Yetişkin Hipokampal Nörogenezinin Yarı-stokastik Nümerik Bir Modeli

Abstract

Dentat girusta (DG) görülen yetişkin nörogenezinin hipokampal bellek ağlarındaki işleve önemli bir katkı sunduğu kabul edilmektedir. Sunulan ayrık sayısal model DG'de bulunan nöral progenitör hücre (NPH) popülasyonlarında ve bu süreçlerin ürünlerindeki (immatür nöron, astrosit ve oligodendrosit popülasyonları) temporal değişimleri modellemeyi amaçlamaktadır. Süreçler toplam hacimde bir limitin olmadığı ve nörogenezi yönlendiren tüm kimyasal ve fiziksel düzenleyicilerin devamlı ulaşılabilir olduğu ideal bir ortamda tanımlanmıştır. Sistem üç temel seviyede bağımsız olarak çalışmaktadır. Her seviye nörogenez süreçlerindeki bir aşama olarak tanımlanmıştır ve popülasyonlar üç temel hücre tipinden oluşmaktadır: Tip I (radyal glia), tip II (geçici çoğalan hücre) ve tip III (nöroblast). Hücre kaderi, her hücre tipi için bir popülasyon limiti olan yarı-stokastik bir süreç (bir seçim) olarak sisteme eklenmiştir. Sunulan model, ayrık süreçlere dayanmasına ve basitleştirilmiş bir yaklaşım izlemesine rağmen, yetişkin nörogenezinin sayısal bir taslağını başarılı şekilde üretmektedir ve farklı modülasyonlarla bir hipokampal trisinaptik devre ağına yerleştirilebilir.

Keywords

• Yetişkin nörogenezi,Subgranüler zon,Hesaplamalı model

A Semi-stochastic Numerical Model of Adult Hippocampal Neurogenesis

Abstract

Adult neurogenesis in dentate gyrus (DG) is a prominent contributor in the dynamics of hippocampal memory networks. This discrete model aims to estimate the temporal changes in the neural progenitor cell (NPC)  populations in DG, together with the products of differentiation – immature neurons, astrocytes and oligodendrocytes. The dynamics are described in an ideal environment, where there is no limit for the total volume and all required chemical and physical cues that direct neurogenesis are continuously available. The system works independently on three levels. Each level is defined as the dynamics in a stage of neurogenesis with three types of NPCs: type I cell (radial glia), type II cell (transiently amplifying cells) and type III cell (neuroblasts). Cell fate was introduced as a semi-stochastic process (a choice) with a population limit for each cell type. Although it is based on discrete processes and has a rather simplistic approach, the simulations successfully provide a numerical template for adult neurogenesis, which can be further modified and implemented in a hippocampal trisynaptic loop network.

Keywords

• Adult neurogenesis,Subgranular zone,Computational model

References

1. [1] Kempermann, G., Song, H., Gage, F. H. 2015. Neurogenesis in the adult hippocampus. Cold Spring Harbor Perspectives in Biology, 7(9), a018812.
2. [2] Kempermann, G. 2015. Adult neurogenesis: An evolutionary Perspective. Cold Spring Harbor Perspectives in Biology, 8(2), a018986.
3. [3] Morrens, J., Van Den Broeck, W., Kempermann G. 2012. Glial cells in adult neurogenesis. Glia, 60(2), 159-174.
4. [4] Ehninger, D., Kempermann, G. 2008. Neurogenesis in the adult hippocampus. Cell and Tissue Research, 331(1), 243-250.
5. [5] Amrein, I., Lipp, H. P. 2009. Adult hippocampal neurogenesis of mammals : evolution and life history. Biology Letters, 5, 141-144.
6. [6] Berg, D.A., Bond, A. M., Ming G., Song, H. 2018. Radial glial cells in the adult dentate gyrus: what are they and where do they come from? Cell and Tissue Research, 7, 277.
7. [7] Seri,B. , Garcia-Verdugo, J. M. , McEwen, B. S. , Alvarez-Buylla, A. 2001. Astrocytes give rise to new neurons in the adult mammalian hippocampus. Journal of Neuroscience, 21(18), 7153-7160.
8. [8] Kronenberg, G., Reuter, K., Steiner, B., Brandt, M. D., Jessberger, S., Yamaguchi, M., Kempermann, G. 2003. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. Journal of Comparative Neurology, 467(4), 455-463.

