Noninvasive and Quantitative Monitoring of Adult Neuronal Stem Cell Migration in Mouse Brain Using Bioluminescence Imaging

It is now generally accepted that continuous neurogenesis occurs in the adult mammalian brain, including that of humans. Modulation of adult neurogenesis can provide therapeutic benefits for various brain disorders, including stroke and Parkinson's disease. The subventricular zone‐olfactory bulb pathway is one of the preferred model systems by which to study neural stem cell proliferation, migration, and differentiation in adult rodent brain. Research on adult neurogenesis would greatly benefit from reliable methods for long‐term noninvasive in vivo monitoring. We have used lentiviral vectors encoding firefly luciferase to stably mark endogenous neural stem cells in the mouse subventricular zone. We show that bioluminescence imaging (BLI) allows quantitative follow‐up of the migration of adult neural stem cells into the olfactory bulb in time. Moreover, we propose a model to fit the kinetic data that allows estimation of migration and survival times of the neural stem cells using in vivo BLI. Long‐term expression of brain‐derived neurotrophic factor in the subventricular zone attenuated neurogenesis, as detected by histology and BLI. In vivo monitoring of the impact of drugs or genes on adult neurogenesis is now within reach.

[1]  F. Gage,et al.  Genetic influence on neurogenesis in the dentate gyrus of adult mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  P. Lledo,et al.  In vivo imaging of migrating neurons in the mammalian forebrain. , 2005, Chemical senses.

[3]  Claes Nordborg,et al.  Human Neuroblasts Migrate to the Olfactory Bulb via a Lateral Ventricular Extension , 2007, Science.

[4]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[5]  L. Mortelmans,et al.  Noninvasive monitoring of long-term lentiviral vector-mediated gene expression in rodent brain with bioluminescence imaging. , 2006, Molecular therapy : the journal of the American Society of Gene Therapy.

[6]  Charles Duyckaerts,et al.  Dopamine depletion impairs precursor cell proliferation in Parkinson disease , 2004, Nature Neuroscience.

[7]  A. Carleton,et al.  Local neurons play key roles in the mammalian olfactory bulb , 2003, Journal of Physiology-Paris.

[8]  J. Barrio,et al.  Noninvasive, repetitive, quantitative measurement of gene expression from a bicistronic message by positron emission tomography, following gene transfer with adenovirus. , 2002, Molecular therapy : the journal of the American Society of Gene Therapy.

[9]  J. García-Verdugo,et al.  Thymidine Analogs Are Transferred from Prelabeled Donor to Host Cells in the Central Nervous System After Transplantation: A Word of Caution , 2006, Stem cells.

[10]  M. Kokaia,et al.  Decreased expression of brain‐derived neurotrophic factor in BDNF+/− mice is associated with enhanced recovery of motor performance and increased neuroblast number following experimental stroke , 2006, Journal of neuroscience research.

[11]  Arturo Alvarez-Buylla,et al.  Chain Migration of Neuronal Precursors , 1996, Science.

[12]  Stanley J. Wiegand,et al.  Infusion of Brain-Derived Neurotrophic Factor into the Lateral Ventricle of the Adult Rat Leads to New Neurons in the Parenchyma of the Striatum, Septum, Thalamus, and Hypothalamus , 2001, The Journal of Neuroscience.

[13]  I. Black,et al.  Marrow Stromal Cells Transplanted to the Adult Brain Are Rejected by an Inflammatory Response and Transfer Donor Labels to Host Neurons and Glia , 2006, Stem cells.

[14]  E. Hirsch,et al.  Dopaminergic Substantia Nigra Neurons Project Topographically Organized to the Subventricular Zone and Stimulate Precursor Cell Proliferation in Aged Primates , 2006, The Journal of Neuroscience.

[15]  Alan P. Koretsky,et al.  Magnetic resonance imaging of the migration of neuronal precursors generated in the adult rodent brain , 2006, NeuroImage.

[16]  D. H. Bell,et al.  Mitotic neuroblasts in the 9-day-old and 11-month-old rodent hippocampus , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  A. Benraiss,et al.  Adenoviral Brain-Derived Neurotrophic Factor Induces Both Neostriatal and Olfactory Neuronal Recruitment from Endogenous Progenitor Cells in the Adult Forebrain , 2001, The Journal of Neuroscience.

[18]  Y. R. Kim,et al.  Neural stem cell transplant survival in brains of mice: assessing the effect of immunity and ischemia by using real-time bioluminescent imaging. , 2006, Radiology.

[19]  Ralph Weissleder,et al.  In vivo tracking of neural progenitor cell migration to glioblastomas. , 2003, Human gene therapy.

[20]  Zeger Debyser,et al.  Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo. , 2006, Human gene therapy.

[21]  B. Nuttin,et al.  Optimized lentiviral vector production and purification procedure prevents immune response after transduction of mouse brain , 2003, Gene Therapy.

[22]  E. Arenas,et al.  Neuroprotection by GDNF-secreting stem cells in a Huntington's disease model: optical neuroimage tracking of brain-grafted cells , 2007, Gene Therapy.

[23]  Ralph Weissleder,et al.  Imaging of Stem Cell Recruitment to Ischemic Infarcts in a Murine Model , 2004, Stroke.

[24]  Stanley J. Wiegand,et al.  Intraventricular Administration of BDNF Increases the Number of Newly Generated Neurons in the Adult Olfactory Bulb , 1998, Molecular and Cellular Neuroscience.

[25]  Zeger Debyser,et al.  Characterization of lentiviral vector-mediated gene transfer in adult mouse brain. , 2002, Human gene therapy.

[26]  C. Cepko,et al.  Multipotent neural cell lines can engraft and participate in development of mouse cerebellum , 1992, Cell.

[27]  Daniel A. Lim,et al.  Subventricular Zone Astrocytes Are Neural Stem Cells in the Adult Mammalian Brain , 1999, Cell.

[28]  T. Shimazaki,et al.  [Mammalian neural stem cells]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[29]  F. Gage,et al.  Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[30]  V. Baekelandt,et al.  Upscaling of lentiviral vector production by tangential flow filtration , 2005, The journal of gene medicine.

[31]  O. Lindvall,et al.  Suppression of Insult-Induced Neurogenesis in Adult Rat Brain by Brain-Derived Neurotrophic Factor , 2002, Experimental Neurology.

[32]  G. Feng,et al.  In vivo imaging of juxtaglomerular neuron turnover in the mouse olfactory bulb. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Ralph Weissleder,et al.  Glioma therapy and real‐time imaging of neural precursor cell migration and tumor regression , 2005, Annals of neurology.

[34]  I. Martins,et al.  The lymphocytic choriomeningitis virus envelope glycoprotein targets lentiviral gene transfer vector to neural progenitors in the murine brain. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[35]  B. Mintz,et al.  Base substitution at different alternative splice donor sites of the tyrosinase gene in murine albinism. , 1996, Genomics.