Relationship between Age and Neurogenesis in Old World Monkeys

DOI: 10.4236/nm.2013.43028   PDF   HTML     3,898 Downloads   5,707 Views  


Hippocampal neurogenesis continues throughout the lifespan of adult mammals, but the rates decline dramatically with increasing age. Among the factors that have been shown to affect neurogenesis, aging has been shown to be one of its most potent regulators in mice. The mechanism for the decline in neurogenesis with age is thought to be related to age-dependent changes in local and systemic neuroendocrinology and neurochemistry, as well as internal changes to precursor cells that result in decreased reactivity to normal stimuli. Since most of the data about neurogenesis and age were established from rodent studies, we sought to study this relationship in nonhuman primates in five previously studied cohorts of bonnet monkeys (Macaca radiata). In the present study, we statistically analyze the relationship of age and hippocampal neurogenesis rates, as measured by the number of DCX expressing cells in the subgranular zone of the dentate gyrus in 71 subjects with ages ranging from 3.5 to 17 years. We observed a non-significant relationship between age and doublecortin for subjects less than nine years old (corresponding to young and full adulthood) but a linear significant decline for subjects 9 years or greater (middle age and senescence). In contrast to previous studies that show neurogenesis to decline linearly throughout the lifespan, this study shows that neurogenesis occurs steadily throughout adulthood and begins to decline in middle age in bonnet macaques.

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T. Perera, A. Yaretskiy, A. Rozenboym, Z. Audi, C. Lipira, J. Tang, J. Hill, L. Thirumangalakudi, D. Lee, A. Dwork and J. Coplan, "Relationship between Age and Neurogenesis in Old World Monkeys," Neuroscience and Medicine, Vol. 4 No. 3, 2013, pp. 172-180. doi: 10.4236/nm.2013.43028.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] J. Altman and G. D. Das, “Autoradiographic and Histological Evidence of Postnatal Hippocampal Neurogenesis in Rats,” The Journal of Comparative Neurology, Vol. 124, No. 3, 1965, pp. 319-335. doi:10.1002/cne.901240303
[2] N. B. Hastings and E. Gould, “Rapid Extension of Axons into the CA3 Region by Adult-Generated Granule Cells,” Journal of Comparative Neurology, Vol. 415, No. 1, 1999, pp. 144-144. doi:10.1002/(SICI)1096-9861(19991206)415:1<144::AID-CNE10>3.0.CO;2-7
[3] E. A. Markakis and F. H. Gage, “Adult-Generated Neurons in the Dentate Gyrus Send Axonal Projections to Field CA3 and Are Surrounded by Synaptic Vesicles,” The Journal of Comparative Neurology, Vol. 406, No. 4, 1999, pp 449-460. doi:10.1002/(SICI)1096-9861(19990419)406:4<449::AID-CNE3>3.0.CO;2-I
[4] H. van Praag, A. F. Schinder, B. R. Christie, N. Toni, T. D. Palmer and F. H. Gage, “Functional Neurogenesis in the Adult Hippocampus,” Nature, Vol. 415, No. 6875, 2002, pp. 1030-1034. doi:10.1038/4151030a
[5] P. Ambrogini, D. Lattanzi, S. Ciuffoli, D. Agostini, L. Bertini, V. Stocchi, S. Santi and R. Cuppini, “Morpho-Functional Characterization of Neuronal Cells at Different Stages of Maturation in Granule Cell Layer of Adult Rat Dentate Gyrus,” Brain Research, Vol. 1017, No. 1-2, 2004, pp. 21-31. doi:10.1016/j.brainres.2004.05.039
[6] H. G. Kuhn, H. Dickinson-Anson and F. H. Gage, “Neurogenesis in the Dentate Gyrus of the Adult Rat: Age-Related Decrease of Neuronal Progenitor Proliferation,” The Journal of Neuroscience, Vol. 16, No. 6, 1996, pp. 2027-2033.
[7] G. Kempermann, H. G. Kuhn and F. Gage, “Experience-Induced Neurogenesis in the Senescent Dentate Gyrus,” The Journal of Neuroscience, Vol. 18, No. 9, 1998, pp. 3206-3212.
