Early age-related changes in adult hippocampal neurogenesis in C57 mice

Strong age-related declines in conjunction with comparatively easy experimental manipulations of adult hippocampal neurogenesis have generated considerable public and scientific interest in the prospect of "new neurons for old brains". Only few studies addressed the time course of the natural changes, which are the substrate for interventions that may realize this prospect. We provide a monthly or bimonthly account of cell proliferation, neurogenesis and cell death during the first 9 months of the life of C57Bl/6J mice. Ki67- and DCX-positive cell numbers declined exponentially without an intermittent plateau ( approximately 40% per month). Cell death in relation to cell proliferation was lowest at 1 month, increased at 2 months to remain constant until 4 months, and decreased again at 5 months to remain stable until 9 months. Granule cell number did not change with age. Our results suggest that manipulations of proliferation and neurogenesis may, at any time, interact with strong natural changes of these processes. Mediators of their age-related decline may be studied over periods much shorter than those typically used.

[1]  Gerd Kempermann,et al.  Natural variation and genetic covariance in adult hippocampal neurogenesis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[2]  A. Shetty,et al.  The window and mechanisms of major age‐related decline in the production of new neurons within the dentate gyrus of the hippocampus , 2006, Aging cell.

[3]  H. Gundersen,et al.  The efficiency of systematic sampling in stereology — reconsidered , 1999, Journal of microscopy.

[4]  C. Gross,et al.  Diminished adult neurogenesis in the marmoset brain precedes old age , 2007, Proceedings of the National Academy of Sciences.

[5]  D. Abrous,et al.  Adult Neurogenesis : From Precursors to Network and Physiology , 2005 .

[6]  L. Galea,et al.  Sex differences in cell proliferation, cell death and defensive behavior following acute predator odor stress in adult rats , 2003, Brain Research.

[7]  T. Palmer,et al.  Vascular niche for adult hippocampal neurogenesis , 2000, The Journal of comparative neurology.

[8]  F. Gage,et al.  Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus , 1999, Nature Neuroscience.

[9]  A. Convit,et al.  Cortisol levels during human aging predict hippocampal atrophy and memory deficits , 1998, Nature Neuroscience.

[10]  W. Cowan,et al.  An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat , 1975, The Journal of comparative neurology.

[11]  G. Šimić,et al.  Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease , 1997, The Journal of comparative neurology.

[12]  P. Luiten,et al.  Cerebral microvascular pathology in aging and Alzheimer's disease , 2001, Progress in Neurobiology.

[13]  B. Mcewen,et al.  Sex and seasonal differences in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles. , 1999, Neuroscience.

[14]  Christian Mirescu,et al.  Stress and adult neurogenesis , 2006, Hippocampus.

[15]  Jürgen Winkler,et al.  Transient expression of doublecortin during adult neurogenesis , 2003, The Journal of comparative neurology.

[16]  G. Lynch,et al.  Hippocampal aging and adrenocorticoids: quantitative correlations. , 1978, Science.

[17]  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.

[18]  B. Mcewen,et al.  Sex and seasonal changes in the rate of cell proliferation in the dentate gyrus of adult wild meadow voles , 1999, Neuroscience.

[19]  A. Shetty,et al.  Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus , 2005, Experimental Neurology.

[20]  H. Cameron,et al.  Decreased neurogenesis in aged rats results from loss of granule cell precursors without lengthening of the cell cycle , 2007, The Journal of comparative neurology.

[21]  D. Dupret,et al.  Lifelong corticosterone level determines age-related decline in neurogenesis and memory , 2006, Neurobiology of Aging.

[22]  Fred H. Gage,et al.  Exercise Enhances Learning and Hippocampal Neurogenesis in Aged Mice , 2005, The Journal of Neuroscience.

[23]  Mark J. West,et al.  Regionally specific loss of neurons in the aging human hippocampus , 1993, Neurobiology of Aging.

[24]  A. Shetty,et al.  Stem/progenitor cell proliferation factors FGF‐2, IGF‐1, and VEGF exhibit early decline during the course of aging in the hippocampus: Role of astrocytes , 2005, Glia.

[25]  C. Cooper-Kuhn,et al.  Is it all DNA repair? Methodological considerations for detecting neurogenesis in the adult brain. , 2002, Brain research. Developmental brain research.

