach for revealing regions associated with spontaneous pain-associated brain activities and their causal relationships.

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

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