Abstract
Neurogenesis is defined as a process that includes the proliferation of neural stem/progenitor cells (NPCs) and the differentiation of these cells into new neurons that integrate into the existing neuronal circuitry. MicroRNAs (miRNAs) are a recently discovered class of small non-protein coding RNA molecules implicated in a wide range of diverse gene regulatory mechanisms. More and more data demonstrate that numerous miRNAs are expressed in a spatially and temporally controlled manners in the nervous system, which suggests that miRNAs have important roles in the gene regulatory networks involved in both brain development and adult neural plasticity. This review summarizes the roles of miRNAs-mediated gene regulation in the nervous system with focus on neurogenesis in both embryonic and adult brains.
Similar content being viewed by others
References
Ahn, S., & Joyner, A. L. (2005). In vivo analysis of quiescent adult neural stem cells responding to sonic hedgehog. Nature, 437, 894–897.
Alonso, M., Viollet, C., Gabellec, M. M., Meas-Yedid, V., Olivo-Marin, J. C., & Lledo, P. M. (2006). Olfactory discrimination learning increases the survival of adult-born neurons in the olfactory bulb. Journal of Neuroscience, 26, 10508–10513.
Balordi, F., & Fishell, G. (2007). Hedgehog signaling in the subventricular zone is required for both the maintenance of stem cells and the migration of newborn neurons. Journal of Neuroscience, 27, 5936–5947.
Barkho, B. Z., Munoz, A. E., Li, X., Li, L., Cunningham, L. A., & Zhao, X. (2008). Endogenous matrix metalloproteinase (MMP)-3 and MMP-9 promote the differentiation and migration of adult neural progenitor cells in response to chemokines. Stem Cells, 26, 3139–3149.
Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.
Borchert, G. M., Lanier, W., & Davidson, B. L. (2006). RNA polymerase III transcribes human microRNAs. Nature Structural and Molecular Biology, 13, 1097–1101.
Burns, K. A., Ayoub, A. E., Breunig, J. J., Adhami, F., Weng, W. L., Colbert, M. C., et al. (2007). Nestin-CreER mice reveal DNA synthesis by nonapoptotic neurons following cerebral ischemia-hypoxia. Cerebral Cortex, 17, 2585–2592.
Cameron, H. A., Tanapat, P., & Gould, E. (1998). Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience, 82, 349–354.
Carthew, R. W., & Sontheimer, E. J. (2009). Origins and mechanisms of miRNAs and siRNAs. Cell, 136, 642–655.
Chalfie, M., Horvitz, H. R., & Sulston, J. E. (1981). Mutations that lead to reiterations in the cell lineages of C. elegans. Cell, 24, 59–69.
Chen, C., Ridzon, D. A., Broomer, A. J., Zhou, Z., Lee, D. H., Nguyen, J. T., et al. (2005). Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Research, 33, e179.
Cheng, L. C., Pastrana, E., Tavazoie, M., & Doetsch, F. (2009). miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nature Neuroscience, 12, 399–408.
Chi, S. W., Zang, J. B., Mele, A., & Darnell, R. B. (2009). Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps. Nature [Epub ahead of print].
Choi, P. S., Zakhary, L., Choi, W. Y., Caron, S., Alvarez-Saavedra, E., Miska, E. A., et al. (2008). Members of the miRNA-200 family regulate olfactory neurogenesis. Neuron, 57, 41–55.
Conaco, C., Otto, S., Han, J. J., & Mandel, G. (2006). Reciprocal actions of REST and a microRNA promote neuronal identity. Proceedings of the National Academy of Sciences of the United States of America, 103, 2422–2427.
Corbin, J. G., Gaiano, N., Juliano, S. L., Poluch, S., Stancik, E., & Haydar, T. F. (2008). Regulation of neural progenitor cell development in the nervous system. Journal of Neurochemistry, 106, 2272–2287.
Curtis, M. A., Kam, M., Nannmark, U., Anderson, M. F., Axell, M. Z., Wikkelso, C., et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science, 315, 1243–1249.
Devor, E. J., Huang, L., Abdukarimov, A., & Abdurakhmonov, I. Y. (2009). Methodologies for in vitro cloning of small RNAs and application for plant genome(s). International Journal of Plant Genomics, 2009, 915061.
Doetsch, F. (2003). A niche for adult neural stem cells. Current Opinion in Genetics and Development, 13, 543–550.