[26]  P. Coleman How old is old? , 1989, Neurobiology of Aging.

[27]  H. Kettenmann,et al.  Type‐2 cells as link between glial and neuronal lineage in adult hippocampal neurogenesis , 2006, Glia.

[28]  G. Kempermann,et al.  Neurogenesis in the adult hippocampus , 2007, Cell and Tissue Research.

[29]  P. Eriksson,et al.  Gender and Strain Influence on Neurogenesis in Dentate Gyrus of Young Rats , 2001, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[30]  Douglas Curran-Everett,et al.  Guidelines for reporting statistics in journals published by the American Physiological Society. , 2004, American journal of physiology. Endocrinology and metabolism.

[31]  H. Bruunsgaard,et al.  Inflammatory mediators in the elderly , 2004, Experimental Gerontology.

[32]  R. McKay,et al.  Restoring production of hippocampal neurons in old age , 1999, Nature Neuroscience.

[33]  F. Gage,et al.  More hippocampal neurons in adult mice living in an enriched environment , 1997, Nature.

[34]  Jürgen Winkler,et al.  Doublecortin expression levels in adult brain reflect neurogenesis , 2005, The European journal of neuroscience.

[35]  Radiation injury and neurogenesis , 2003, Current opinion in neurology.

[36]  E. Azmitia,et al.  Gender-specific 5-HT1A receptor changes in BrdU nuclear labeling patterns in neonatal dentate gyrus. , 2005, Brain research. Developmental brain research.

[37]  D. Ingram,et al.  Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice , 2004, Neurobiology of Aging.

[38]  J. Winkler,et al.  Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain , 2000, Neuroscience Letters.

[39]  L. Galea,et al.  Reproductive status influences the survival of new cells in the dentate gyrus of adult male meadow voles , 2003, Neuroscience Letters.

[40]  R. Burwell,et al.  Individual differences in aging: Implications for stereological studies of neuron loss , 1996, Neurobiology of Aging.

[41]  Hans-Peter Lipp,et al.  Granule cell number, cell death and cell proliferation in the dentate gyrus of wild‐living rodents , 2004, The European journal of neuroscience.

[42]  Hiroki Toda,et al.  Inflammatory Blockade Restores Adult Hippocampal Neurogenesis , 2003, Science.

[43]  S. Mcconnell,et al.  Doublecortin Is a Developmentally Regulated, Microtubule-Associated Protein Expressed in Migrating and Differentiating Neurons , 1999, Neuron.

[44]  Michela Gallagher,et al.  Effects of aging on the hippocampal formation in a naturally occurring animal model of mild cognitive impairment , 2003, Experimental Gerontology.

[45]  R. McKay,et al.  Regulation of neurogenesis by growth factors and neurotransmitters. , 1998, Journal of neurobiology.

[46]  P. Coleman How old is old? , 2004, Neurobiology of aging.

[47]  P. Rakić,et al.  Continuation of neurogenesis in the hippocampus of the adult macaque monkey. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  R. McKay,et al.  Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus , 2001, The Journal of comparative neurology.

[49]  W. Streit,et al.  Microglia in the Aging Brain , 2006, Journal of neuropathology and experimental neurology.

[50]  Fred H. Gage,et al.  A role for adult TLX-positive neural stem cells in learning and behaviour , 2008, Nature.

[51]  C. Cotman,et al.  Region specific neuron loss in the aged canine hippocampus is reduced by enrichment , 2008, Neurobiology of Aging.

[52]  K. Jin,et al.  Neurogenesis and aging: FGF‐2 and HB‐EGF restore neurogenesis in hippocampus and subventricular zone of aged mice , 2003, Aging cell.

[53]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[54]  Elizabeth Gould,et al.  Is there a link between adult neurogenesis and learning? , 2006, Hippocampus.

[55]  D. Abrous,et al.  Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Boonstra,et al.  The utility of Ki-67 and BrdU as proliferative markers of adult neurogenesis , 2002, Journal of Neuroscience Methods.

[57]  E. Fuchs,et al.  Preservation of hippocampal neuron numbers in aged rhesus monkeys , 2003, Neurobiology of Aging.

[58]  J. Altman,et al.  Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats , 1965, The Journal of comparative neurology.

[59]  M. Gayoso,et al.  A versatile and simple method for staining nervous tissue using Giemsa dye , 1985, Journal of Neuroscience Methods.

