ИЗМЕНЕНИЯ В НЕЙРОГЕННОЙ НИШЕ ГИППОКАМПА КРЫС ПРИ ГИПОКСИЧЕСКОМ ВОЗДЕЙСТВИИ
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Ключевые слова

гипобарическая гипоксия
цитохромоксидаза
глутаминсинтетаза
нейрогенез
гиппокамп

Аннотация

Одной из наиболее уязвимых к гипоксии структур мозга является гиппокамп. Поддержание пула клеток нейрогенной ниши в субгранулярной зоне гиппокампа (SGZ) обеспечивается адаптационными механизмами, среди которых — изменение функционирования комплексов дыхательной цепи митохондрий и реакция астроглии, обеспечивающей метаболическую поддержку нейронов. С целью изучения динамики адаптационных изменений нейронов и глии в зубчатой извилине гиппокампа в условиях гипоксии на модели периодической гипобарической гипоксии (5000 м, эквивалентно 10.5% О2), при однократном (60 мин) и многократном (8 и 20 эпизодов) воздействии у низкоустойчивых крыс иммуноморфологическими методами выявляли особенности локализации и содержания комплекса IV дыхательной цепи митохондрий (MTCO1), маркерных астроцитарных белков: глутаминсинтетазы (GS) и GFAP, а также даблкортина (DCX) – маркера незрелых нейронов. При однократной гипоксии значимо повышалось содержание MTCO1 в нейронах, а при восьмикратном воздействии увеличивалось количество глутаминсинтетазы (GS) в астроцитах зубчатой извилины гиппокампа. Изменения содержания GS были наиболее выражены в отростках астроцитов, что говорит о перераспределении GS при гипоксии. Количество DCX+ нейронов в SGZ значимо снижалось после 20 эпизодов гипоксии, при этом в полиморфном слое обнаруживались DCX+ клетки глиальной морфологии, а окрашивание на GFAP показало увеличение количества астроцитов в полиморфном слое, что может быть связано в том числе со смещением направления дифференцировки клеток нейрогенной ниши. Таким образом, при гипоксии в SGZ гиппокампа на начальном этапе происходит интенсификация работы дыхательной цепи нейронов зернистого слоя с последующей активацией астроцитов, модулирующих обмен глутамата. Наличие взаимосвязи между динамикой адаптационных реакций энергообмена в нейронах и глии и изменениями нейрогенеза после 20 эпизодов гипоксии позволяет предположить, что при многократной гипоксии происходит сдвиг дифференцировки нейральных предшественников SGZ в направлении астроглии, однако, этот вопрос требует дальнейшего изучения для более точного определения природы DCX+ клеток.

https://doi.org/10.31857/S0044452923040022
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Литература

Zhang H, Roman RJ, Fan F (2022) Hippocampus is more susceptible to hypoxic injury: has the Rosetta Stone of regional variation in neurovascular coupling been deciphered? GeroScience 44(1): 127–130. https://doi.org/10.1007/s11357-021-00449-4

Abbott LC, Nigussie F (2020) Adult neurogenesis in the mammalian dentate gyrus. Anat Histol Embryol 49(1): 3–16. https://doi.org/10.1111/ahe.12496

Morgun AV, Osipova ED, Boytsova EB, Shuvaev AN, Komleva YK, Trufanova LV, Vais EF, Salmina AB (2019) Astroglia-mediated regulation of cell development in the model of neurogenic niche in vitro treated with Aβ1-42. Biomed Khim 65(5): 366–373. https://doi.org/10.18097/PBMC20196505366

Egorova A, Baranich T, Brydun A, Glinkina V, Sukhorukov V (2022) Morphological and Histophysiological Features of the Brain Capillary Endothelium. J Evol Biochem Physiol 58:755–768. https://doi.org/10.1134/S0022093022030115

Mohyeldin A, Garzón-Muvdi T, Quiñones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7(2): 150–161. https://doi.org/10.1016/j.stem.2010.07.007