Duan, X., Chang, J. H., Ge, S., Faulkner, R. L., Kim, J. Y., Kitabatake, Y., et al. (2007). Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 130, 1146–1158.
Dupret, D., Revest, J. M., Koehl, M., Ichas, F., De Giorgi, F., Costet, P., et al. (2008). Spatial relational memory requires hippocampal adult neurogenesis. PLoS ONE, 3, e1959.
Eriksson, P. S., Perfilieva, E., Bjork-Eriksson, T., Alborn, A. M., Nordborg, C., Peterson, D. A., et al. (1998). Neurogenesis in the adult human hippocampus. Nature Medicine, 4, 1313–1317.
Ferri, A. L. M., Cavallaro, M., Braida, D., Di Cristofano, A., Canta, A., Vezzani, A., et al. (2004). Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development, 131, 3805–3819.
Fiore, R., Siegel, G., & Schratt, G. (2008). MicroRNA function in neuronal development, plasticity and disease. Biochimica Et Biophysica Acta-Gene Regulatory Mechanisms, 1779, 471–478.
Gentner, B., Schira, G., Giustacchini, A., Amendola, M., Brown, B. D., Ponzoni, M., et al. (2009). Stable knockdown of microRNA in vivo by lentiviral vectors. Nature Methods, 6, 63–66.
Giraldez, A. J., Cinalli, R. M., Glasner, M. E., Enright, A. J., Thomson, J. M., Baskerville, S., et al. (2005). MicroRNAs regulate brain morphogenesis in zebrafish. Science, 308, 833–838.
Graham, V., Khudyakov, J., Ellis, P., & Pevny, L. (2003). SOX2 functions to maintain neural progenitor identity. Neuron, 39, 749–765.
Gritti, A., Frolichsthal-Schoeller, P., Galli, R., Parati, E. A., Cova, L., Pagano, S. F., et al. (1999). Epidermal and fibroblast growth factors behave as mitogenic regulators for a single multipotent stem cell-like population from the subventricular region of the adult mouse forebrain. Journal of Neuroscience, 19, 3287–3297.
Hafner, M., Landgraf, P., Ludwig, J., Rice, A., Ojo, T., Lin, C., et al. (2008). Identification of microRNAs and other small regulatory RNAs using cDNA library sequencing. Methods, 44, 3–12.
Houbaviy, H. B., Dennis, L., Jaenisch, R., & Sharp, P. A. (2005). Characterization of a highly variable eutherian microRNA gene. RNA, 11, 1245–1257.
Houbaviy, H. B., Murray, M. F., & Sharp, P. A. (2003). Embryonic stem cell-specific microRNAs. Developmental Cell, 5, 351–358.
Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., et al. (2008). Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nature Neuroscience, 11, 1153–1161.
Jessberger, S., Clark, R. E., Broadbent, N. J., Clemenson, G. D., Consiglio, A., Lie, D. C., et al. (2009). Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learning and Memory, 16, 147–154.
Jin, K. L., Wang, X. M., Xie, L., Mao, X. O., Zhu, W., Wang, Y., et al. (2006). Evidence for stroke-induced neurogenesis in the human brain. Proceedings of the National Academy of Sciences of the United States of America, 103, 13198–13202.
Kanellopoulou, C., Muljo, S. A., Kung, A. L., Ganesan, S., Drapkin, R., Jenuwein, T., et al. (2005). Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes and Development, 19, 489–501.
Kapsimali, M., Kloosterman, W. P., de Bruijn, E., Rosa, F., Plasterk, R. H. A., & Wilson, S. W. (2007). MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biology, 8, R173.
Keller, G. (2005). Embryonic stem cell differentiation: Emergence of a new era in biology and medicine. Genes and Development, 19, 1129–1155.
Keller, G., Kennedy, M., Papayannopoulou, T., & Wiles, M. V. (1993). Hematopoietic commitment during embryonic stem-cell differentiation in culture. Molecular and Cellular Biology, 13, 473–486.
Kempermann, G., & Kronenberg, G. (2003). Depressed new neurons—Adult hippocampal neurogenesis and a cellular plasticity hypothesis of major depression. Biological Psychiatry, 54, 499–503.
Kempermann, G., Kuhn, H. G., & Gage, F. H. (1997). More hippocampal neurons in adult mice living in an enriched environment. Nature, 386, 493–495.
