I.P. Pavlov Journal of Higher Nervous ActivityI.P. Pavlov Journal of Higher Nervous ActivityЖурнал высшей нервной деятельности им. И.П. Павлова0044-46773034-5316The Russian Academy of Sciences65209210.31857/S0044467724030074ФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬФИЗИОЛОГИЧЕСКИЕ МЕХАНИЗМЫ ПОВЕДЕНИЯ ЖИВОТНЫХ: ВОСПРИЯТИЕ ВНЕШНИХ СТИМУЛОВ, ДВИГАТЕЛЬНАЯ АКТИВНОСТЬ, ОБУЧЕНИЕ И ПАМЯТЬResearch ArticleHypoxic preconditioning in rats with low and high prepulse inhibition of acoustic startle is implemented through topographically different sensory inputs. Working hypothesisГипоксическое прекондиционирование у крыс с низким и высоким предстимульным торможением акустического вздрагивания осуществляется через топографически различные сенсорные входы. Рабочая гипотезаZakharovaE. I.ЗахароваЕ. И.
Russian Federation
zakharova-ei@yandex.ruStorozhevaZ. I.СторожеваЗ. И.
Russian Federation
zakharova-ei@yandex.ruProshinA. T.ПрошинА. Т.
Russian Federation
zakharova-ei@yandex.ruMonakovM. Y.МонаковМ. Ю.
Russian Federation
zakharova-ei@yandex.ruDudchenkoA. M.ДудченкоА. М.
Russian Federation
zakharova-ei@yandex.ruInstitute of General Pathology and PathophysiologyФГБНУ Институт общей патологии и патофизиологииFederal Research Center for Original and Promising Biomedical and Pharmaceutical TechnologiesФГБНУ ФИЦ оригинальных и перспективных биомедицинских и фармацевтических технологий2410202474333635202022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://innoscience.ru/0044-4677/article/view/652092

The neurotransmitter and network mechanisms of hypoxic preconditioning are practically unknown. Previously, in rats, we identified the key role of the hippocampus and its cholinergic projections in the preconditioning mechanism of single-exposure of moderate hypobaric hypoxia (HBH) based on the association between the efficiency of HBH and the magnitude of Prepulse Inhibition of Acoustic Startle (PPI). This study presents the first data on PPI-dependent neuronal networks of hypoxic preconditioning and their cholinergic components. The activity of synaptic choline acetyltransferase (ChAT), an indicator of cholinergic function, was used for a correlation analysis of ChAT response to HBH in the hippocampus, cerebral cortex, and caudal brainstem in animals with different levels of PPI. In rats with PPI < 40%, ChAT activity was correlated in the hippocampus, cortex and caudal brainstem, while in rats with PPI > 40% in the hippocampus and cortex. It is hypothesized that HBH is realized through topographically different sensory inputs, namely through respiratory neurons of the brainstem in rats with low PPI and respiratory neurons of the olfactory epithelium in rats with high PPI.

Нейромедиаторные и сетевые механизмы гипоксического прекондиционирования практически не изучены. Ранее на крысах мы выявили ключевую роль гиппокампа и его холинергических проекций в прекондиционирующем механизме однократной умеренной гипобарической гипоксии (ГБГ) благодаря ассоциации между эффективностью ГБГ и величиной предстимульного торможения в акустической стартл-реакции (ПСТ). В настоящем исследовании представлены первые данные о ПСТ-зависимых нейрональных сетях гипоксического прекондиционирования и их холинергических компонентах. Для корреляционного анализа использовалась активность синаптической холинацетилтрансферазы (ХАТ), индикатора холинергической функции как показатель реакции на ГБГ в гиппокампе, коре головного мозга и каудальном отделе ствола головного мозга у животных с различным уровнем ПСТ. У крыс с ПСТ < 40% активность ХАТ коррелировала в гиппокампе, коре и каудальном отделе ствола мозга, а у крыс с ПСТ > 40% – в гиппокампе и коре головного мозга. Предполагается, что ГБГ реализуется через топографически различные сенсорные входы, а именно через дыхательные нейроны ствола мозга у крыс с низким уровнем ПСТ и дыхательные нейроны обонятельного эпителия у крыс с высоким уровнем ПСТ.

