Brain Structure and Function

, Volume 223, Issue 6, pp 2859–2877 | Cite as

Memory retrieval-induced activation of adult-born neurons generated in response to damage to the dentate gyrus

  • Andrea Aguilar-Arredondo
  • Angélica Zepeda
Original Article


The dentate gyrus (DG) is a neurogenic structure that exhibits functional and structural reorganization after injury. Neurogenesis and functional recovery occur after brain damage, and the possible relation between both processes is a matter of study. We explored whether neurogenesis and the activation of new neurons correlated with DG recovery over time. We induced a DG lesion in young adult rats through the intrahippocampal injection of kainic acid and analyzed functional recovery and the activation of new neurons after animals performed a contextual fear memory task (CFM) or a control spatial exploratory task. We analyzed the number of BrdU+ cells that co-localized with doublecortin (DCX) or with NeuN within the damaged DG and evaluated the number of cells in each population that were labelled with the activity marker c-fos after either task. At 10 days post-lesion (dpl), a region of the granular cell layer was devoid of cells, evidencing the damaged area, whereas at 30 dpl this region was significantly smaller. At 10 dpl, the number of BrdU+/DCX+/c-fos positive cells was increased compared to the sham-lesion group, but CFM was impaired. At 30 dpl, a significantly greater number of BrdU+/NeuN+/c-fos positive cells was observed than at 10 dpl, and activation correlated with CFM recovery. Performance in the spatial exploratory task induced marginal c-fos immunoreactivity in the BrdU+/NeuN+ population. We demonstrate that neurons born after the DG was damaged survive and are activated in a time- and task-dependent manner and that activation of new neurons occurs along functional recovery.


Plasticity Kainic acid Adult-born neurons activation Hippocampus Injury Cognitive demand IEG Hilus 



This work was supported by Grants from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) 203015 and Consejo Nacional de Ciencia y Tecnología (CONACyT) 176589. Aguilar-Arredondo is a doctoral student from Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM) and was supported by CONACYT 270435. We thank Clorinda Arias for providing helpful comments on the manuscript and Josué Ramirez Jarquín, Miguel Tapia and Patricia Ferrera for providing technical support.


This work was supported by grants from Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT) 203015 and Consejo Nacional de Ciencia y Tecnología (CONACyT) 176589 and 270435.

Compliance with ethical standards

This work has not been published previously, nor is it under review in any other journal. All authors of the study accept the contents of the manuscript and consent to the submission of the work. None of the authors have been cited for any scientific misconduct.

Conflict of interest

The authors have no conflicts of interest to declare.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Human and animal rights statement

All procedures involving animals were performed in accordance with the ethical standards of the institution or practice at which the studies were conducted.