[8] B. Leuner, Y. Kozorovitskiy, C. G. Gross and E. Gould, “Diminished Adult Neurogenesis in the Marmoset Brain Precedes Old Age,” Proceedings of the National Academy of Sciences, Vol. 104, No. 43, 2007, pp. 17169-17173. doi:10.1073/pnas.0708228104
[9] E. Gould, A. J. Reeves, M. Fallah, P. Tanapat, C. G. Gross and E. Fuchs, “Hippocampal Neurogenesis in Adult Old World Primates,” Proceedings of the National Academy of Sciences, Vol. 96, No. 9, 1999, pp. 5263-5267. doi:10.1073/pnas.96.9.5263
[10] C. G. Schrago and C. A. M. Russo, “Timing the Origin of New World Monkeys,” Molecular Biology and Evolution, Vol. 20, No. 10, 2003, pp.1620-1625. doi:10.1093/molbev/msg172
[11] G. R. Aravindan, N. Ravindranath, K. Gopalakrishnan and N. R. Moudgal, “DNA Flow-Cytometric Analysis of Testicular Germ Cell Populations of the Bonnet Monkey (Macaca radiata) as a Function of Sexual Maturity,” Journal of Reproduction and Fertility, Vol. 89, No. 2, 1990, pp. 397-406. doi:10.1530/jrf.0.0890397
[12] A. J. Rao, V. Ramesh, S. G. Ramachandra, H. N. Krishnamurthy, N. Ravindranath and N. R. Moudgal, “Growth and Reproductive Parameters of Bonnet Monkey (Macaca radiata),” Primates, Vol. 39, No. 1, 1998, pp. 97-107. doi:10.1007/BF02557748
[13] T. D. Perera, A. J. Dwork, K. A. Keegan, L. Thirumangalakudi, C. M. Lipira, N. Joyce, C. Lange, J. D. Higley, G. Rosoklija, R. Hen, H. A. Sackeim and J. D. Coplan, “Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates,” PLoS ONE, Vol. 6, No. 4, 2011, p. 17600. doi:10.1371/journal.pone.0017600
[14] J. D. Coplan, M. W. Andrews, L. A. Rosenblum, M. J. Owens, S. Friedman, J. M. Gorman and C. B. Nemeroff, “Persistent Elevations of Cerebrospinal Fluid Concentrations of Corticotropin-Releasing Factor in Adult Nonhuman Primates Exposed to Early-Life Stressors: Implications for the Pathophysiology of Mood and Anxiety Disorders,” Proceedings of the National Academy of Sciences, Vol. 93, No. 4, 1996, pp. 1619-1623. doi:10.1073/pnas.93.4.1619
[15] L. A. Rosenblum, C. Forger, S. Noland, R. C. Trost and J. D. Coplan, “Response of Adolescent Bonnet Macaques to an Acute Fear Stimulus as a Function of Early Rearing Conditions,” Developmental Psychobiology, Vol. 39, No. 1, 2001, pp. 40-45. doi:10.1002/dev.1026
[16] J. Hill, J. E. Tang, et al., “Effects of Ziprasidone on Neurogenesis and Depressive Behavior in Adult Monkeys,” Biological Psychiatry, Vol. 69, No. 9, 2011, p. 126S.
[17] S. Couillard-Despres, B. Winner, S. Schaubeck, R. Aigner, M. Vroemen, N. Weidner, U. Bogdahn, J. Winkler, H. G. Kuhn and L. Aigner, “Doublecortin Expression Levels in Adult Brain Reflect Neurogenesis,” European Journal of Neuroscience, Vol. 21, No. 1, 2005, pp. 1-14. doi:10.1111/j.1460-9568.2004.03813.x
[18] D. R. Kornack and P. Rakic, “Continuation of Neurogenesis in the Hippocampus of the Adult Macaque Monkey,” Proceedings of the National Academy of Sciences, Vol. 96, No. 10, 1999, pp. 5768-5773. doi:10.1073/pnas.96.10.5768
[19] L. B. Ngwenya, A. Peters and D. L. Rosene, “Maturational Sequence of Newly Generated Neurons in the Dentate Gyrus of the Young Adult Rhesus Monkey,” The Journal of Comparative Neurology, Vol. 498, No. 2, 2006, pp. 204-216. doi:10.1002/cne.21045
[20] L. B. Ngwenya, D. L. Rosene and A. Peters, “An Ultrastructural Characterization of the Newly Generated Cells in the Adult Monkey Dentate Gyrus,” Hippocampus, Vol. 18, No. 2, 2008, pp. 210-220. doi:10.1002/hipo.20384
[21] T. D. Perera, D. Lu, L. Thirumangalakudi, E. L. Smith, A. Yaretskiy, L. A. Rosenblum, J. G. Kral and J. D. Coplan, “Correlations between Hippocampal Neurogenesis and Metabolic Indices in Adult Nonhuman Primates,” Neural Plasticity, Vol. 2011, 2011, pp. 1-6. doi:10.1155/2011/875307
