title: Lithium Accumulates in Neurogenic Brain Regions as Revealed by High Resolution Ion Imaging.
abstract: Lithium (Li) is a potent mood stabilizer and displays neuroprotective and neurogenic properties. Despite extensive investigations, the mechanisms of action have not been fully elucidated, especially in the juvenile, developing brain. Here we characterized lithium distribution in the juvenile mouse brain during 28 days of continuous treatment that result in clinically relevant serum concentrations. By using Time-of-Flight Secondary Ion Mass Spectrometry- (ToF-SIMS) based imaging we were able to delineate temporospatial lithium profile throughout the brain and concurrent distribution of endogenous lipids with high chemical specificity and spatial resolution. We found that Li accumulated in neurogenic regions and investigated the effects on hippocampal neurogenesis. Lithium increased proliferation, as judged by Ki67-immunoreactivity, but did not alter the number of doublecortin-positive neuroblasts at the end of the treatment period. Moreover, ToF-SIMS revealed a steady depletion of sphingomyelin in white matter regions during 28d Li-treatment, particularly in the olfactory bulb. In contrast, cortical levels of cholesterol and choline increased over time in Li-treated mice. This is the first study describing ToF-SIMS imaging for probing the brain-wide accumulation of supplemented Li in situ. The findings demonstrate that this technique is a powerful approach for investigating the distribution and effects of neuroprotective agents in the brain.
authors.affiliation: Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.|Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Giulia
authors.initials: G
authors.lastname: Zanni
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michno
authors.affiliation: Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Di Martino
authors.affiliation: Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Tjärnlund-Wolf
authors.affiliation: Department of Chemistry-Biomedical Centre, Uppsala University, Uppsala, Sweden.
authors.forename: Jean
authors.initials: J
authors.lastname: Pettersson
authors.affiliation: Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Charlotte Elizabeth
authors.initials: CE
authors.lastname: Mason
authors.affiliation: Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Gustaf
authors.initials: G
authors.lastname: Hellspong
authors.affiliation: Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.|Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
authors.affiliation: Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.|Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.|Department of Chemistry and Chemical Engineering, Chalmers University of Technology, Gothenburg, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hanrieder
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001835:Body Weight; D001921:Brain / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D007700:Kinetics; D050356:Lipid Metabolism; D008094:Lithium / Q000097:blood / Q000378:metabolism*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism
chemical_list: D008094:Lithium