vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ18.454vavilov-1813Research ArticleРЕПРОДУКТИВНЫЕ ТЕХНОЛОГИИPHYSIOLOGICAL GENETICSВлияние физической активности на структурную асимметрию гиппокампа мышиEffect of physical activity on structural asymmetry of mouse hippocampushttps://orcid.org/0000-0002-8144-9090ЗапараТ. А.ZaparaT. A.Zapara_t@mail.ruhttps://orcid.org/0000-0002-0674-0574РомащенкоА. В.RomashchenkoA. V.https://orcid.org/0000-0003-4284-8635ПроскураА. Л.ProskuraA. L.https://orcid.org/0000-0001-5198-8926РатушнякА. С.RatushnyakA. S.Институт вычислительных технологий Сибирского отделения Российской академии наукРоссияThe Institute of Computational Technologies, SB RASRussian FederationИнститут вычислительных технологий Сибирского отделения Российской академии наук; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияThe Institute of Computational Technologies, SB RAS; Institute of Cytology and Genetics, SB RASRussian Federation20180201201922810841089Copyright © Запара Т.А., Ромащенко А.В., Проскура А.Л., Ратушняк А.С., 20192019Запара Т.А., Ромащенко А.В., Проскура А.Л., Ратушняк А.С.Zapara T.A., Romashchenko A.V., Proskura A.L., Ratushnyak A.S.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/1813

Актуальность исследований взрослого нейрогенеза очевидна в связи с потенциальной возможностью использования новых нейронов для замещения нейронов, утраченных в процессе жизни. Несмотря на значительные усилия, мало что известно о конечной судьбе этих клеток, функциональной значимости их связей и регуляции их развития. Физическая активность значительно повышает в зубчатой извилине гиппокампа количество делящихся прогениторов, которые далее преобразуются в новые нейроны. Существующие иммуногистохимические методы маркировки новых нейронов не позволяют проследить временную динамику изменений объемов структур мозга у одного и того же животного, индуцированных внешними воздействиями, такими как добровольные физические нагрузки. Это делает актуальной задачу разработки и совершенствования методов долговременного контроля изменений, которые происходят во взрослом гиппокампе вследствие индукции нейрогенеза. Основной целью настоящей работы было с помощью магнитно­резонансной томографии на сверхвысокопольном томографе неинвазивно проследить временную динамику изменений объемов гиппокампа у одних и тех же животных, имевших добровольные физические нагрузки, которые, как известно, инициируют нейрогенез в зубчатой извилине гиппокампа. Обнаружено, что добровольные физические нагрузки не изменяли общий объем гиппокампа мыши. Однако разница в соотношении объемов между правой и левой частями гиппокампа была достоверно ниже по сравнению с контрольной группой. Проведены реконструкция и анализ белок­белковых взаимодействий, которые обеспечивают выживание большего количества новых нейронов и их интеграцию в существующие нейрональные сети в гиппокампе. Предложенный подход позволяет неинвазивно регистрировать изменения, в том числе лево­правую асимметрию по соотношению объемов этих парных структур мозга.

The relevance of studies of adult neurogenesis is evident in connection with the potential use of these new neurons to replace neurons lost in the process of life. Despite considerable efforts, little is known about the fnal fate of these cells, the functional signifcance of their connections and the regulation of their development. It is known that physical activity signifcantly increases the number of fssile progenitors, the precursors of new neurons in the dentate gyrus of the hippocampus. The existing immunohistochemical methods for labeling new neurons do not allow tracing the temporal dynamics of changes in the volume of brain structures in the same animal, induced by external impacts, such as voluntary exercise. This makes it an urgent task to develop and improve methods for long­term control of changes that occur in the adult hippocampus due to the induction of neurogenesis. The main purpose of this work was to non­invasively track, by using magnetic resonance imaging (MRI), the temporal dynamics of changes in the volume of the hippocampus in the same animals that had voluntary physical activity. It was found that voluntary exercise did not change the total volume of the mouse hippocampus. However, the difference in the volume ratio between the right and left parts of the hippocampus was signifcantly lower compared with the control group. The reconstruction and analysis of protein­protein interactions that ensure the survival of a large number of new neurons and their integration into existing neural networks in the hippocampus have been carried out. The proposed approach allows the non­invasive registration of changes in the ratio of the volumes of these paired brain structures.