[22] R. G. Smith, L. Betancourt and Y. Sun, “Molecular Endocrinology and Physiology of the Aging Central Nervous System,” Endocrine Reviews, Vol. 26, No. 2, 2005, pp. 203-250. doi:10.1210/er.2002-0017
[23] H. A. Cameron and R. D. G. McKay, “Restoring Production of Hippocampal Neurons in Old Age,” Nature Neuroscience, Vol. 2, No. 10, 1999, pp. 894-897. doi:10.1038/13197
[24] K. Jin, Y. Sun, L. Xie, S. Batteur, X. O. Mao, C. Smelick, A. Logvinova and D. A. Greenberg, “Neurogenesis and Aging: FGF-2 and HB-EGF Restore Neurogenesis in Hippocampus and Subventricular Zone of Aged Mice,” Aging Cell, Vol. 2, No. 3, 2003, pp. 175-183. doi:10.1046/j.1474-9728.2003.00046.x
[25] W. P. Gray, K. May and L. E. Sundstrom, “Seizure Induced Dentate Neurogenesis Does Not Diminish with Age in Rats,” Neuroscience Letters, Vol. 330, No. 3, 2002, pp. 235-238. doi:10.1016/S0304-3940(02)00810-8
[26] A. Olariu, K. M. Cleaver and H. A. Cameron, “Decreased Neurogenesis in Aged Rats Results from Loss of Granule Cell Precursors without Lengthening of the Cell Cycle,” The Journal of Comparative Neurology, Vol. 501, No. 4, 2007, pp. 659-667. doi:10.1002/cne.21268
[27] H. A. Cameron and E. Gould, “Adult Neurogenesis Is Regulated by Adrenal Steroids in the Dentate Gyrus,” Neuroscience, Vol. 61, No. 2, 1994, pp. 203-209. doi:10.1016/0306-4522(94)90224-0
[28] P. Ambrogini, L. Orsini, C. Mancini, P. Ferri, I. Barbanti and R. Cuppini, “Persistently High Corticosterone Levels but Not Normal Circadian Fluctuations of the Hormone Affect Cell Proliferation in the Adult Rat Dentate Gyrus,” Neuroendocrinology, Vol. 76, No. 6, 2002, pp. 366-372. doi:10.1159/000067581
[29] K. Pham, J. Nacher, P. R. Hof and B. S. McEwen, “Repeated Restraint Stress Suppresses Neurogenesis and Induces Biphasic PSA-NCAM Expression in the Adult Rat Dentate Gyrus,” European Journal of Neuroscience, Vol. 17, No. 4, 2003, pp. 879-886. doi:10.1046/j.1460-9568.2003.02513.x
[30] V. M. Heine, S. Maslam, J. Zareno, M. Joels and P. J. Lucassen, “Suppressed Proliferation and Apoptotic Changes in the Rat Dentate Gyrus after Acute and Chronic Stress Are Reversible,” European Journal of Neuroscience, Vol. 19, No. 1, 2004, pp. 131-144. doi:10.1046/j.1460-9568.2003.03100.x
[31] E. Gould, H. A. Cameron, D. C. Daniels, C. S. Woolley and B. S. McEwen, “Adrenal Hormones Suppress Cell Division in the Adult Rat Dentate Gyrus,” The Journal of Neuroscience, Vol. 12 , No. 9, 1992, pp. 3642-3650.
[32] M. F. Montaron, E. Drapeau, D. Dupret, P. Kitchener, C. Aurousseau, M. Le Moal, P. V. Piazza and D. N. Abrous, “Lifelong Corticosterone Level Determines Age-Related Decline in Neurogenesis and Memory,” Neurobiology of Aging, Vol. 27, No. 4, 2006, pp. 645-654. doi:10.1016/j.neurobiolaging.2005.02.014
[33] M. F. Montaron, K. G. Petry, J. J. Rodriguez, M. Marinelli, C. Aurousseau, G. Rougon, M. Le Moal and D. N. Abrous, “Adrenalectomy Increases Neurogenesis but Not PSA-NCAM Expression in Aged Dentate Gyrus,” European Journal of Neuroscience, Vol. 11, No. 4, 1999, pp. 1479-1485. doi:10.1046/j.1460-9568.1999.00579.x
[34] A. Garcia, B. Steiner, G. Kronenberg, A. Bick-Sander and G. Kempermann, “Age-Dependent Expression of Glucocorticoid-and Mineralocorticoid Receptors on Neural Precursor Cell Populations in the Adult Murine Hippocampus,” Aging Cell, Vol. 3, No. 6, 2004, pp. 363-363. doi:10.1111/j.1474-9728.2004.00130.x
[35] H. A. Cameron, B. S. McEwen and E. Gould, “Regulation of Adult Neurogenesis by Excitatory Input and NMDA Receptor Activation in the Dentate Gyrus,” The Journal of Neuroscience, Vol. 15, No. 6, 1995, pp. 4687-4692.