Kennedy, M., & Keller, G. M. (2003). Hematopoietic commitment of ES cells in culture. Differentiation of Embryonic Stem Cells, 365, 39–59.
Kilpatrick, T. J., & Bartlett, P. F. (1993). Cloning and growth of multipotential neural precursors—Requirements for proliferation and differentiation. Neuron, 10, 255–265.
Kim, V. N., Han, J., & Siomi, M. C. (2009). Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology, 10, 126–139.
Kim, J., Inoue, K., Ishii, J., Vanti, W. B., Voronov, S. V., Murchison, E., et al. (2007). A microRNA feedback circuit in midbrain dopamine neurons. Science, 317, 1220–1224.
Kim, J., Krichevsky, A., Grad, Y., Hayes, G. D., Kosik, K. S., Church, G. M., et al. (2004). Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proceedings of the National Academy of Sciences of the United States of America, 101, 360–365.
Kornack, D. R., & Rakic, P. (2001). The generation, migration, and differentiation of olfactory neurons in the adult primate brain. Proceedings of the National Academy of Sciences of the United States of America, 98, 4752–4757.
Krichevsky, A. M., Sonntag, K. C., Isacson, O., & Kosik, K. S. (2006). Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells, 24, 857–864.
Lagace, D. C., Whitman, M. C., Noonan, M. A., Ables, J. L., DeCarolis, N. A., Arguello, A. A., et al. (2007). Dynamic contribution of nestin-expressing stem cells to adult neurogenesis. Journal of Neuroscience, 27, 12623–12629.
Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W., & Tuschl, T. (2002). Identification of tissue-specific microRNAs from mouse. Current Biology, 12, 735–739.
Landgraf, P., Rusu, M., Sheridan, R., Sewer, A., Iovino, N., Aravin, A., et al. (2007). A mammalian microRNA expression atlas based on small RNA library sequencing. Cell, 129, 1401–1414.
Larson, J., Jessen, R. E., Kim, D., Fine, A. K. S., & du Hoffmann, J. (2005). Age-dependent and selective impairment of long-term potentiation in the anterior piriform cortex of mice lacking the fragile X mental retardation protein. Journal of Neuroscience, 25, 9460–9469.
Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans Heterochronic gene Lin-4 encodes small RNAS with antisense complementarity to Lin-14. Cell, 75, 843–854.
Li, X., Barkho, B. Z., Luo, Y., Smrt, R. D., Santistevan, N. J., Liu, C., et al. (2008). Epigenetic regulation of the stem cell mitogen Fgf-2 by Mbd1 in adult neural stem/progenitor cells. Journal of Biological Chemistry, 283, 27644–27652.
Li, O., Li, J. M., & Droge, P. (2007). DNA architectural factor and proto-oncogene HMGA2 regulates key developmental genes in pluripotent human embryonic stem cells. FEBS Letters, 581, 3533–3537.
Li, O., Vasudevan, D., Davey, C. A., & Droge, P. (2006). High-level expression of DNA architectural factor HMGA2 and its association with nucleosomes in human embryonic stem cells. Genesis, 44, 523–529.
Li, X. K., & Zhao, X. Y. (2008). Epigenetic regulation of mammalian stem cells. Stem Cells and Development, 17, 1043–1052.
Lie, D. C., Dziewczapolski, G., Willhoite, A. R., Kaspar, B. K., Shults, C. W., & Gage, F. H. (2002). The adult substantia nigra contains progenitor cells with neurogenic potential. Journal of Neuroscience, 22, 6639–6649.
Lu, Y., Thomson, J. M., Wong, H. Y. F., Hammond, S. M., & Hogan, B. L. M. (2007). Transgenic over-expression of the microRNA miR-17–92 cluster promotes proliferation and inhibits differentiation of lung epithelial progenitor cells. Developmental Biology, 310, 442–453.
Lytle, J. R., Yario, T. A., & Steitz, J. A. (2007). Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proceedings of the National Academy of Sciences of the United States of America, 104, 9667–9672.
Makeyev, E. V., Zhang, J. W., Carrasco, M. A., & Maniatis, T. (2007). The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative Pre-mRNA splicing. Molecular Cell, 27, 435–448.
Martin, G. R. (1981). Isolation of a pluripotent cell-line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem-cells. Proceedings of the National Academy of Sciences of the United States of America-Biological Sciences, 78, 7634–7638.