9. [9] Gebara, E., Bonaguidi, M. A., Beckervordersandforth, R., Sultan, S., Udry, F., Gijs, P. J., Lie, D. C., Ming, G. L., Song, H., Toni, N. 2016. Heterogeneity of Radial Glia-Like Cells in the Adult Hippocampus. Stem Cells, 34(4), 997-1010.
10. [10] Amaral, D. G., Witter, M. P. 1989. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience, 31(3), 571-591.
11. [11] Jinno, S. 2011. Topographic differences in adult neurogenesis in the mouse hippocampus: a stereology-based study using endogenous markers. Hippocampus, 21(5), 467-480.
12. [12] Piatti, V. C., Davies-Sala, M. G., Esposito, M. S., Mongiat, L.A., Trinchero, M.F., Schinder, A.F. 2011. The timing for neuronal maturation in the adult hippocampus is modulated by local network activity. Journal of Neuroscience, 31(21), 997-1010.
13. [13] Jhaveri, D. J., O'Keeffe, I., Robinson, G. J., Zhao, Q. Y., Zhang, Z. H., Nink, V., Narayanan,R. K., Osborne, G.W., Wray, N. R., Bartlett, P.F. 2015. Purification of neural precursor cells reveals the presence of distinct, stimulus-specific subpopulations of quiescent precursors in the adult mouse hippocampus.Journal of Neuroscience, 35(21), 8132-8144.
14. [14] Hodge, R D., Kowalczyk, T.D., Wolf, S. A., Encinas, J. M., Rippey, C., Enikopolov, G., Kempermann, G., Hevner, R. F. 2008. Intermediate progenitors in adult hippocampal neurogenesis: Tbr2 expression and coordinate regulation of neuronal output. Journal of Neuroscience, 28(4), 3707-3717.
15. [15] Berg, D. A., Yoon, K., Will, B., Xiao, A.Y., Kim, N., Christian, K. M., Song, H., Ming, G. 2015. Tbr2-expressing intermediate progenitor cells in the adult mouse hippocampus are unipotent neuronal precursors with limited amplification capacity under homeostasis. Frontiers in Biology, 10(3), 262-271.
16. [16] Garcia, A. D., Doan, N. B., Imura, T., Bush, T. G., Sofroniew, M. V. 2004. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nature Neuroscience, 7(11), 1233-1241.
17. [17] Suh, H., Consiglio, A., Ray, J., Sawai, T., D'Amour, K. A., Gage, F. H. 2007. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell, 1(5), 515-28.
18. [18] Huttner, W. B. 2015. Stem cells: slow and steady wins the race. Nature Neuroscience, 18, 613-614.
19. [19] Rusznak, Z., Henskens, W., Schofield, E., Kim, W. S., Fu, Y. 2016. Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration. Experimental Neurobiology,25(3),103-112.
20. [20] Colak, D., Mori, T., Brill, M. S., Pfeifer, A., Falk, S., Deng, C., Monteiro, R., Mummery, C., Sommer, L., Götz, M. 2008. Adult neurogenesis requires Smad4-mediated bone morphogenic protein signaling in stem cells. Journal of Neuroscience, 28, 434-446.
21. [21] Hack, M. A., Sugimori, M., Lundberg, C., Nakafuku, M., Götz, M. 2004. Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6. Molecular and Cellular Neuroscience,25,664–678.
22. [22] Doetsch, F., Petreanu, L., Caille, I., Garcia-Verdugo, J. M., Alvarez-Buylla, A. 2002. EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron,36,1021–1034.
23. [23] Heins, N., Malatesta, P., Cecconi, F., Nakafuku, M., Tucker, K. L., Hack, M. A., Chapouton, P., Barde, Y. A.,G,tz, M. 2002. Glial cells generate neurons: the role of the transcription factor Pax6.Nature Neuroscience,5,308–315.
24. [24] Berninger, B., Costa, M. R., Koch, U., Schroeder, T., Sutor, B., Grothe, B., Götz, M. 2007. Functional properties of neurons derived from in vitro reprogrammed postnatal astroglia. Journal of Neuroscience,27,8654–8664.