[36] J. Nacher, D. R. Rosell, G. Alonso-Losa and B. S. McEwen, “NMDA Receptor Antagonist Treatment Induces a Long-Lasting Increase in the Number of Proliferating Cells, PSA-NCAM-Immunoreactive Granule Neurons and Radial Glia in the Adult Rat Dentate Gyrus,” European Journal of Neuroscience, Vol. 13, No. 3, 2001, pp. 512-520. doi:10.1046/j.0953-816x.2000.01424.x
[37] J. Nacher, G. Alonso-Llosa, D. R. Rosell and B. S. McEwen, “NMDA Receptor Antagonist Treatment Increases the Production of New Neurons in the Aged Rat Hippocampus,” Neurobiology of Aging, Vol. 24, No. 2, 2003, pp. 273-284.doi:10.1016/S0197-4580(02)00096-9
[38] H. A. Cameron, P. Tanapat and E. Gould, “Adrenal Steroids and N-Methyl-D-Aspartate Receptor Activation Regulate Neurogenesis in the Dentate Gyrus of Adult Rats through a Common Pathway,” Neuroscience, Vol. 82, No. 2, 1997, pp. 349-354. doi:10.1016/S0306-4522(97)00303-5
[39] W. Mayo, O. George, S. Darbra, J. J Bouyer, M. Vallée, M. Darnaudéry, M. Pallarès, V. Lemaire-Mayo, M. Le Moal, P. V. Piazza and N. Abrous, “Individual Differences in Cognitive Aging: Implication of Pregnenolone Sulfate,” Progress in Neurobiology, Vol. 7, No. 1, 2003, pp. 43-48. doi:10.1016/j.pneurobio.2003.09.006
[40] G. Segovia, A. G. Yagüe, J. M. García-Verdugo and F. Mora, “Environmental Enrichment Promotes Neurogenesis and Changes the Extracellular Concentrations of Glutamate and GABA in the Hippocampus of Aged Rats,” Brain Research Bulletin, Vol. 70, No.1, 2006, pp. 8-14. doi:10.1016/j.brainresbull.2005.11.005
[41] M. Banasr, M. Hery, R. Printemps and A. Daszuta, “Serotonin-Induced Increases in Adult Cell Proliferation and Neurogenesis Are Mediated through Different and Common 5-HT Receptor Subtypes in the Dentate Gyrus and the Subventricular Zone,” Neuropsychopharmacology, Vol. 29, No. 3, 2004, p. 11. doi:10.1038/sj.npp.1300320
[42] H. G. Kuhn, J. Winkler, G. Kempermann, L. J. Thal and F. H. Gage, “Epidermal Growth Factor and Fibroblast Growth Factor-2 Have Different Effects on Neural Progenitors in the Adult Rat Brain,” The Journal of Neuroscience, Vol. 17, No. 15, 1997, pp. 5820-5829.
[43] E. Enwere, T. Shingo, C. Gregg, H. Fujikawa, S. Ohta and S. Weiss, “Aging Results in Reduced Epidermal Growth Factor Receptor Signaling, Diminished Olfactory Neurogenesis, and Deficits in Fine Olfactory Discrimination,” The Journal of Neuroscience, Vol. 24, No. 38, 2004, pp. 8354-8365. doi:10.1523/JNEUROSCI.2751-04.2004
[44] A. K. Shetty, B. Hattiangady and G. A. Shetty, “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,” Glia, Vol. 51, No. 3, 2005, pp. 173-186. doi:10.1002/glia.20187
[45] T. D. Palmer, A. R. Willhoite and F. H. Gage, “Vascular Niche for Adult Hippocampal Neurogenesis,” The Journal of Comparative Neurology, Vol. 425, No. 4, 2000, pp 479-494. doi:10.1002/1096-9861(20001002)425:4<479::AID-CNE2>3.0.CO;2-3
[46] B. Hattiangady and A. K. Shetty, “Aging Does Not Alter the Number or Phenotype of Putative Stem/Progenitor Cells in the Neurogenic Region of the Hippocampus,” Neurobiology of Aging, Vol. 29, No. 1, 2008, pp. 129-147. doi:10.1016/j.neurobiolaging.2006.09.015
[47] T. D. Perera, J. D. Coplan, C. M. Lipira, C. Carpio, M. Arif, G. B. Rosoklija, S. Lisanby, G. B. Spitzer, B. Scharf, A. J. Dwork, L. A. Rosenblum and H. A. Sackeim, “ECS Induces Neurogenesis in the Adult Monkey Dentate Gyrus,” Journal of Neuroscience, Vol. 27, No. 18, 2007, pp. 4894-4901.

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