Mayoral, R. J., Pipkin, M. E., Pachkov, M., van Nimwegen, E., Rao, A., & Monticelli, S. (2009). MicroRNA-221–222 regulate the cell cycle in mast cells. Journal of Immunology, 182, 433–445.
Mellios, N., Huang, H. S., Grigorenko, A., Rogaev, E., & Akbarian, S. (2008). A set of differentially expressed miRNAs, including miR-30a–5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex. Human Molecular Genetics, 17, 3030–3042.
Molofsky, A. V., Pardal, R., Iwashita, T., Park, I. K., Clarke, M. F., & Morrison, S. J. (2003). Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425, 962–967.
Morozova, O., & Marra, M. A. (2008). Applications of next-generation sequencing technologies in functional genomics. Genomics, 92, 255–264.
Morshead, C. M., Reynolds, B. A., Craig, C. G., Mcburney, M. W., Staines, W. A., Morassutti, D., et al. (1994). Neural stem-cells in the adult mammalian forebrain—a relatively quiescent subpopulation of subependymal cells. Neuron, 13, 1071–1082.
Mott, J. L., Kobayashi, S., Bronk, S. F., & Gores, G. J. (2007). mir-29 regulates Mcl-1 protein expression and apoptosis. Oncogene, 26, 6133–6140.
Nishino, J., Kim, I., Chada, K., & Morrison, S. J. (2008). Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell, 135, 227–239.
Noctor, S. C., Martinez-Cerdeno, V., Ivic, L., & Kriegstein, A. R. (2004). Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neuroscience, 7, 136–144.
Orom, U. A., Nielsen, F. C., & Lund, A. H. (2008). MicroRNA-10a binds the 5′ UTR of ribosomal protein mRNAs and enhances their translation. Molecular Cell, 30, 460–471.
Packer, A. N., Xing, Y., Harper, S. Q., Jones, L., & Davidson, B. L. (2008). The bifunctional microRNA miR-9/miR-9* regulates REST and CoREST and is downregulated in Huntington’s disease. Journal of Neuroscience, 28, 14341–14346.
Palmer, T. D., Markakis, E. A., Willhoite, A. R., Safar, F., & Gage, F. H. (1999). Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. Journal of Neuroscience, 19, 8487–8497.
Palmer, T. D., Takahashi, J., & Gage, F. H. (1997). The adult rat hippocampus contains primordial neural stem cells. Molecular and Cellular Neuroscience, 8, 389–404.
Parent, J. M., Yu, T. W., Leibowitz, R. T., Geschwind, D. H., Sloviter, R. S., & Lowenstein, D. H. (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. Journal of Neuroscience, 17, 3727–3738.
Pencea, V., Bingaman, K. D., Freedman, L. J., & Luskin, M. B. (2001). Neurogenesis in the subventricular zone and rostral migratory stream of the neonatal and adult primate forebrain. Experimental Neurology, 172, 1–16.
Pomraning, K. R., Smith, K. M., & Freitag, M. (2009). Genome-wide high throughput analysis of DNA methylation in eukaryotes. Methods, 47, 142–150.
Reynolds, B. A., Tetzlaff, W., & Weiss, S. (1992). A multipotent Egf-responsive striatal embryonic progenitor-cell produces neurons and astrocytes. Journal of Neuroscience, 12, 4565–4574.
Sanosaka, T., Namihira, M., & Nakashima, K. (2009). Epigenetic mechanisms in sequential differentiation of neural stem cells. Epigenetics, 4, 89–92.
Schratt, G. M., Tuebing, F., Nigh, E. A., Kane, C. G., Sabatini, M. E., Kiebler, M., et al. (2006). A brain-specific microRNA regulates dendritic spine development. Nature, 439, 283–289. (Erratum in Nature 441, 902).
Sempere, L. F., Freemantle, S., Pitha-Rowe, I., Moss, E., Dmitrovsky, E., & Ambros, V. (2004). Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biology, 5, R13.
Shi, Y. H., Lie, D. C., Taupin, P., Nakashima, K., Ray, J., Yu, R. T., et al. (2004). Expression and function of orphan nuclear receptor TLX in adult neural stem cells. Nature, 427, 78–83.
Shihabuddin, L. S., Horner, P. J., Ray, J., & Gage, F. H. (2000). Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. Journal of Neuroscience, 20, 8727–8735.