hypoxic preconditioningneuronal/ neural networksHBHPPIhippocampuscerebral cortexcaudal brainstemcholinergic forebrain projective neurons and interneurons‘light’ and ‘heavy’ synaptosomessynaptic membrane-bound and soluble ChATгипоксическое прекондиционированиенейронные (биологические) сетиГБГПСТгиппокампкора головного мозгакаудальный ствол головного мозгахолинергические проекцинные нейроны из ядер переднего мозга и интернейроны“легкие” и “тяжелые” синаптосомысинаптическая мембраносвязанная и водорастворимая ХАТAkopyan N.S., Baklavadzhyan O.G., Karapetyan M.A. Effects of acute hypoxia on the EEG and impulse activity of the neurons of variousconelly brain structures in rats. Neurosci. Behav. Physiol. 1984. 14 (5): 405–411.AlQot H.E., Rylett R.J. A novel transgenic mouse model expressing primate-specific nuclear choline acetyltransferase: insights into potential cholinergic vulnerability. Sci Rep. 2023. 13 (1): 3037.Ando S., Komiyama T., Sudo M., Higaki Y., Ishida K., Costello J.T., Katayama K. The interactive effects of acute exercise and hypoxia on cognitive performance: A narrative review. Scand. J. Med. Sci. Sports. 2020. 30 (3): 384–398.Appelbaum L.G., Shenasa M.A., Stolz L., Daskalakis Z. Synaptic plasticity and mental health: methods, challenges and opportunities. Neuropsychopharmacology. 2022. 48: 113–120.Ashhad S., Kam K., Del Negro C.A., Feldman J.L. Breathing Rhythm and Pattern and Their Influence on Emotion. Annu. Rev. Neurosci. 2022. 45: 223–247.Bagwe P., Sathaye S. Significance of Choline Acetyltransferase Enzyme in Tackling Neurodegenerative Diseases. Current Molecular Biology Reports. 2022. 8: 9–22.Bautista T.G., Sun Q.J., Zhao W.J., Pilowsky P.M. Cholinergic inputs to laryngeal motoneurons functionally identified in vivo in rat: A combined electrophysiological and microscopic study. J. Comp. Neurol. 2010. 518: 4903–4916.Biagioni F., Gaglione A., Giorgi F.S., Bucci D., Moyanova S., De. Fusco A., Madonna, M., Fornai F. Degeneration of cholinergic basal forebrain nuclei after focally evoked status epilepticus. Neurobiol. Dis. 2019. 121: 76–94.Bleymehl K., Pérez-Gómez A., Omura M., Moreno-Pérez A., Macías D., Bai Z., Johnson R.S., Leinders-Zufall T., Zufall F., Mombaerts P.A. Sensor for Low Environmental Oxygen in the Mouse Main Olfactory Epithelium. Neuron. 2016. 92: 1196–1203.Carey R.M., Verhagen J.V., Wesson D.W., Pírez N., Wachowiak M. Temporal structure of receptor neuron input to the olfactory bulb imaged in behaving rats. J. Neurophysiol. 2009. 101: 1073–1088.Cheng Q., Lamb P., Stevanovic K., Bernstein B.J., Fry S.A., Cushman J.D., Yakel J.L. Differential signalling induced by α7 nicotinic acetylcholine receptors in hippocampal dentate gyrus in vitro and in vivo. J. Physiol. 2021. 599 (20): 4687–4704.Connelly T., Yu .Y., Grosmaitre X., Wang J., Santarelli L.C., Savigner A., Qiao X., Wang Z., Storm D.R., Ma. M. G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons. Proc. Natl. Acad. Sci. U S A. 2015. 112: 590–595.Das M., Das D.K. Molecular Mechanism of Preconditioning. IUBMB Life. 2008. 60: 199–203.de Curtis M., Uva L., Lévesque M., Biella G., Avoli M. Piriform cortex ictogenicity in vitro. Exp. Neurol. 2019. 321: 113014.Dudchenko A.M., Zakharova E.I., Storozheva Z.I. Method for Predicting the Limit of Resistance of Animals to Severe Hypoxia after Hypoxic Preconditioning. RF Patent 2571603. 4 July 2014.Dunbar G.L., Rylett R.J., Schmidt B.M., Sinclair R.C., Williams L.R. Hippocampal choline acetyltransferase activity correlates with spatial learning in aged rats. Brain Res. 1993. 604 (1–2): 266–272.Fonnum F. Radiochemical microassays for the determination of choline acetyltransferase and acetylcholinesterase activities. Biochem. J. 1969. 