Neuronal loss as a consequence of brain injury, stroke and neurodegenerative disorders causes functional impairments ranging from cognitive impairments to physical disabilities. Extensive rehabilitation and trainning may lead to neuroprotection and promote functional recovery, although little is known about the molecular and cellular mechanisms driving this event. To investigate the underlying mechanisms and levels of functional recovery elicited by repeated physical training or environmental enrichment, we generated an inducible mouse model of selective CA1 hippocampal neuronal loss. Following the CA1 neuronal injury, mice underwent one of the above mentioned conditions for 3 months. Exposure to either of these stimuli promoted functional cognitive recovery, which was associated with increased neurogenesis in the subgranular zone of dentate gyrus and enhanced synaptogenesis in the CA1 subfield. Notably, a significant correlation was found between the functional recovery and increased synaptogenesis among survived CA1 neurons. Collectively, these results support the utilization of cognitive and physical stimulation as approaches to promote recovery after neuronal loss and demonstrate the potential of this novel mouse model for the development of therapeutic strategies for various neurological disorders associated with focal neuronal loss.
J. M. Garbusinski, M. A. van der Sande, E. J. Bartholome, M. Dramaix, A. Gaye, R. Coleman, O. A. Nyan, R. W. Walker, K. P. McAdam and G.E. Walraven, “Stroke Presentation and Outcome in Developing Countries: A Prospective Study in the Gambia,” Stroke, Vol. 36, No. 7, 2005, pp. 1388-1393. doi:10.1161/01.STR.0000170717.91591.7d
H. W. Querfurth and F. M. LaFerla, “Alzheimer’s Disease,” The New England Journal of Medicine, Vol. 362, No. 4, 2010, pp. 329-344. doi:10.1056/NEJMra0909142
M. M. Daadi, A. S. Davis, A. Arac, Z. Li, A. L. Maag, R. Bhatnagar, K. Jiang, G. Sun, J. C. Wu and G. K. Steinberg, “Human Neural Stem Cell Grafts Modify Microglial Response and Enhance Axonal Sprouting in Neonatal Hypoxic-Ischemic Brain Injury,” Stroke, Vol. 41, No. 3, 2010, pp. 516-523. doi:10.1161/STROKEAHA.109.573691
P. Stroemer, S. Patel, A. Hope, C. Oliveira, K. Pollock and J. Sinden, “The Neural Stem Cell Line CTX0E03 Promotes Behavioral Recovery and Endogenous Neurogenesis after Experimental Stroke in a Dose-Dependent Fashion,” Neurorehabilitation & Neural Repair, Vol. 23, No. 9, 2009, pp. 895-909. doi:10.1177/1545968309335978
T. R. Yamasaki, M. Blurton-Jones, D. A. Morrissette, M. Kitazawa, S. Oddo and F. M. LaFerla, “Neural Stem Cells Improve Memory in an Inducible Mouse Model of Neuronal Loss,” Journal of Neuroscience, Vol. 27, No. 44, 2007, pp. 11925-11933. doi:10.1523/JNEUROSCI.1627-07.2007
A. M. Auriat, S. Wowk and F. Colbourne, “Rehabilitation after Intracerebral Hemorrhage in Rats Improves Recovery with Enhanced Dendritic Complexity but No Effect on Cell Proliferation,” Behavioural Brain Research, Vol. 214, No. 1, 2010, pp. 42-47. doi:10.1016/j.bbr.2010.04.025
R. P. Allred, M. A. Maldonado, J. E. Hsu and T. A. Jones, “Training the “Less-Affected” Forelimb after Unilateral Cortical Infarcts Interferes with Functional Recovery of the Impaired Forelimb In Rats,” Restorative Neurology and Neuroscience, Vol. 23, No. 5-6, 2005, pp. 297-302.
