title: Improved visualization of neuronal injury following glial activation by manganese enhanced MRI.
abstract: Research directed at anatomical, integrative and functional activities of the central nervous system (CNS) can be realized through bioimaging. A wealth of data now demonstrates the utility of magnetic resonance imaging (MRI) towards unraveling complex neural connectivity operative in health and disease. A means to improve MRI sensitivity is through contrast agents and notably manganese (Mn²⁺). The Mn²⁺ ions enter neurons through voltage-gated calcium channels and unlike other contrast agents such as gadolinium, iron oxide, iron platinum and imaging proteins, provide unique insights into brain physiology. Nonetheless, a critical question that remains is the brain target cells serving as sources for the signal of Mn²⁺ enhanced MRI (MEMRI). To this end, we investigated MEMRI's abilities to detect glial (astrocyte and microglia) and neuronal activation signals following treatment with known inflammatory inducing agents. The idea is to distinguish between gliosis (glial activation) and neuronal injury for the MEMRI signal and as such use the agent as a marker for neural activity in inflammatory and degenerative disease. We now demonstrate that glial inflammation facilitates Mn²⁺ neuronal ion uptake. Glial Mn²⁺ content was not linked to its activation. MEMRI performed on mice injected intracranially with lipopolysaccharide was associated with increased neuronal activity. These results support the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults including neuroinflammation. We conclude that the MEMRI signal enhancement is induced by inflammation stimulating neuronal Mn²⁺ uptake.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Aditya N
authors.initials: AN
authors.lastname: Bade
authors.forename: Biyun
authors.initials: B
authors.lastname: Zhou
authors.forename: Adrian A
authors.initials: AA
authors.lastname: Epstein
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.forename: Jiangtao
authors.initials: J
authors.lastname: Luo
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boska
authors.forename: Yutong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018920:Coculture Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008345:Manganese / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D016716:PC12 Cells; D051381:Rats; D015854:Up-Regulation / Q000502:physiology
chemical_list: D008345:Manganese