  1. Aguilar-Arredondo A, Arias C, Zepeda A (2015) Evaluating the functional state of adult-born neurons in the adult dentate gyrus of the hippocampus: from birth to functional integration. Rev Neurosci. CrossRefPubMedGoogle Scholar
  2. Altman J, Das GD (1965) Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124:319–335CrossRefPubMedGoogle Scholar
  3. Åmellem I, Suresh S, Chang CC et al (2017) A critical period for antidepressant-induced acceleration of neuronal maturation in adult dentate gyrus. Transl Psychiatry 7:e1235. CrossRefPubMedPubMedCentralGoogle Scholar
  4. Beining M, Jungenitz T, Radic T et al (2017) Adult-born dentate granule cells show a critical period of dendritic reorganization and are distinct from developmentally born cells. Brain Struct Funct 222:1427–1446. CrossRefPubMedGoogle Scholar
  5. Bengzon J, Kokaia Z, Elmer E et al (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci 94:10432–10437. CrossRefPubMedGoogle Scholar
  6. Besnard A, Serge L, Jocelyne C (2014) Comparative dynamics of MAPK/ERK signalling components and immediate early genes in the hippocampus and amygdala following contextual fear conditioning and retrieval. Brain Struct Funct 219:415–430. CrossRefPubMedGoogle Scholar
  7. Brandt MD, Jessberger S, Steiner B et al (2003) Transient calretinin expression defines early postmitotic step of neuronal differentiation in adult hippocampal neurogenesis of mice. Mol Cell Neurosci 24:603–613. CrossRefPubMedGoogle Scholar
  8. Bruel-Jungerman E (2006) Long-term potentiation enhances neurogenesis in the adult dentate gyrus. J Neurosci 26:5888–5893. CrossRefPubMedGoogle Scholar
  9. Clark PJ, Bhattacharya TK, Miller DS et al (2012) New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks. Hippocampus 22:1860–1867. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cohen RE, Macedo-Lima M, Miller KE, Brenowitz EA (2016) Adult neurogenesis leads to the functional reconstruction of a telencephalic neural circuit. J Neurosci 36:8947–8956. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Del Río JA, Heimrich B, Borrell V et al (1997) A role for Cajal–Retzius cells and reelin in the development of hippocampal connections. Nature 385:70–74. CrossRefPubMedGoogle Scholar
  12. Deng W, Saxe MD, Gallina IS, Gage FH (2009) Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 29:13532–13542. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Dong H, Csernansky C, Goico B, Csernansky JG (2003) Hippocampal neurogenesis follows kainic acid-induced apoptosis in neonatal rats. J Neurosci 23:1742–1749CrossRefPubMedGoogle Scholar
  14. Esposito MS (2005) Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J Neurosci 25:10074–10086. CrossRefPubMedGoogle Scholar
  15. Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59. CrossRefPubMedGoogle Scholar
  16. Haas CA, Frotscher M (2010) Reelin deficiency causes granule cell dispersion in epilepsy. Exp Brain Res 200:141–149. CrossRefPubMedGoogle Scholar
  17. Hattiangady B, Rao MS, Shetty AK (2008) Plasticity of hippocampal stem/progenitor cells to enhance neurogenesis in response to kainate-induced injury is lost by middle age. Aging Cell 7:207–224. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Heinrich C (2006) Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. J Neurosci 26:4701–4713. CrossRefPubMedGoogle Scholar
  19. Hernández-Ortega K, Ferrera P, Arias C (2007) Sequential expression of cell-cycle regulators and Alzheimer’s disease–related proteins in entorhinal cortex after hippocampal excitotoxic damage. J Neurosci Res 85:1744–1751. CrossRefPubMedGoogle Scholar
  20. Hosford BE, Liska JP, Danzer SC (2016) Ablation of newly generated hippocampal granule cells has disease-modifying effects in epilepsy. J Neurosci 36:11013–11023. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Jessberger S, Kempermann G (2003) Adult-born hippocampal neurons mature into activity-dependent responsiveness. Eur J Neurosci 18:2707–2712. CrossRefPubMedGoogle Scholar
  22. Jin K, Minami M, Xie L et al (2004) Ischemia-induced neurogenesis is preserved but reduced in the aged rodent brain. Aging Cell 3:373–377. CrossRefPubMedGoogle Scholar
  23. Kaplan M, Hinds J (1977) Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science 197:1092–1094. CrossRefPubMedGoogle Scholar