[60]  G. Alonso Proliferation of progenitor cells in the adult rat brain correlates with the presence of vimentin‐expressing astrocytes , 2001, Glia.

[61]  D. Ingram,et al.  Stereological analysis of astrocyte and microglia in aging mouse hippocampus , 1998, Neurobiology of Aging.

[62]  J. Koolhaas,et al.  Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat , 2008, Behavioural Brain Research.

[63]  F. Gage,et al.  Neurogenesis in the adult human hippocampus , 1998, Nature Medicine.

[64]  T. Palmer,et al.  Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[65]  M. West,et al.  Estimators of the precision of stereological estimates: An example based on the CA1 pyramidal cell layer of rats , 2005, Neuroscience.

[66]  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.

[67]  M. Gallagher,et al.  Production of new cells in the rat dentate gyrus over the lifespan: relation to cognitive decline , 2003, The European journal of neuroscience.

[68]  I. Black,et al.  Hippocampal granule neuron production and population size are regulated by levels of bFGF , 2002, The European journal of neuroscience.

[69]  H. Cameron,et al.  Short‐term and long‐term survival of new neurons in the rat dentate gyrus , 2003, The Journal of comparative neurology.

[70]  J. Fike,et al.  Radiation effects on neural precursor cells in the dentate gyrus , 2007, Cell and Tissue Research.

[71]  A. Shetty,et al.  Newly born cells in the ageing dentate gyrus display normal migration, survival and neuronal fate choice but endure retarded early maturation , 2005, The European journal of neuroscience.

[72]  Gerd Kempermann,et al.  Experience-Induced Neurogenesis in the Senescent Dentate Gyrus , 1998, The Journal of Neuroscience.

[73]  S. Bennett,et al.  Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis , 2001, Neuroscience.

[74]  M. Tuszynski,et al.  Hippocampal cell genesis does not correlate with spatial learning ability in aged rats , 2003, The Journal of comparative neurology.

[75]  F. Bronson,et al.  Life History AND BIOECONOMY OF THE House Mouse , 1992, Biological reviews of the Cambridge Philosophical Society.

[76]  H. Lipp,et al.  Reversible effect of X‐irradiation on proliferation, neurogenesis, and cell death in the dentate gyrus of adult mice , 2007, Hippocampus.

[77]  H. Cameron,et al.  Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus , 1994, Neuroscience.

[78]  S. Fischer,et al.  Gender and endogenous levels of estradiol do not influence adult hippocampal neurogenesis in mice , 2007, Hippocampus.

[79]  A. Shetty,et al.  Aging does not alter the number or phenotype of putative stem/progenitor cells in the neurogenic region of the hippocampus , 2008, Neurobiology of Aging.

[80]  G. Kempermann,et al.  Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli , 2003, The Journal of comparative neurology.

[81]  Gerd Kempermann,et al.  Physical exercise prevents age-related decline in precursor cell activity in the mouse dentate gyrus , 2006, Neurobiology of Aging.

[82]  C. Mandyam,et al.  Adult neurogenesis: can analysis of cell cycle proteins move us "Beyond BrdU"? , 2007, Current pharmaceutical biotechnology.

[83]  H. Lipp,et al.  Marked species and age‐dependent differences in cell proliferation and neurogenesis in the hippocampus of wild‐living rodents , 2004, Hippocampus.

[84]  M. Marinelli,et al.  Adrenalectomy increases neurogenesis but not PSA‐NCAM expression in aged dentate gyrus , 1999, The European journal of neuroscience.

[85]  D. Ingram,et al.  Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice , 1998, Neurobiology of Aging.

[86]  J. Hinds,et al.  Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. , 1977, Science.

[87]  D. German,et al.  Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease , 2006, The Journal of comparative neurology.

[88]  R. Sapolsky A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults , 1985, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[89]  T. Seki,et al.  Age‐related production of new granule cells in the adult dentate gyrus , 1995, Neuroreport.

[90]  M. Picciotto,et al.  Alteration of hippocampal cell proliferation in mice lacking the β2 subunit of the neuronal nicotinic acetylcholine receptor , 2004, Synapse.

[91]  R. Sutherland,et al.  The aging hippocampus: A multi-level analysis in the rat , 2006, Neuroscience.