115: 465–472.Fontanini A., Spano P., Bower J.M.Ketamine-Xylazine-induced slow (< 1.5 Hz) oscillations in the rat piriform (olfactory) cortex are functionally correlated with respiration. J. Neurosci. 2003. 23: 7993–8001.Gavrilova S.A., Samojlenkova N.S., Pirogov Yu.A., Khudoerkov R.M., Koshelev V.B. Neuroprotective effect of hypoxic preconditioning in the rat brain with focal ischemia. Pathogenesis. 2008. 6 (3): 13–17. In RussianGirin B., Juventin M., Garcia S., Lefèvre L., Amat C., Fourcaud-Trocmé N., Buonviso N. The deep and slow breathing characterizing rest favors brain respiratory-drive. Sci. Rep. 2021. 11 (1): 7044.Gu .Z., Yakel J.L.Cholinergic Regulation of Hippocampal Theta Rhythm. Biomedicines. 2022. 10: 745.Heck D.H., Kozma R., Kay L.M. The rhythm of memory: How breathing shapes memory function. J. Neurophysiol. 2019. 122: 563–571.Hummos A., Nair S.S. An integrative model of the intrinsic hippocampal theta rhythm. PLoS ONE. 2017. 12: e0182648.Jones B.E. Immunohistochemical study of choline acetyltransferase immunoreactive processes and cells innervating the pontomedullary reticular formation in the rat. J. Comp. Neurol. 1990. 295: 485–514.Juventin M., Ghibaudo V., Granget J., Amat C., Courtiol E., Buonviso N. Respiratory influence on brain dynamics: the preponderant role of the nasal pathway and deep slow regime. Pflugers Arch. 2023. 475 (1): 23–35.Karalis N., Sirota A. Breathing coordinates cortico-hippocampal dynamics in mice during offline states. Nat. Commun. 2022. 13: 467.Kirstein M., Cambrils A., Segarra A., Melero A., Varea E. Cholinergic Senescence in the Ts65Dn Mouse Model for Down Syndrome. Neurochem Res. 2022. 47 (10), 3076–3092.Kitchigina V.F. Mechanisms of the regularion and the functional significance of the Theta-Rhytm. Roles of serotonergic and noradrenergic systems. Zh. Vyssh. Nerv. Deiat. 2004. 54: 101–119. In RussianKobzar A.I. Applied Mathematical Statistics. For Engineers and Scientists. Moscow: FIZMATLIT, 2006. 816 p. In RussianKoike K., Yoo S.J., Bleymehl K., Omura M., Zapiec B., Pyrski M. et al. Danger perception and stress response through an olfactory sensor for the bacterial metabolite hydrogen sulfide. Neuron. 2021. 109 (15): 2469–2484.e7.Lara-González E., Padilla-Orozco M., Fuentes-Serrano A., Bargas J., Duhne M. Translational neuronal ensembles: Neuronal microcircuits in psychology, physiology, pharmacology and pathology. Front. Syst. Neurosci. 2022. 16: 979680.Liu H., Shi R., Liao R., Liu Y., Che J., Bai Z., Cheng N., Ma H. Machine Learning Based on Event-Related EEG of Sustained Attention Differentiates Adults with Chronic High-Altitude Exposure from Healthy Controls. Brain Sci. 2022 12 (12):1677.Lockmann A.L., Laplagne D.A., Leão R.N., Tort A.B. A Respiration-Coupled Rhythm in the Rat Hippocampus Independent of Theta and Slow Oscillations. J. Neurosci. 2016. 36: 5338–5352.Lowry O.H., Rosenbrough N.J., Farr A.L., Randall R.J. Protein measurement with the Folin phenol reagent. Biol. Chem. 1959. 193: 265–275.Lukyanova L.D., Germanova E.L., Kopaladze R.A. Development of resistance of an organism under various conditions of hypoxic preconditioning: role of the hypoxic period and reoxygenation. Bull. Exp. Biol. Med. 2009. 147: 400–404.Lukyanova L.D., Germanova E.L,. Tsibina T.A., Kopaladze R.A., Dudchenko A.M. Efficiency and mechanism for different regimens of hypoxic training: The possibility of optimization of hypoxic therapy. Pathogenesis, 2008, 6: 32–36. In RussianLykhmus O., Kalashnyk O., Uspenska K., Horid’ko T., Kosyakova H., Komisarenko S., Skok M. Different Effects of Nicotine and N-Stearoyl-ethanolamine on Episodic Memory and Brain Mitochondria of α7 Nicotinic Acetylcholine Receptor Knockout Mice. Biomolecules. 2020. 