  24. Kawai T, Takagi N, Miyake-Takagi K et al (2004) Characterization of BrdU-positive neurons induced by transient global ischemia in adult hippocampus. J Cereb Blood Flow Metab 24:548–555. CrossRefPubMedGoogle Scholar
  25. Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355–362. CrossRefPubMedGoogle Scholar
  26. Kempermann G, Kuhn HG, Gage FH (1997) Genetic influence on neurogenesis in the dentate gyrus of adult mice. Proc Natl Acad Sci USA 94:10409–10414. CrossRefPubMedGoogle Scholar
  27. Kernie SG, Parent JM (2010) Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37:267–274. CrossRefPubMedGoogle Scholar
  28. Kozlowski DA, Jones TA, Schallert T (1994) Pruning of dendrites and restoration of function after brain damage: role of the NMDA receptor. Restor Neurol Neurosci 7:119–126. CrossRefPubMedGoogle Scholar
  29. Lee I, Kesner RP (2004) Differential contributions of dorsal hippocampal subregions to memory acquisition and retrieval in contextual fear-conditioning. Hippocampus 14:301–310. CrossRefPubMedGoogle Scholar
  30. Liquitaya-Montiel A, Aguilar-Arredondo A, Arias C, Zepeda A (2012) Insulin growth factor-I promotes functional recovery after a focal lesion in the dentate gyrus. CNS Neurol Disord Drug Targets. CrossRefPubMedGoogle Scholar
  31. Liu J, Solway K, Messing RO, Sharp FR (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci 18:7768–7778CrossRefPubMedGoogle Scholar
  32. Lois C, Alvarez-Buylla a (1993) Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci USA 90:2074–2077. CrossRefPubMedGoogle Scholar
  33. Magnusson JP, Goritz C, Tatarishvili J et al (2014) A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science 346:237–241. CrossRefPubMedGoogle Scholar
  34. Ming G, Song H (2011) Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70:687–702. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Myers CE, Bermudez-Hernandez K, Scharfman HE (2013) The influence of ectopic migration of granule cells into the hilus on dentate gyrus-CA3 function. PLoS One 8:e68208. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Neuberger EJ, Swietek B, Corrubia L et al (2017) Enhanced dentate neurogenesis after brain injury undermines long-term neurogenic potential and promotes seizure susceptibility. Stem Cell Rep 9:972–984. CrossRefGoogle Scholar
  37. Ogita K, Nishiyama N, Sugiyama C et al (2005) Regeneration of granule neurons after lesioning of hippocampal dentate gyrus: evaluation using adult mice treated with trimethyltin chloride as a model. J Neurosci Res 82:609–621. CrossRefPubMedGoogle Scholar
  38. Orcinha C, Münzner G, Gerlach J et al (2016) Seizure-induced motility of differentiated dentate granule cells is prevented by the central reelin fragment. Front Cell Neurosci. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Overstreet-Wadiche LS, Westbrook GL (2006) Functional maturation of adult-generated granule cells. Hippocampus 16:208–215. CrossRefPubMedGoogle Scholar
  40. Parent JM, Yu TW, Leibowitz RT et al (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738CrossRefPubMedGoogle Scholar
  41. Parent JM, Elliott RC, Pleasure SJ et al (2006) Aberrant seizure-induced neurogenesis in experimental temporal lobe epilepsy. Ann Neurol 59:81–91. CrossRefPubMedGoogle Scholar
  42. Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates. Elsevier, New YorkGoogle Scholar
  43. Phillips RG, LeDoux JE (1992) Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274–285. CrossRefPubMedGoogle Scholar
  44. Piatti VC, Davies-Sala MG, Esposito MS et al (2011) The timing for neuronal maturation in the adult hippocampus is modulated by local network activity. J Neurosci 31:7715–7728. CrossRefPubMedPubMedCentralGoogle Scholar
  45. Platschek S, Cuntz H, Vuksic M et al (2016) A general homeostatic principle following lesion induced dendritic remodeling. Acta Neuropathol Commun 4:19. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Platschek S, Cuntz H, Deller T, Jedlicka P (2017) Lesion-induced dendritic remodeling as a new mechanism of homeostatic structural plasticity in the adult brain. In: Van Ooyen A, Butz-Ostendorf M (eds) The rewiring brain: a computational approach to structural plasticity in the adult brain. Academic Press, San Diego, pp 203–218CrossRefGoogle Scholar
  47. Radic T, Frieß L, Vijikumar A et al (2017) Differential postnatal expression of neuronal maturation markers in the dentate gyrus of mice and rats. Front Neuroanat. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Ramirez-Amaya V, Marrone DF, Gage FH et al (2006) Integration of new neurons into functional neural networks. J Neurosci 26:12237–12241. CrossRefPubMedGoogle Scholar
