Revealing Age-related Changes of Adult Hippocampal Neurogenesis Using Mathematical Models

Overview

Journal Development

Specialty Biology

Date 2017 Dec 13

PMID 29229768

Citations 22

Authors

Frederik Ziebell

Sascha Dehler

Ana Martin-Villalba

Anna Marciniak-Czochra

Affiliations

Soon will be listed here.

Abstract

New neurons are continuously generated in the dentate gyrus of the adult hippocampus. This continuous supply of newborn neurons is important to modulate cognitive functions. Yet the number of newborn neurons declines with age. Increasing Wnt activity upon loss of dickkopf 1 can counteract both the decline of newborn neurons and the age-related cognitive decline. However, the precise cellular changes underlying the age-related decline or its rescue are fundamentally not understood. The present study combines a mathematical model and experimental data to address features controlling neural stem cell (NSC) dynamics. We show that available experimental data fit a model in which quiescent NSCs may either become activated to divide or may undergo depletion events, such as astrocytic transformation and apoptosis. Additionally, we demonstrate that old NSCs remain quiescent longer and have a higher probability of becoming re-activated than depleted. Finally, our model explains that high NSC-Wnt activity leads to longer time in quiescence while enhancing the probability of activation. Altogether, our study shows that modulation of the quiescent state is crucial to regulate the pool of stem cells throughout the life of an animal.

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References

Seib D, Corsini N, Ellwanger K, Plaas C, Mateos A, Pitzer C . Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline. Cell Stem Cell. 2013; 12(2):204-14. DOI: 10.1016/j.stem.2012.11.010. View

Chabab S, Lescroart F, Rulands S, Mathiah N, Simons B, Blanpain C . Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors during Heart Morphogenesis. Cell Rep. 2016; 14(1):1-10. PMC: 4709258. DOI: 10.1016/j.celrep.2015.12.013. View

Qu Q, Sun G, Li W, Yang S, Ye P, Zhao C . Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol. 2009; 12(1):31-40. PMC: 2880892. DOI: 10.1038/ncb2001. View

Lie D, Colamarino S, Song H, Desire L, Mira H, Consiglio A . Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005; 437(7063):1370-5. DOI: 10.1038/nature04108. View

Weekes S, Barker B, Bober S, Cisneros K, Cline J, Thompson A . A multicompartment mathematical model of cancer stem cell-driven tumor growth dynamics. Bull Math Biol. 2014; 76(7):1762-82. PMC: 4140966. DOI: 10.1007/s11538-014-9976-0. View

Furutachi S, Matsumoto A, Nakayama K, Gotoh Y . p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis. EMBO J. 2013; 32(7):970-81. PMC: 3616292. DOI: 10.1038/emboj.2013.50. View

Doupe D, Alcolea M, Roshan A, Zhang G, Klein A, Simons B . A single progenitor population switches behavior to maintain and repair esophageal epithelium. Science. 2012; 337(6098):1091-3. PMC: 3527005. DOI: 10.1126/science.1218835. View

Encinas J, Vaahtokari A, Enikolopov G . Fluoxetine targets early progenitor cells in the adult brain. Proc Natl Acad Sci U S A. 2006; 103(21):8233-8. PMC: 1461404. DOI: 10.1073/pnas.0601992103. View

Jinno S . Decline in adult neurogenesis during aging follows a topographic pattern in the mouse hippocampus. J Comp Neurol. 2010; 519(3):451-66. DOI: 10.1002/cne.22527. View

10.

Klein A, Nakagawa T, Ichikawa R, Yoshida S, Simons B . Mouse germ line stem cells undergo rapid and stochastic turnover. Cell Stem Cell. 2010; 7(2):214-24. DOI: 10.1016/j.stem.2010.05.017. View

11.

Ming G, Song H . Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron. 2011; 70(4):687-702. PMC: 3106107. DOI: 10.1016/j.neuron.2011.05.001. View

12.

Busch K, Klapproth K, Barile M, Flossdorf M, Holland-Letz T, Schlenner S . Fundamental properties of unperturbed haematopoiesis from stem cells in vivo. Nature. 2015; 518(7540):542-6. DOI: 10.1038/nature14242. View

13.

Gao X, Arlotta P, Macklis J, Chen J . Conditional knock-out of beta-catenin in postnatal-born dentate gyrus granule neurons results in dendritic malformation. J Neurosci. 2007; 27(52):14317-25. PMC: 6673436. DOI: 10.1523/JNEUROSCI.3206-07.2007. View

14.

Bouchard-Cannon P, Mendoza-Viveros L, Yuen A, Kaern M, Cheng H . The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit. Cell Rep. 2013; 5(4):961-73. DOI: 10.1016/j.celrep.2013.10.037. View

15.

Watson J, Rulands S, Wilkinson A, Wuidart A, Ousset M, Van Keymeulen A . Clonal Dynamics Reveal Two Distinct Populations of Basal Cells in Slow-Turnover Airway Epithelium. Cell Rep. 2015; 12(1):90-101. PMC: 4518462. DOI: 10.1016/j.celrep.2015.06.011. View

16.

Ziebell F, Martin-Villalba A, Marciniak-Czochra A . Mathematical modelling of adult hippocampal neurogenesis: effects of altered stem cell dynamics on cell counts and bromodeoxyuridine-labelled cells. J R Soc Interface. 2014; 11(94):20140144. PMC: 3973376. DOI: 10.1098/rsif.2014.0144. View

17.

Flossdorf M, Rossler J, Buchholz V, Busch D, Hofer T . CD8(+) T cell diversification by asymmetric cell division. Nat Immunol. 2015; 16(9):891-3. DOI: 10.1038/ni.3235. View

18.

Frede J, Greulich P, Nagy T, Simons B, Jones P . A single dividing cell population with imbalanced fate drives oesophageal tumour growth. Nat Cell Biol. 2016; 18(9):967-78. PMC: 5870829. DOI: 10.1038/ncb3400. View

19.

Li B, Sierra A, Deudero J, Semerci F, Laitman A, Kimmel M . Multitype Bellman-Harris branching model provides biological predictors of early stages of adult hippocampal neurogenesis. BMC Syst Biol. 2017; 11(Suppl 5):90. PMC: 5629620. DOI: 10.1186/s12918-017-0468-3. View

20.

Michor F, Hughes T, Iwasa Y, Branford S, Shah N, Sawyers C . Dynamics of chronic myeloid leukaemia. Nature. 2005; 435(7046):1267-70. DOI: 10.1038/nature03669. View