25. [25] Heinrich, C., Blum, R., Gascón, S., Masserdotti, G., Tripathi, P., Sánchez, R., Tiedt, S., Schroeder, T, Götz M, Berninger B. 2010. Directing astroglia from the cerebral cortex into subtype specific functional neurons. PLoS Biology,8,e1000373.
26. [26] Niu, W., Zang, T., Zou, Y., Fang, S., Smith, D. K., Bachoo, R., Zhang, C. L. 2013. In vivo reprogramming of astrocytes to neuroblasts in the adult brain. Nature Cell Biology,15,1164–1175.
27. [27] Jackson, E. L., Garcia-Verdugo, J. M., Gil-Perotin, S., Roy, M., Quinones-Hinojosa, A., VandenBerg, S., Alvarez-Buylla, A. 2006. PDGFR alpha-positive B cells are neural stem cells in the adult SVZ that form glioma-like growths in response to increased PDGF signaling. Neuron,51,187–199.
28. [28] Goncalves, J. T., Schafer, S. T., Gage, F. H. 2016. Adult Neurogenesis in the Hippocampus: From Stem Cells to Behavior. Cell,167,897-914.
29. [29] Klempin, F., Beis, D., Mosienko, V., Kempermann, G., Bader, M., Alenina, N. 2013. Serotonin is required for exercise-induced adult hippocampal neurogenesis. Journal of Neuroscience, 33(19), 8270-8275.
30. [30] Lugert, S., Kremer, T., Jagasia, r., Herrmann, A., Aigner, S., Giachino, C., Mendez-David, I., Gardier, A.M., Carralot, J. P., Meistermann, H., Augustin, A., Saxe, M. D., Lamerz, J., Duran-Pacheco, G., Ducret, A., Taylor, V., David, D. J., Czech, C. 2017. Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis. Scientific Reports, 7, 46543.
31. [31] Miller, J.A., Nathanson, J., Franjic, D., Shim, S., Dalley, R.A., Shapouri, S., Smith, K. A., Sunkin, S. M., Bernard, A., Bennett, J. L., Lee, C., Hawrylycz, M. J., Jones, A. R., Amaral, D. G., Sestan, N., Gage, F. H., Lein, E. S. 2013. Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Development, 140, 4633-4644.
32. [32] Ashbourn, J. M.iller, J., Reumers, V., Baekelandt, V., Geris, L. 2012. A mathematical model of adult subventricular neurogenesis. Journal of Royal Society,Interface, 9(75), 2414-2423.
33. [33] Ziebell, F., Martin-Villalba, A., Marciniak-Czohra, A. 2014. Mathematical modelling of adult hippocampal neurogenesis: effects of altered stem cell dynamics on cell counts and bromodeoxyuridine-labelled cells. Journal of Royal Society,Interface, 11(94), 20140144.
34. [34] Choi, M.L., Begeti, F., Barker, R.A., Kim, N. 2015. A simple assessment model to quantifying the dynamic hippocampal neurogenic process in the adult mammalian brain. Hippocampus, 26(4), 517-529.
35. [35] Ziebell, F., Dehler, S., Martin-Villalba, A., Marciniak-Czohra, A. 2018. Revealing age-related changes of adult hippocampal neurogenesis using mathematical models. Development, 145(1), dev153544.
36. [36] Kuhn, H. G., Dickinson-Anson, H., Gage, F. H. 1996. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. Journal of Neuroscience, 16(6), 2027-2033.
37. [37] Encinas, J. M., Michurina, T.V., Peunova, N., Park, J.H., Tordo, J., Peterson, D.A., Fishell, G., Koulakov, A., Enikopolov, G. 2011. Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus. Cell Stem Cell, 8(5), 566-579.
38. [38] Rolyan, H., Scheffold, A., Heinrich, A., Begus-Nahrmann, Y., Langkopf, B.H., Hölter, S.M., Vogt-Weisenhorn,D. M., Liss, B., Wurst, W., Lie,D. C., Thal, D. R., Biber, K., Rudolph, K. L. 2011. Telomere shortening reduces Alzheimer's disease amyloid pathology in mice. Brain, 134(7), 2044-2056.