Chen H, Ma D, Yue F, Qi Y, Dou M, Cui L, Xing Y (2022) The Potential Role of Hypoxia-Inducible Factor-1 in the Progression and Therapy of Central Nervous System Diseases. Cur Neuropharmacol 20(9): 1651–1666. https://doi.org/10.2174/1570159X19666210729123137

Zheng X, Boyer L, Jin M, Mertens J, Kim Y, Ma L, Ma L, Hamm M, Gage FH, Hunter T (2016) Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation. eLife 5: e13374. https://doi.org/10.7554/eLife.13374

Lukyanova L, Germanova E, Khmil N, Pavlik L, Mikheeva I, Shigaeva M, Mironova G (2021) Signaling Role of Mitochondrial Enzymes and Ultrastructure in the Formation of Molecular Mechanisms of Adaptation to Hypoxia. Int J Mol Sci 22(16): 8636. https://doi.org/10.3390/ijms22168636

Arnold S (2012) Cytochrome c oxidase and its role in neurodegeneration and neuroprotection. Adv Exp Med Biol 748: 305–339. https://doi.org/10.1007/978-1-4614-3573-0_13

Yang L, Venneti S, Nagrath D (2017) Glutaminolysis: A Hallmark of Cancer Metabolism. Ann Rev Biomed Engineer 19: 163–194. https://doi.org/10.1146/annurev-bioeng-071516-044546

Namba T, Dóczi J, Pinson A, Xing L, Kalebic N, Wilsch-Bräuninger M, Long KR, Vaid S, Lauer J, Bogdanova A, Borgonovo B, Shevchenko A, Keller P, Drechsel D, Kurzchalia T, Wimberger P, Chinopoulos C, Huttner WB (2020) Human-Specific ARHGAP11B Acts in Mitochondria to Expand Neocortical Progenitors by Glutaminolysis. Neuron 105(5): 867–881.e9. https://doi.org/10.1016/j.neuron.2019.11.027

Turner DA, Adamson DC (2011) Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism. J Neuropathol Exp Neurol 70(3): 167–176. https://doi.org/10.1097/NEN.0b013e31820e1152

Schousboe A (2019) Metabolic signaling in the brain and the role of astrocytes in control of glutamate and GABA neurotransmission. Neurosci Let 689: 11–13. https://doi.org/10.1016/j.neulet.2018.01.038

Sonnewald U, Qu H, Aschner M (2002) Pharmacology and toxicology of astrocyte-neuron glutamate transport and cycling. J Pharmacol Exp Ther 301(1): 1–6. https://doi.org/10.1124/jpet.301.1.1

Jayakumar AR, Norenberg MD (2016) Glutamine Synthetase: Role in Neurological Disorders. Adv Neurobiol 13: 327–350. https://doi.org/10.1007/978-3-319-45096-4_13

Gibbs ME, O'Dowd BS, Hertz L, Robinson SR, Sedman GL, Ng KT (1996) Inhibition of glutamine synthetase activity prevents memory consolidation. Brain research. Cogn Brain Res 4(1): 57–64. https://doi.org/10.1016/0926-6410(96)00020-1

Son H, Kim S, Jung DH, Baek JH, Lee DH, Roh GS, Kang SS, Cho GJ, Choi WS, Lee DK, Kim HJ (2019) Insufficient glutamine synthetase activity during synaptogenesis causes spatial memory impairment in adult mice. Sci Rep 9(1): 252. https://doi.org/10.1038/s41598-018-36619-2

Miller JA, Nathanson J, Franjic D, Shim S, Dalley RA, Shapouri S, Smith KA, Sunkin SM, Bernard A, Bennett JL, Lee CK, Hawrylycz MJ, Jones AR, Amaral DG, Šestan N, Gage FH, Lein ES (2013) Conserved molecular signatures of neurogenesis in the hippocampal subgranular zone of rodents and primates. Development (Cambridge, England) 140(22): 4633–4644. https://doi.org/10.1242/dev.097212

Goh TY, Basah SN, Yazid H, Safar MJA, Saad FSA (2018) Performance Analysis of Image Thresholding: Otsu Technique. Measurement 114: 298–307. https://doi.org/10.1016/j.measurement.2017.09.052