магнитно-резонансная томографиявзрослый нейрогенезструктурная асимметрия мозгаmagnetic resonance imagingadult neurogenesisstructural asymmetry of the brainReferencesAkers K.G., Martinez-Canabal A., Restivo L., Yiu A.P., De Cristofaro A., Hsiang H.L., Wheeler A.L., Guskjolen A., Niibori Y., Shoji H., Ohira K., Richards B.A., Miyakawa T., Josselyn S.A., Frankland P.W. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344(6184):598-602. DOI 10.1126/science.1248903.Akers K.G., Martinez-Canabal A., Restivo L., Yiu A.P., De Cristofaro A., Hsiang H.L., Wheeler A.L., Guskjolen A., Niibori Y., Shoji H., Ohira K., Richards B.A., Miyakawa T., Josselyn S.A., Frankland P.W. Hippocampal neurogenesis regulates forgetting during adulthood and infancy. Science. 2014;344(6184):598-602. DOI 10.1126/science.1248903.Anai M., Shojima N., Katagiri H., Ogihara T., Sakoda H., Onishi Y., Ono H., Fujishiro M., Fukushima Y., Horike N., Viana A., Kikuchi M., Noguchi N., Takahashi S., Takata K., Oka Y., Uchijima Y., Kurihara H., Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J. Biol. Chem. 2005;280(18):18525-18535. DOI 10.1074/jbc.M500586200.Anai M., Shojima N., Katagiri H., Ogihara T., Sakoda H., Onishi Y., Ono H., Fujishiro M., Fukushima Y., Horike N., Viana A., Kikuchi M., Noguchi N., Takahashi S., Takata K., Oka Y., Uchijima Y., Kurihara H., Asano T. A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis. J. Biol. Chem. 2005;280(18):18525-18535. DOI 10.1074/jbc.M500586200.Bhatt D.H., Zhang S., Gan W.B. Dendritic spine dynamics. Annu. Rev. Physiol. 2009;71:261-282. DOI 10.1146/annurev.physiol.010908.163140.Bhatt D.H., Zhang S., Gan W.B. Dendritic spine dynamics. Annu. Rev. Physiol. 2009;71:261-282. DOI 10.1146/annurev.physiol.010908.163140.Brown J., Cooper-Kuhn C.M., Kempermann G., Van Praag H., Winkler J., Gage F.H., Kuhn H.G. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci. 2003;17(10):2042-2046.Brown J., Cooper-Kuhn C.M., Kempermann G., Van Praag H., Winkler J., Gage F.H., Kuhn H.G. Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis. Eur. J. Neurosci. 2003;17(10):2042-2046.Christie B.R., Cameron H.A. Neurogenesis in the adult hippocampus. Hippocampus. 2006;16(3):199-207. DOI 10.1002/hipo.20151.Christie B.R., Cameron H.A. Neurogenesis in the adult hippocampus. Hippocampus. 2006;16(3):199-207. DOI 10.1002/hipo.20151.Dayer A.G., Ford A.A., Cleaver K.M., Yassaee M., Cameron H.A. Short-term and long-term survival of new neurons in the rat dentate gyrus. J. Comp. Neurol. 2003;460(4):563-572. DOI 10.1002/cne.10675.Dayer A.G., Ford A.A., Cleaver K.M., Yassaee M., Cameron H.A. Short-term and long-term survival of new neurons in the rat dentate gyrus. J. Comp. Neurol. 2003;460(4):563-572. DOI 10.1002/cne.10675.Deng W., Saxe M.D., Gallina I.S., Gage F.H. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J. Neurosci. 2009;29(43):13532-13542. DOI 10.1523/JNEUROSCI.3362-09.2009.Deng W., Saxe M.D., Gallina I.S., Gage F.H. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J. Neurosci. 2009;29(43):13532-13542. DOI 10.1523/JNEUROSCI.3362-09.2009.Deshpande A., Bergami M., Ghanem A., Conzelmann K.K., Lepier A., Götz M., Beninger B. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc. Natl. Acad. Sci. USA. 2013;110(12): E1152-E1161. DOI 10.1073/pnas.1218991110.Deshpande A., Bergami M., Ghanem A., Conzelmann K.K., Lepier A., Götz M., Beninger B. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc. Natl. Acad. Sci. USA. 2013;110(12): E1152-E1161. DOI 10.1073/pnas.1218991110.Drew L.J., Fusi S., Hen R. Adult neurogenesis in the mammalian hippocampus: why the dentate gyrus? Learn. Mem. 2013;20(12):710-729. DOI 10.1101/lm.026542.112.Drew L.J., Fusi S., Hen R. Adult neurogenesis in the mammalian hippocampus: why the dentate gyrus? Learn. Mem. 2013;20(12):710-729. DOI 10.1101/lm.026542.112.Duan X., Chang J.H., Ge S., Faulkner R.L., Kim J.Y., Kitabatake Y., Liu X.B., Yang C.H., Jordan J.D., Ma D.K., Liu C.Y., Ganesan S., Cheng H.J., Ming G.L., Lu B., Song H. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130(6):1146-1158. DOI 10.1016/j.cell.2007.07.010.Duan X., Chang J.H., Ge S., Faulkner R.L., Kim J.Y., Kitabatake Y., Liu X.B., Yang C.H., Jordan J.D., Ma D.K., Liu C.Y., Ganesan S., Cheng H.J., Ming G.L., Lu B., Song H. Disrupted-in-schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell. 2007;130(6):1146-1158. DOI 10.1016/j.cell.2007.07.010.El-Gaby M., Shipton O.A., Paulsen O. Synaptic plasticity and memory: new insights from hippocampal left-right asymmetries. Neuroscientist. 2015;21(5):490-502. DOI 10.1177/1073858414550658.El-Gaby M., Shipton O.A., Paulsen O. Synaptic plasticity and memory: new insights from hippocampal left-right asymmetries. Neuroscientist. 2015;21(5):490-502. DOI 10.1177/1073858414550658.Enomoto A., Murakami H., Asai N., Morone N., Watanabe T., Kawai K., Murakumo Y., Usukura J., Kaibuchi K., Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell. 2005;9(3):389-402. DOI 10.1016/j.devcel.2005.08.001.Enomoto A., Murakami H., Asai N., Morone N., Watanabe T., Kawai K., Murakumo Y., Usukura J., Kaibuchi K., Takahashi M. Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev. Cell. 2005;9(3):389-402. DOI 10.1016/j.devcel.2005.08.001.Faulkner R.L., Jang M.H., Liu X.B., Duan X., Sailor K.A., Kim J.Y., Ge S., Jones E.G., Ming G.L., Song H., Cheng H.J. Development of hippocampal mossy fber synaptic outputs by new neurons in the adult brain. Proc. Natl. Acad. Sci. USA. 2008;105(37):14157-14162. DOI 10.1073/pnas.0806658105.Faulkner R.L., Jang M.H., Liu X.B., Duan X., Sailor K.A., Kim J.Y., Ge S., Jones E.G., Ming G.L., Song H., Cheng H.J. Development of hippocampal mossy fber synaptic outputs by new neurons in the adult brain. Proc. Natl. Acad. Sci. USA. 2008;105(37):14157-14162. DOI 10.1073/pnas.0806658105.Fournier N.M., Duman R.S. Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav. Brain Res. 2012;227(2): 440-449. DOI 10.1016/J.BBR.2011.04.022.Fournier N.M., Duman R.S. Role of vascular endothelial growth factor in adult hippocampal neurogenesis: implications for the pathophysiology and treatment of depression. Behav. Brain Res. 2012;227(2): 440-449. DOI 10.1016/J.BBR.2011.04.022.Fukuda S., Kato F., Tozuka Y., Yamaguchi M., Miyamoto Y., Hisatsune T. Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J. Neurosci. 2003;23(28):9357-9366.Fukuda S., Kato F., Tozuka Y., Yamaguchi M., Miyamoto Y., Hisatsune T. Two distinct subpopulations of nestin-positive cells in adult mouse dentate gyrus. J. Neurosci. 2003;23(28):9357-9366.Haber M., Zhou L., Murai K.K. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J. Neurosci. 2006;26(35):8881-8891. DOI 10.1523/JNEUROSCI.1302-06.2006.Haber M., Zhou L., Murai K.K. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J. Neurosci. 