10 (2): 226.Ma X., Zhang Y., Wang L., Li .N., Barkai E., Zhang X., Lin L., Xu J. The Firing of Theta State-Related Septal Cholinergic Neurons Disrupt Hippocampal Ripple Oscillations via Muscarinic Receptors. J. Neurosci. 2020. 40 (18): 3591–3603.Maslov L.N., Lishmanov Yu.B., Emelianova T.V., Prut D.A., Kolar F., Portnichenko A.G. et al. Hypoxic Preconditioning as Novel Approach to Prophylaxis of Ischemic and Reperfusion Damage of Brain and Heart. Angiol. Sosud. Khir. 2011; 17 (3): 27–36. In RussianMonmaur P., Fage D., M’Harzi M., Delacour J., Scatton B.Decrease in both choline acetyltransferase activity and EEG patterns in the hippocampal formation of the rat following septal macroelectrode implantation. Brain Res. 1984. 293 (1): 178–183.Müller C., Remy S. Septo-hippocampal interaction. Cell Tissue Res. 2018. 373 (3): 565–575.Navarrete-Opazo A., Mitchell G.S. Therapeutic potential of intermittent hypoxia: a matter of dose. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014. 307 (10): R1181–R1197.Obermayer J., Luchicchi A., Heistek T.S., de Kloet S.F., Terra H., Bruinsma B. et al. Prefrontal cortical ChAT-VIP interneurons provide local excitation by cholinergic synaptic transmission and control attention. Nat. Commun. 2019. 10: 5280.Paxinos G., Watson Ch. Rat Brain in Stereotaxic Coordinates, Fourth Edition, San Diego: Academic Press, 1998, 474 p.Phillips M.E., Sachdev R.N., Willhite D.C., Shepherd G.M. Respiration drives network activity and modulates synaptic and circuit processing of lateral inhibition in the olfactory bulb. J. Neurosci. 2012. 32: 85–98.Radhakrishnan S., Martin C.A., Dhayanithy G., Reddy M.S., Rela M., Kalkura S.N., Sellathamby S. Hypoxic Preconditioning Induces Neuronal Differentiation of Infrapatellar Fat Pad Stem Cells through Epigenetic Alteration. ACS Chem. Neurosci. 2021. 12: 704–718.Ramadan M.Z., Ghaleb A.M., Ragab A.E. Using Electroencephalography (EEG) Power Responses to Investigate the Effects of Ambient Oxygen Content, Safety Shoe Type, and Lifting Frequency on the Worker’s Activities. Biomed. Res. Int. 2020: 7956037.Rybnikova E.A., Nalivaeva N.N., Zenko M.Y., Baranova K.A. Intermittent Hypoxic Training as an Effective Tool for Increasing the Adaptive Potential, Endurance and Working Capacity of the Brain. Front. Neurosci. 2022. 16: 941740.Sadigh-Eteghad S., Vatandoust S.M., Mahmoudi J., Rahigh Aghsan S., Majdi A. Cotinine ameliorates memory and learning impairment in senescent mice. Brain Res. Bull. 2020. 164: 65–74.Sampath D., Sathyanesan M., Newton S.S. Cognitive dysfunction in major depression and Alzheimer’s disease is associated with hippocampal-prefrontal cortex dysconnectivity. Neuropsychiatr. Dis. Treat. 2017. 13: 1509–1519.Salimi M., Ayene F., Parsazadegan T., Nazari M., Jamali Y., Raoufy M.R. Nasal airflow promotes default mode network activity. Respir. Physiol. Neurobiol. 2023. 307:103981.Sawada M., Sato M. The effect of dimethyl sulfoxide on the neuronal excitability and cholinergic transmission in Aplysia ganglion cells. Ann. N. Y. Acad. Sci. 1975. 243: 337–357.Semba K., Reiner P.B., McGeer E.G., Fibiger H.C. Brainstem projecting neurons in the rat basal forebrain: Neurochemical, topographical, and physiological distinctions from cortically projecting cholinergic neurons. Brain Res. Bull. 1989. 22: 501–509.Shenkarev Z.O., Shulepko M.A., Bychkov M.L., Kulbatskii D.S., Shlepova O.V., Vasilyeva N.A. et al. Water-soluble variant of human Lynx1 positively modulates synaptic plasticity and ameliorates cognitive impairment associated with α7–nAChR dysfunction. J. Neurochem. 2020. 155 (1):45–61.Sheriff A., Pandolfi G., Nguyen V.S., Kay L.M. Long-Range Respiratory and Theta Oscillation Networks Depend on Spatial Sensory Context. J. Neurosci. 2021. 41: 9957–9970.Vaaga C.E., Westbrook G.L. Parallel processing of afferent olfactory sensory information. J. Physiol. 