Refaeli R, Doron A, Benmelech-Chovav A, Groysman M, Kreisel T, Loewenstein Y, Goshen I (2021) Features of hippocampal astrocytic domains and their spatial relation to excitatory and inhibitory neurons. Glia 69(10): 2378–2390. https://doi.org/10.1002/glia.24044

Anlauf E, Derouiche A (2013) Glutamine synthetase as an astrocytic marker: its cell type and vesicle localization. Front Endocrinol 4: 144. https://doi.org/10.3389/fendo.2013.00144

Quebedeaux TM, Song H, Giwa-Otusajo J, Thompson LP (2022) Chronic Hypoxia Inhibits Respiratory Complex IV Activity and Disrupts Mitochondrial Dynamics in the Fetal Guinea Pig Forebrain. Reproduct Sci (Thousand Oaks, Calif.) 29(1): 184–192. https://doi.org/10.1007/s43032-021-00779-w

Tan XL, Liu JZ, Cao LF, Deng ZC, Li YH (2002) [Effects of hypoxic exposure on coordinative expression of cytochrome oxidase subunits I and IV in rat cerebral cortex]. Sheng Li Xue Bao 54(6): 519–524.

Kang JJ, Guo B, Liang WH, Lam CS, Wu SX, Huang XF, Wong-Riley MTT, Fung ML, Liu YY (2019) Daily acute intermittent hypoxia induced dynamic changes in dendritic mitochondrial ultrastructure and cytochrome oxidase activity in the pre-Bötzinger complex of rats. Exp Neurol 313: 124–134. https://doi.org/10.1016/j.expneurol.2018.12.008

Kang JJ, Fung ML, Zhang K, Lam CS, Wu SX, Huang XF, Yang SJ, Wong-Riley MTT, Liu YY (2020) Chronic intermittent hypoxia alters the dendritic mitochondrial structure and activity in the pre-Bötzinger complex of rats. FASEB J: Official Publ Federat Am Society Exp Biol 34(11): 14588–14601. https://doi.org/10.1096/fj.201902141R

Lisowski P, Kannan P, Mlody B, Prigione A (2018) Mitochondria and the dynamic control of stem cell homeostasis. EMBO Reports 19(5): e45432. https://doi.org/10.15252/embr.201745432

Cui, P, Zhang P, Yuan L, Wang L, Guo X, Cui G, Zhang Y, Li M, Zhang X, Li X, Yin Y, Yu Z (2021) HIF-1α Affects the Neural Stem Cell Differentiation of Human Induced Pluripotent Stem Cells via MFN2-Mediated Wnt/β-Catenin Signaling. Front Cell Devel Biol 9: 671704. https://doi.org/10.3389/fcell.2021.671704

Chen HL, Pistollato F, Hoeppner DJ, Ni HT, McKay RD, Panchision DM (2007) Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels. Stem Cells (Dayton, Ohio) 25(9): 2291–2301. https://doi.org/10.1634/stemcells.2006-0609

Khuu MA, Pagan CM, Nallamothu T, Hevner RF, Hodge RD, Ramirez JM, Garcia AJ 3rd (2019) Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus. J Neurosci: Official J Society Neurosci 39(7):1320–1331. https://doi.org/10.1523/JNEUROSCI.1359-18.2018

Kasahara Y, Nakashima H, Nakashima K (2023) Seizure-induced hilar ectopic granule cells in the adult dentate gyrus. Front Neurosci 17:1150283. https://doi.org/10.3389/fnins.2023.1150283

Cameron MC, Zhan RZ, Nadler JV (2011) Morphologic integration of hilar ectopic granule cells into dentate gyrus circuitry in the pilocarpine model of temporal lobe epilepsy. J Comp Neurol 519(11):2175–2192. https://doi.org/10.1002/cne.22623

Kunze A, Achilles A, Keiner S, Witte OW, Redecker C (2015) Two distinct populations of doublecortin-positive cells in the perilesional zone of cortical infarcts. BMC Neurosci 16:20. https://doi.org/10.1186/s12868-015-0160-8