Shimozaki, K., Namihira, M., Nakashima, K., & Taga, T. (2005). Stage- and site-specific DNA demethylation during neural cell development from embryonic stem cells. Journal of Neurochemistry, 93, 432–439.
Suh, M. R., Lee, Y., Kim, J. Y., Kim, S. K., Moon, S. H., Lee, J. Y., et al. (2004). Human embryonic stem cells express a unique set of microRNAs. Developmental Biology, 270, 488–498.
Sun, Y. J., Jin, K. L., Childs, J. T., Xie, L., Mao, X. O., & Greenberg, D. A. (2005). Neuronal nitric oxide synthase and ischemia-induced neurogenesis. Journal of Cerebral Blood Flow and Metabolism, 25, 485–492.
Tay, Y., Zhang, J. Q., Thomson, A. M., Lim, B., & Rigoutsos, I. (2008). MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature, 455, 1124.
Temple, S. (2001). The development of neural stem cells. Nature, 414, 112–117.
Thai, T. H., Calado, D. P., Casola, S., Ansel, K. M., Xiao, C. C., Xue, Y. Z., et al. (2007). Regulation of the germinal center response by microRNA-155. Science, 316, 604–608.
Vasudevan, S., Tong, Y., & Steitz, J. A. (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science, 318, 1931–1934.
Visvanathan, J., Lee, S., Lee, B., Lee, J. W., & Lee, S. K. (2007). The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes and Development, 21, 744–749.
Wang, S. S., Aurora, A. B., Johnson, B. A., Qi, X. X., McAnally, J., Hill, J. A., et al. (2008a). The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Developmental Cell, 15, 261–271.
Wang, Y., Baskerville, S., Shenoy, A., Babiarz, J. E., Baehner, L., & Blelloch, R. (2008b). Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nature Genetics, 40, 1478–1483.
Wang, Y. L., Keys, D. N., Au-Young, J. K., & Chen, C. F. (2009). MicroRNAs in embryonic stem cells. Journal of Cellular Physiology, 218, 251–255.
Wang, Y. M., Medvid, R., Melton, C., Jaenisch, R., & Blelloch, R. (2007). DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genetics, 39, 380–385.
Weiss, S., Dunne, C., Hewson, J., Wohl, C., Wheatley, M., Peterson, A. C., et al. (1996). Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. Journal of Neuroscience, 16, 7599–7609.
Williams, A. E. (2008). Functional aspects of animal microRNAs. Cellular and Molecular Life Sciences, 65, 545–562.
Xu, J., Zeng, J. Q., Wan, G., Hu, G. B., Yan, H., & Ma, L. X. (2009). Construction of siRNA/miRNA expression vectors based on a one-step PCR process. BMC Biotechnology, 9, 53.
Yu, J. Y., Chung, K. H., Deo, M., Thompson, R. C., & Turner, D. L. (2008). MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation. Experimental Cell Research, 314, 2618–2633.
Yu, F., Yao, H., Zhu, P. C., Zhang, X. Q., Pan, Q. H., Gong, C., et al. (2007). Iet-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell, 131, 1109–1123.
Zhao, C. M., Deng, W., & Gage, F. H. (2008a). Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645–660.
Zhao, J. J., Lin, J. H., Yang, H., Kong, W., He, L. L., Ma, X., et al. (2008b). MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. Journal of Biological Chemistry, 283, 31079–31086.
Zhao, C., Sun, G., Li, S., & Shi, Y. (2009). A feedback regulatory loop involving microRNA-9 and nuclear receptor TLX in neural stem cell fate determination. Nature Structural and Molecular Biology, 16, 365–371.
Zhao, X., Ueba, T., Christie, B. R., Barkho, B., McConnell, M. J., Nakashima, K., et al. (2003). Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proceedings of the National Academy of Sciences of the United States of America, 100, 6777–6782.
Acknowledgments
We would like to thank Dr. Weixiang Guo for helping with the figures and Dr. Zhaoqian Teng for helping with the references. Images in this manuscript were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Facility (http://hsc.unm.edu/crtc/microscopy/facility.html). This work is funded by NIH MH080434 and MH078972).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Liu, C., Zhao, X. MicroRNAs in Adult and Embryonic Neurogenesis. Neuromol Med 11, 141–152 (2009). https://doi.org/10.1007/s12017-009-8077-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-009-8077-y