2016. 594: 6715–6732.Wirt R.A., Hyman J.M. Integrating Spatial Working Memory and Remote Memory: Interactions between the Medial Prefrontal Cortex and Hippocampus. Brain Sci. 2017. 7 (4): 43.Wood G.K., Tomasiewicz H., Rutishauser U., Magnuson T., Quirion R., Rochford J., Srivastava L.K. NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle. Neuroreport. 1998. 9: 461–4666.Woolf N.J., Butcher L.L. Cholinergic systems in the rat brain: IV. Descending projections of the pontomesencephalic tegmentum. Brain Res. Bull. 1989. 23: 519–540.Yang Y., Gritton H., Sarter M., Aton S.J., Booth V., Zochowski M. Theta-gamma coupling emerges from spatially heterogeneous cholinergic neuromodulation. PLoS Comput. Biol. 2021. 17: e1009235.Yoder R.M., Pang K.C. Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm. Hippocampus. 2005. 15: 381–392.Zakharova E.I., Dudchenko A.M. Hypoxic Preconditioning Eliminates Differences in the Innate Resistance of Rats to Severe Hypoxia. Journal of Biomedical Science and Engineering. 2016. 9: 563–575.Zakharova E.I., Dudchenko A.M. Synaptic soluble and membrane-bound choline acetyltransferase as a marker of cholinergic function in vitro and in vivo. Neurochemistry. Ed. Heinbockel T. Rijeka: InTechOpen, 2014. 5: 143–178 pp.Zakharova E.I., Dudchenko A.M., Germanova E.L. Effects of preconditioning on the resistance to acute hypobaric hypoxia and their correction with selective antagonists of nicotinic receptors. Bull. Exp. Biol. Med. 2011. 151 (2): 179–182.Zakharova E.I., Proshin A.T., Monakov M.Y., Dudchenko A.M. Cholinergic Internal and Projection Systems of Hippocampus and Neocortex Critical for Early Spatial Memory Consolidation in Normal and Chronic Cerebral Hypoperfusion Conditions in Rats with Different Abilities to Consolidation: The Role of Cholinergic Interneurons of the Hippocampus. Biomedicines. 2022. 10: 1532.Zakharova E.I., Proshin A.T., Monakov M.Y., Dudchenko A.M. Effect of Intrahippocampal Administration of α7 Subtype Nicotinic Receptor Agonist PNU-282987 and Its Solvent Dimethyl Sulfoxide on the Efficiency of Hypoxic Preconditioning in Rats. Molecules. 2021. 26: 7387.Zakharova E.I., Storozheva E.I., Proshin A.T., Monakov M.Y., Dudchenko A.M. The Acoustic Sensorimotor Gating Predicts the Efficiency of Hypoxic Preconditioning. Participation of the Cholinergic System in This Phenomenon. J. Biomed. Sci. Eng. 2018a. 11: 10–25.Zakharova E.I., Storozheva Z.I., Proshin A.T., Monakov M.Y., Dudchenko A.M. Hypoxic Preconditioning: The multiplicity of central neurotransmitter mechanisms and method of predicting its efficiency. Hypoxia and Anoxia. Eds. Das K.K., Biradar M.S., London: InTechOPEN, 2018b. 6: 95–131 pp.Zakharova E.I., Storozheva Z.I., Proshin A.T., Monakov M.Y., Dudchenko A.M. Opposite Pathways of Cholinergic Mechanisms of Hypoxic Preconditioning in the Hippocampus: Participation of Nicotinic α7 Receptors and Their Association with the Baseline Level of Startle Prepulse Inhibition. Brain Sci. 2020. 11: 12.Zenko M.Y., Rybnikova E.A.Cross Adaptation: from F.Z. Meerson to the Modern State of the Problem. Part 1. Adaptation, Cross-Adaptation and Cross-Sensitization. Usp. Fiziol. Nauk. 2019. 50 (4): 3–13. In RussianZhou G., Olofsson J.K., Koubeissi M.Z., Menelaou G., Rosenow, J., Schuele S.U. et al. Human hippocampal connectivity is stronger in olfaction than other sensory systems. Prog. Neurobiol. 2021. 201: 102027.Zinchenko V.P., Gaidin S.G., Teplov I.Yu., Kosenkov A.M., Sergeev A.I., Dolgacheva L.P., Tuleuhanov S.T. Visualization, Properties, and Functions of GABAergic Hippocampal Neurons Containing Calcium-Permeable Kainate and AMPA Receptors. Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology. 2020. 14: 44–53.