Moura DMS, Brandão JA, Lentini C, Heinrich C, Queiroz CM, Costa MR (2020) Evidence of Progenitor Cell Lineage Rerouting in the Adult Mouse Hippocampus After Status Epilepticus. Front Neurosci 14: 571315. https://doi.org/10.3389/fnins.2020.571315

Schlecht A, Vallon M, Wagner N, Ergün S, Braunger BM (2021) TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain. Biomolecules 11(9): 1360. https://doi.org/10.3390/biom11091360

Dzhalilova DS, Diatroptov ME, Tsvetkov IS, Makarova OV, Kuznetsov SL (2018) Expression of Hif-1α, Nf-κb, and Vegf Genes in the Liver and Blood Serum Levels of HIF-1α, Erythropoietin, VEGF, TGF-β, 8-Isoprostane, and Corticosterone in Wistar Rats with High and Low Resistance to Hypoxia. Bull Exp Biol Med 165(6): 781–785. https://doi.org/10.1007/s10517-018-4264-x

Baumann J, Tsao CC, Patkar S, Huang SF, Francia S, Magnussen SN, Gassmann M, Vogel J, Köster-Hegmann C, Ogunshola OO (2022) Pericyte, but not astrocyte, hypoxia inducible factor-1 (HIF-1) drives hypoxia-induced vascular permeability in vivo. Fluids Barriers CNS 19(1): 6. https://doi.org/10.1186/s12987-021-00302-y

Luo J (2022) TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications. Biomedicines 10(5): 1206. https://doi.org/10.3390/biomedicines10051206

Wachs FP, Winner B, Couillard-Despres S, Schiller T, Aigner R, Winkler J, Bogdahn U, Aigner L (2006) Transforming growth factor-beta1 is a negative modulator of adult neurogenesis. J Neuropathol Exp Neurol 65(4): 358–370. https://doi.org/10.1097/01.jnen.0000218444.53405.f0

Mathieu P, Piantanida AP, Pitossi F (2010) Chronic expression of transforming growth factor-beta enhances adult neurogenesis. Neuroimmunomodulation 17(3): 200–201. https://doi.org/10.1159/000258723

Sen E, Basu A, Willing LB, Uliasz TF, Myrkalo JL, Vannucci SJ, Hewett SJ, Levison SW (2011) Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties. ASN neuro 3(3): e00062. https://doi.org/10.1042/AN20100029

Lee A, Lingwood BE, Bjorkman ST, Miller SM, Poronnik P, Barnett NL, Colditz P, Pow DV (2010) Rapid loss of glutamine synthetase from astrocytes in response to hypoxia: implications for excitotoxicity. J Chem Neuroanatomy 39(3): 211–220. https://doi.org/10.1016/j.jchemneu.2009.12.002

Papageorgiou IE, Gabriel S, Fetani AF, Kann O, Heinemann U (2011) Redistribution of astrocytic glutamine synthetase in the hippocampus of chronic epileptic rats. Glia 59(11): 1706–1718. https://doi.org/10.1002/glia.21217

Воронков, ДН, Сальникова ОВ, Худоерков РМ (2017) Иммуноцитохимические и морфометрические изменения астроглии в перифокальной зоне моделируемого инфаркта мозга. Анналы клин и экспер неврол 11(1): 40–46. [Voronkov DN, Salnikova OV, Khudoerkov RM (2017) Immunocytochemical and morphometric changes in astroglial cells in the perifocal zone of the cerebral infarction model. Annals Clin Exp Neurol 11(1): 40–46. (In Russ)]. https://doi.org/ 10.18454/ACEN.2017.1.6158

Zhou Y, Dhaher R, Parent M, Hu QX, Hassel B, Yee SP, Hyder F, Gruenbaum SE, Eid T, Danbolt NC (2019) Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration. Neurochem Internat 123: 22–33. https://doi.org/10.1016/j.neuint.2018.07.009