J. Biernaskie, A. Szymanska, V. Windle and D. Corbett, “Bi-Hemispheric Contribution to Functional Motor Recovery of the Affected Forelimb Following Focal Ischemic Brain Injury in Rats,” European Journal of Neuroscience, Vol. 21, No. 4, 2005, pp. 989-999. doi:10.1111/j.1460-9568.2005.03899.x
S. H. Im, J. H. Yu, E. S. Park, J. E. Lee, H. O. Kim, K. I. Park, G. W. Kim, C. I. Park and S. R. Cho, “Induction of Striatal Neurogenesis Enhances Functional Recovery in an Adult Animal Model of Neonatal Hypoxic-Ischemic Brain Injury,” Neuroscience, Vol. 169, No. 1, 2010, pp. 259-268. doi:10.1016/j.neuroscience.2010.04.038
Repeated Physical Training and Environmental Enrichment Induce Neurogenesis and Synaptogenesis Following Neuronal Injury in an Inducible Mouse Model — Oak Academic Publishing
W. L. Li, S. P. Yu, M. E. Ogle, X. S. Ding and L. Wei, “Enhanced Neurogenesis and Cell Migration Following Focal Ischemia and Peripheral Stimulation in Mice,” Developmental Neurobiology, Vol. 68, No. 13, 2008, pp. 1474-1486. doi:10.1002/dneu.20674
C. Zhao, J. Wang, S. Zhao and Y. Nie, “Constraint-Induced Movement Therapy Enhanced Neurogenesis and Behavioral Recovery after Stroke in Adult Rats,” The Tohoku Journal of Experimental Medicine, Vol. 218, No. 4, 2009, pp. 301-308. doi:10.1620/tjem.218.301
F. Wurm, S. Keiner, A. Kunze, O. W. Witte and C. Redecker, “Effects of Skilled Forelimb Training on Hippocampal Neurogenesis and Spatial Learning after Focal Cortical Infarcts in the Adult Rat Brain,” Stroke, Vol. 38, No. 10, 2007, pp. 2833-2840. doi:10.1161/STROKEAHA.107.485524
M. Kitazawa, K. N. Green, A. Caccamo and F. M. LaFerla, “Genetically Augmenting Abeta42 Levels in Skeletal Muscle Exacerbates Inclusion Body Myositis-Like Pathology and Motor Deficits in Transgenic Mice,” American Journal of Pathology, Vol. 168, No. 6, 2006, pp. 1986-1997. doi:10.2353/ajpath.2006.051232
S. J. Lupien, S. Gaudreau, B. M. Tchiteya, F. Maheu, S. Sharma, N. P. Nair, R. L. Hauger, B. S. McEwen and M. J. Meaney, “Stress-Induced Declarative Memory Impairment in Healthy Elderly Subjects: Relationship to Cortisol Reactivity,” Journal of Clinical Endocrinology & Metabolism, Vol. 82, No. 7, 1997, pp. 2070-2075. doi:10.1210/jc.82.7.2070
K. Mizoguchi, M. Yuzurihara, A. Ishige, H. Sasaki, D. H. Chui and T. Tabira, “Chronic Stress Induces Impairment of Spatial Working Memory Because of Prefrontal Dopaminergic Dysfunction,” Journal of Neuroscience, Vol. 20, No. 4, 2000, pp. 1568-1574.
C. Sandi, J. C. Woodson, V. F. Haynes, C. R. Park, K. Touyarot, M. A. Lopez-Fernandez, C. Venero and D. M. Diamond, “Acute Stress-Induced Impairment of Spatial Memory Is Associated with Decreased Expression of Neural Cell Adhesion Molecule in the Hippocampus and Prefrontal Cortex,” Biological Psychiatry, Vol. 57, No. 8, 2005, pp. 856-864. doi:10.1016/j.biopsych.2004.12.034
F. D. Rose, E. A. Attree, B. M. Brooks and D. A. Johnson, “Virtual Environments in Brain Damage Rehabilitation: A Rationale from Basic Neuroscience,” Studies in Health Technology and Informatics, Vol. 58, 1998, pp. 233-242.
N. Madronal, C. Lopez-Aracil, A. Rangel, J. A. del Rio, J. M. Delgado-Garcia and A. Gruart, “Effects of Enriched Physical and Social Environments on Motor Performance, Associative Learning, and Hippocampal Neurogenesis in Mice,” PLoS One, Vol. 5, No. 6, 2010, p. e11130. doi:10.1371/journal.pone.0011130
O. Lazarov, J. Robinson, Y. P. Tang, I. S. Hairston, Z. Korade-Mirnics, V. M. Lee, L. B. Hersh, R. M. Sapolsky, K. Mirnics and S. S. Sisodia, “Environmental Enrichment Reduces Abeta Levels and Amyloid Deposition in Transgenic Mice,” Cell, Vol. 120, No. 5, 2005, pp. 701-713. doi:10.1016/j.cell.2005.01.015
O. Bendel, T. Bueters, M. von Euler, S. Ove Ogren, J. Sandin and G. von Euler, “Reappearance of Hippocampal CA1 Neurons after Ischemia Is Associated with Recovery of Learning and Memory,” Journal of Cerebral Blood Flow & Metabolism, Vol. 25, No. 12, 2005, pp. 1586-1595. doi:10.1038/sj.jcbfm.9600153
T. Kirino, “Delayed Neuronal Death in the Gerbil Hippo-Campus Following Ischemia,” Brain Research, Vol. 239, No. 1, 1982, pp. 57-69. doi:10.1016/0006-8993(82)90833-2
H. Nakatomi, T. Kuriu, S. Okabe, S. Yamamoto, O. Hatano, N. Kawahara, A. Tamura, T. Kirino and M. Nakafuku, “Regeneration of Hippocampal Pyramidal Neurons after Ischemic Brain Injury by Recruitment of Endogenous Neural Progenitors,” Cell, Vol. 110, No. 4, 2002, pp. 429-441. doi:10.1016/S0092-8674(02)00862-0
S. J. Wong-Goodrich, M. J. Glenn, T. J. Mellott, Y. B. Liu, J. K. Blusztajn and C. L. Williams, “Water Maze Experience and Prenatal Choline Supplementation Differentially Promote Long-Term Hippocampal Recovery from Seizures in Adulthood,” Hippocampus, Vol. 21, No. 6, 2011, pp, 584-608.
