Abstract
RationaleDividing cells can be detected in the live brain by positron emission tomography or optical imaging. Here we apply proton magnetic resonance spectroscopy (1HMRS) and a widely used spectral fitting algorithm to characterize the effect of increased neurogenesis after electroconvulsive shock in the live rodent brain via spectral signatures representing mobile lipids resonating at ∼1.30 ppm. In addition, we also apply the same 1HMRS methodology to metabolically profile glioblastomas with actively dividing cells growing in RCAS-PDGF mice.Methods 1HMRS metabolic profiles were acquired on a 9.4T MRI instrument in combination with LCModel spectral analysis of: 1) rat brains before and after ECS or sham treatments and 2) RCAS-PDGF mice with glioblastomas and wild-type controls. Quantified 1HMRS data were compared to post-mortem histology.ResultsDividing cells in the rat hippocampus increased ∼3-fold after ECS compared to sham treatment. Quantification of hippocampal metabolites revealed significant decreases in N-acetyl-aspartate but no evidence of an elevated signal at ∼1.3 ppm (Lip13a+Lip13b) in the ECS compared to the sham group. In RCAS-PDGF mice a high density (22%) of dividing cells characterized glioblastomas. Nile Red staining revealed a small fraction (3%) of dying cells with intracellular lipid droplets in the tumors of RCAS-PDGF mice. Concentrations of NAA were lower, whereas lactate and Lip13a+Lip13b were found to be significantly higher in glioblastomas of RCAS-PDGF mice, when compared to normal brain tissue in the control mice.ConclusionsMetabolic profiling using 1HMRS in combination with LCModel analysis did not reveal correlation between Lip13a+Lip13b spectral signatures and an increase in neurogenesis in adult rat hippocampus after ECS. However, increases in Lip13a+Lip13b were evident in glioblastomas suggesting that a higher density of actively dividing cells and/or the presence of lipid droplets is necessary for LCModel to reveal mobile lipids.
Highlights
Production of new neurons in the adult brain is associated with cognitive function, response to therapies, neurodegenerative diseases, and aging [1,2,3]
The RCASTVA-J12p16/M9Pten mouse models are based on the RCAS/tva technology, where transgenic mice carrying a viral receptor produced selectively in nestin-expressing cells are intracranially injected by a suspension of cultured mammalian cells expressing genes that can result in malignant cell transformation, such as PDGF or Kras
The cortical 1HMRS spectra were of inferior quality compared to those acquired in the hippocampus and five cortical spectra were discarded from the final analysis due to highly aberrant baseline LCModel fittings
Summary
Production of new neurons in the adult brain is associated with cognitive function, response to therapies, neurodegenerative diseases, and aging [1,2,3]. Synthesized DNA of proliferating cells incorporates 18F-FLT much the same way it incorporates halogenated thymidine analogs 5bromo, or 5-chloro-29-deoxyuridine (BrdU and CldU), enabling the use of PET for the detection of dividing cells, including neuronal progenitors [5,7,8] Another imaging technique which has been tested for tracking of neurogenesis in the live brain is proton magnetic resonance spectroscopy (1HMRS) [9,10,11]. The origin of the 1.28 ppm signal in NPCs is thought to stem from mobile fatty acyl chains of triacylglycerides (TG), free fatty acids, and cholesteryl esters [13] residing in the cytoplasm or near the cell membranes of neural progenitor cells (NPCs) This possibility is supported by the association between intracellular lipid bodies either adjacent to the plasma membrane or within the cytoplasm and the 1HMRS TG signal in various tissues including brain [13].
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