2006;26(35):8881-8891. DOI 10.1523/JNEUROSCI.1302-06.2006.Huang J., Manning B.D. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem. Soc. Trans. 2009;37(Pt. 1): 217-222. DOI 10.1042/BST0370217.Huang J., Manning B.D. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem. Soc. Trans. 2009;37(Pt. 1): 217-222. DOI 10.1042/BST0370217.Kim J.Y., Duan X., Liu C.Y., Jang M.H., Guo J.U., Pow-anpongkul N., Kang E., Song H., Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009;63(6):761-773. DOI 10.1016/j.neuron.2009.08.008.Kim J.Y., Duan X., Liu C.Y., Jang M.H., Guo J.U., Pow-anpongkul N., Kang E., Song H., Ming G.L. DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212. Neuron. 2009;63(6):761-773. DOI 10.1016/j.neuron.2009.08.008.Kitamura T., Asai N., Enomoto A., Maeda K., Kato T., Ishida M., Jiang P., Watanabe T., Usukura J., Kondo T., Costantini F., Murohara T., Takahashi M. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat. Cell. Biol. 2008;10(3):329- 337. DOI 10.1038/ncb1695.Kitamura T., Asai N., Enomoto A., Maeda K., Kato T., Ishida M., Jiang P., Watanabe T., Usukura J., Kondo T., Costantini F., Murohara T., Takahashi M. Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat. Cell. Biol. 2008;10(3):329- 337. DOI 10.1038/ncb1695.Knott G.W., Holtmaat A., Wilbrecht L., Welker E., Svoboda K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat. Neurosci. 2006;9(9):1117-1124. DOI 10.1038/nn1747.Knott G.W., Holtmaat A., Wilbrecht L., Welker E., Svoboda K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat. Neurosci. 2006;9(9):1117-1124. DOI 10.1038/nn1747.Kronenberg G., Reuter K., Steiner B., Brandt M.D., Jessberger S., Yamaguchi M., Kempermann G. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J. Comp. Neurol. 2003;467(4):455-463. DOI 10.1002/cne.10945.Kronenberg G., Reuter K., Steiner B., Brandt M.D., Jessberger S., Yamaguchi M., Kempermann G. Subpopulations of proliferating cells of the adult hippocampus respond differently to physiologic neurogenic stimuli. J. Comp. Neurol. 2003;467(4):455-463. DOI 10.1002/cne.10945.Lerch J.P., Yiu A.P., Martinez-Canabal A., Pekar T., Bohbot V.D., Frankland P.W., Henkelman R.M., Josselyn S.A., Sled J.G. Maze training in mice induces MRI-detectable brain shape changes specifc to the type of learning. Neuroimage. 2011;54(3):2086-2095. DOI 10.1016/j.neuroimage.2010.09.086.Lerch J.P., Yiu A.P., Martinez-Canabal A., Pekar T., Bohbot V.D., Frankland P.W., Henkelman R.M., Josselyn S.A., Sled J.G. Maze training in mice induces MRI-detectable brain shape changes specifc to the type of learning. Neuroimage. 2011;54(3):2086-2095. DOI 10.1016/j.neuroimage.2010.09.086.Muramatsu R., Ikegaya Y., Matsuki N., Koyama R. Neonatally born granule cells numerically dominate adult mice dentate gyrus. Neuroscience. 2007;148(3):593-598. DOI 10.1016/j.neuroscience.2007.06.040.Muramatsu R., Ikegaya Y., Matsuki N., Koyama R. Neonatally born granule cells numerically dominate adult mice dentate gyrus. Neuroscience. 2007;148(3):593-598. DOI 10.1016/j.neuroscience.2007.06.040.Nakai T., Nagai T., Tanaka M., Itoh N., Asai N., Enomoto A., Asai M., Yamada S., Saifullah A.B., Sokabe M., Takahashi M., Yamada K. Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor. J. Neurosci. 2014;34(45):14995-5008. DOI 10.1523/JNEUROSCI.2228-14.2014.Nakai T., Nagai T., Tanaka M., Itoh N., Asai N., Enomoto A., Asai M., Yamada S., Saifullah A.B., Sokabe M., Takahashi M., Yamada K. Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor. J. Neurosci. 2014;34(45):14995-5008. DOI 10.1523/JNEUROSCI.2228-14.2014.Ortiz-López L., Vega-Rivera N.M., Babu H., Ramírez-Rodríguez G.B. Brain-derived neurotrophic factor induces cell survival and the migration of murine adult hippocampal precursor cells during differentiation in vitro. Neurotox. Res. 2017;31(1):122-135. DOI 10.1007/S12640-016-9673-X.Ortiz-López L., Vega-Rivera N.M., Babu H., Ramírez-Rodríguez G.B. Brain-derived neurotrophic factor induces cell survival and the migration of murine adult hippocampal precursor cells during differentiation in vitro. Neurotox. Res. 2017;31(1):122-135. DOI 10.1007/S12640-016-9673-X.Palmer T.D., Willhoite A.R., Gage F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 2000;425(4):479-494.Palmer T.D., Willhoite A.R., Gage F.H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 2000;425(4):479-494.Patten A.R., Sickmann H., Hryciw B.N., Kucharsky T., Parton R., Kernick A., Christie B.R. Long-term exercise is needed to enhance synaptic plasticity in the hippocampus. Learn. Mem. 2013;20(11): 642-647. DOI 10.1101/Lm.030635.113.Patten A.R., Sickmann H., Hryciw B.N., Kucharsky T., Parton R., Kernick A., Christie B.R. Long-term exercise is needed to enhance synaptic plasticity in the hippocampus. Learn. Mem. 2013;20(11): 642-647. DOI 10.1101/Lm.030635.113.Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-1101. DOI 10.1126/science.1106148.Sarbassov D.D., Guertin D.A., Ali S.M., Sabatini D.M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005;307(5712):1098-1101. DOI 10.1126/science.1106148.Schnyder S., Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015;80:115-125. DOI 10.1016/j.bone.2015.02.008.Schnyder S., Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015;80:115-125. DOI 10.1016/j.bone.2015.02.008.Seri B., García-Verdugo J.M., Collado-Morente L., McEwen B.S., Alvarez-Buylla A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J. Comp. Neurol. 2004;478(4):359- 378. DOI 10.1002/cne.20288.Seri B., García-Verdugo J.M., Collado-Morente L., McEwen B.S., Alvarez-Buylla A. Cell types, lineage, and architecture of the germinal zone in the adult dentate gyrus. J. Comp. Neurol. 2004;478(4):359- 378. DOI 10.1002/cne.20288.Vanhaesebroeck B., Alessi D.R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 2000;346(Pt. 3):561-576.Vanhaesebroeck B., Alessi D.R. The PI3K-PDK1 connection: more than just a road to PKB. Biochem. J. 2000;346(Pt. 3):561-576.Volinia S., Dhand R., Vanhaesebroeck B., MacDougall L.K., Stein R., Zvelebil M.J., Domin J., Panaretou C., Waterfeld M.D. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34pVps15p protein sorting system. EMBO J. 1995;14(14):3339-3348.Volinia S., Dhand R., Vanhaesebroeck B., MacDougall L.K., Stein R., Zvelebil M.J., Domin J., Panaretou C., Waterfeld M.D. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34pVps15p protein sorting system. EMBO J. 1995;14(14):3339-3348.Yang G., Pan F., Gan W.B. Stably maintained dendritic spines are associated with lifelong memories. Nature. 2009;462(7275):920-924. DOI 10.1038/nature08577.Yang G., Pan F., Gan W.B. Stably maintained dendritic spines are associated with lifelong memories. Nature. 2009;462(7275):920-924. DOI 10.1038/nature08577.

The authors declare that there are no conflicts of interest present.