T. Kitamura, Y. Saitoh, N. Takashima, A. Murayama, Y. Niibori, H. Ageta, M. Sekiguchi, H. Sugiyama and K. Inokuchi, “Adult Neurogenesis Modulates the Hippocampus-Dependent Period of Associative Fear Memory,” Cell, Vol. 139, No. 4, 2009, pp. 814-827. doi:10.1016/j.cell.2009.10.020
W. Deng, M.D. Saxe, I.S. Gallina and F.H. Gage, “Adult-Born Hippocampal Dentate Granule Cells Undergoing Maturation Modulate Learning and Memory in the Brain,” Journal of Neuroscience, Vol. 29, No. 43, 2009, pp. 13532-13542. doi:10.1523/JNEUROSCI.3362-09.2009
M. Blurton-Jones, M. Kitazawa, H. Martinez-Coria, N. A. Castello, F. J. Muller, J. F. Loring, T. R. Yamasaki, W. W. Poon, K. N. Green and F. M. LaFerla, “Neural Stem Cells Improve Cognition via BDNF in a Transgenic Model of Alzheimer Disease,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 32, 2009, pp. 13594-13599. doi:10.1073/pnas.0901402106
C. R. Almli, T. J. Levy, B. H. Han, A. R. Shah, J. M. Gidday and D. M. Holtzman, “BDNF Protects against Spatial Memory Deficits Following Neonatal Hypoxia-Ischemia,” Experimental Neurology, Vol. 166, No. 1, 2000, pp. 99-114. doi:10.1006/exnr.2000.7492
S. Katsuragi, T. Ikeda, I. Date, T. Shingo, T. Yasuhara, K. Mishima, N. Aoo, K. Harada, N. Egashira, K. Iwasaki, M. Fujiwara and T. Ikenoue, “Implantation of Encapsulated Glial Cell Line-Derived Neurotrophic Factor-Secreting Cells Prevents Long-Lasting Learning Impairment Following Neonatal Hypoxic-Ischemic Brain Insult in Rats,” American Journal of Obstetrics & Gynecology, Vol. 192, No. 4, 2005, pp. 1028-1037. doi:10.1016/j.ajog.2005.01.014
S. Lin, L.W. Fan, Y. Pang, P. G. Rhodes, H. J. Mitchell and Z. Cai, “IGF-1 Protects Oligodendrocyte Progenitor Cells and Improves Neurological Functions Following Cerebral Hypoxia-Ischemia in the Neonatal Rat,” Brain Research, Vol. 1063, No. 1, 2005, pp. 15-26. doi:10.1016/j.brainres.2005.09.042
M. Ploughman, S. Granter-Button, G. Chernenko, B. A. Tucker, K. M. Mearow and D. Corbett, “Endurance Exercise Regimens Induce Differential Effects on Brain-Derived Neurotrophic Factor, Synapsin-I and Insulin-Like Growth Factor I after Focal Ischemia,” Neuroscience, Vol. 136, No. 4, 2005, pp. 991-1001. doi:10.1016/j.neuroscience.2005.08.037
H. Sun, J. Zhang, L. Zhang, H. Liu, H. Zhu and Y. Yang, “Environmental Enrichment Influences BDNF and NR1 Levels in the Hippocampus and Restores Cognitive Impairment in Chronic Cerebral Hypoperfused Rats,” Current Neurovascular Research, Vol. 7, No. 4, 2010, pp. 268-280.
M. Ploughman, V. Windle, C. L. MacLellan, N. White, J. J. Dore and D. Corbett, “Brain-Derived Neurotrophic Factor Contributes to Recovery of Skilled Reaching after Focal Ischemia in Rats,” Stroke, Vol. 40, No. 4, 2009, pp. 1490-1495. doi:10.1161/STROKEAHA.108.531806
W. R. Schabitz, T. Steigleder, C. M. Cooper-Kuhn, S. Schwab, C. Sommer, A. Schneider and H. G. Kuhn, “Intravenous Brain-Derived Neurotrophic Factor Enhances Poststroke Sensorimotor Recovery and Stimulates Neurogenesis,” Stroke, Vol. 38, No. 7, 2007, pp. 2165-2172. doi:10.1161/STROKEAHA.106.477331
M. K. Sun, J. Hongpaisan, T. J. Nelson and D. L. Alkon, “Poststroke Neuronal Rescue and Synaptogenesis Mediated in Vivo by Protein Kinase C in Adult Brains,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 36, 2008, pp. 13620-13625. doi:10.1073/pnas.0805952105
L. Zhang, R. L. Zhang, Y. Wang, C. Zhang, Z. G. Zhang, H. Meng and M. Chopp, “Functional Recovery in Aged and Young Rats after Embolic Stroke: Treatment with a Phosphodiesterase Type 5 Inhibitor,” Stroke, Vol. 36, No. 4, 2005, pp. 847-852. doi:10.1161/01.STR.0000158923.19956.73