  49. Saxe MD, Battaglia F, Wang J-W et al (2006) Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci 103:17501–17506. CrossRefPubMedGoogle Scholar
  50. Scharfman HE, Goodman JH, Sollas AL (2000) Granule-like neurons at the hilar/CA3 border after status epilepticus and their synchrony with area CA3 pyramidal cells: functional implications of seizure-induced neurogenesis. J Neurosci 20:6144–6158CrossRefPubMedGoogle Scholar
  51. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM (2005) A role for adult neurogenesis in spatial long-term memory. Neuroscience 130:843–852. CrossRefPubMedGoogle Scholar
  52. Snyder JS, Choe JS, Clifford MA et al (2009a) Adult-born hippocampal neurons are more numerous, faster maturing, and more involved in behavior in rats than in mice. J Neurosci 29:14484–14495. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Snyder JS, Radik R, Wojtowicz JM, Cameron HA (2009b) Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training. Hippocampus 19:360–370. CrossRefPubMedPubMedCentralGoogle Scholar
  54. Suh H, Deng W, Gage FH (2009) Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 25:253–275. CrossRefPubMedGoogle Scholar
  55. Sun D, McGinn MJ, Zhou Z et al (2007) Anatomical integration of newly generated dentate granule neurons following traumatic brain injury in adult rats and its association to cognitive recovery. Exp Neurol 204:264–272. CrossRefPubMedGoogle Scholar
  56. Sun D, Daniels TE, Rolfe A et al (2015) Inhibition of injury-induced cell proliferation in the dentate gyrus of the hippocampus impairs spontaneous cognitive recovery after traumatic brain injury. J Neurotrauma 32:495–505. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Toni N, Teng EM, Bushong EA et al (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727–734. CrossRefPubMedGoogle Scholar
  58. Toni N, Laplagne DA, Zhao C et al (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11:901–907. CrossRefPubMedPubMedCentralGoogle Scholar
  59. van Praag H, Schinder AF, Christie BR et al (2002) Functional neurogenesis in the adult hippocampus. Nature 415:1030–1034. CrossRefPubMedGoogle Scholar
  60. Varela-Nallar L, Rojas-Abalos M, Abbott AC et al (2014) Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1∆E9 transgenic mice in vivo. Front Cell Neurosci. CrossRefPubMedPubMedCentralGoogle Scholar
  61. Villasana LE, Kim KN, Westbrook GL, Schnell E (2015) Functional integration of adult-born hippocampal neurons after traumatic brain injury. eNeuro. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wang J-W, David DJ, Monckton JE et al (2008) Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 28:1374–1384. CrossRefPubMedGoogle Scholar
  63. Wang X, Mao X, Xie L et al (2012) Conditional depletion of neurogenesis inhibits long-term recovery after experimental stroke in mice. PLoS One 7:e38932. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Xu W, Sun X, Song C et al (2016) Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia. Neural Regen Res 11:745. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Yamashita T, Deguchi K, Sawamoto K et al (2006) Neuroprotection and neurosupplementation in ischaemic brain. Biochem Soc Trans 34:1310–1312. CrossRefPubMedGoogle Scholar
  66. Zepeda A, Sengpiel F, Guagnelli MA, Vaca L, Arias C (2004) Functional reorganization of visual cortex maps after ischemic lesions is accompanied by changes in expression of cytoskeletal proteins and NMDA and GABA(A) receptor subunits. J Neurosci 24(8):1812–1821. CrossRefPubMedGoogle Scholar
  67. Zepeda A, Aguilar-Arredondo A, Michel G et al (2013) Functional recovery of the dentate gyrus after a focal lesion is accompanied by structural reorganization in the adult rat. Brain Struct Funct 218:437–453. CrossRefPubMedGoogle Scholar
  68. Zhao C (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3–11. CrossRefPubMedGoogle Scholar
  69. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660. CrossRefPubMedGoogle Scholar
  70. Zhu L, Zhao T, Li H et al (2005) Neurogenesis in the adult rat brain after intermittent hypoxia. Brain Res 1055:1–6. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoMexico, DFMexico

Personalised recommendations