Olfactory bulbectomy in rodents is widely used as a model of the symptoms of clinical depression and neurodegeneration, including cholinergic. Male C57BL/6 mice in the present study underwent olfactory bulbectomy. Formation of long-term nonassociative memory (habituation) and spatial memory were studied two and four weeks after surgery. The effect of bulbectomy on the state of neurons in the medial septal area was studied using immunohistochemical staining for choline acetyltransferase and NeuN at the end of the behavioral studies, i.e., four and seven weeks after surgery. Bulbectomy led to impaired habituation in terms of measures of motor activity in the open field test and impaired spatial learning, but not memory in a water maze at both time points. A decrease in the proportion of cholinergic cells in the medial septal area was seen at four but not seven weeks after surgery. There were no significant changes in the total number of neurons in this part of the brain. Thus, the occurrence of cognitive impairment after olfactory bulbectomy may be associated with the manifestations of transient cholinergic deficit at the early stages of the development of pathology.
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Avetisyan, A. V., Samokhin, A. N., Alexandrova, I. Y., et al., “Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease,” Biochemistry (Mosc.), 81, 615–623 (2016).
Blusztajn, J. K. and Berse, B., “The cholinergic neuronal phenotype in Alzheimer’s disease,” Metab. Brain. Dis., 15, 45–64 (2000).
Bobkova, N. V., Nesterova, I. V., and Nesterov, V. V., “The state of cholinergic structures in forebrain of bulbectomized mice,” Byull. Exp. Biol. Med., 131, No. 5, 427–431 (2001).
Bobkova, N., Garbuz, D. G., Nesterova, I. V., et al., “Therapeutic effect of exogenous hsp70 in mouse models of Alzheimer’s disease,” J. Alzheimers Dis., 38, No. 2, 425–435 (2014).
Capurso, S., Calhoun, M., Sukhov, R., et al., “Deafferentation causes apoptosis in cortical sensory neurons in the adult rat,” J. Neurosci., 17, No. 19, 7372–7384 (1997).
Cenini, G., Lloret, A., and Cascella, R., “Oxidative stress in neurodegenerative diseases: from a mitochondrial point of view,” Oxid. Med. Cell Longev., 2019, 2105607 (2019).
Deiana, S., Platt, B., and Riedel, G., “The cholinergic system and spatial learning,” Behav. Brain Res., 221, No. 2, 389–411 (2011).
Dobryakova, Y., Volobueva, M., Manolova, A., et al., “Cholinergic deficit induced by central administration of 192IgG-Saporin is associated with activation of microglia and cell loss in the dorsal hippocampus of rats,” Front. Neurosci., 13, 146 (2019).
Ennaceur, A., “Tests of unconditioned anxiety pitfalls and disappointments,” Physiol. Behav., 135, 55–71 (2014).
Flores, G., Ibañez-Sandoval, O., Silva-Gómez, A. B., et al., “Neonatal olfactory bulbectomy enhances locomotor activity, exploratory behavior and binding of NMDA receptors in pre-pubertal rats,” Neuroscience, 259, 84–93 (2014).
Gulyaeva, N. V., Bobkova, N. V., Kolosova, N. G., et al., “Molecular and cellular mechanisms of sporadic Alzheimer’s disease: Studies on rodent models in vivo,” Biochemistry (Mosc.), 82, No. 10, 1088–1102 (2017).
Hampel, H., Mesulam, M., Cuello, A., et al., “Revisiting the cholinergic hypothesis in Alzheimer’s disease: emerging evidence from translational and clinical research,” J. Prev. Alzheimers Dis., 6, No. 1, 2–15 (2019).
Hellweg, R., Zueger, M., Fink, K., et al., “Olfactory bulbectomy in mice leads to increased BDNF levels and decreased serotonin turnover in depression-related brain areas,” Neurobiol. Dis., 25, No. 1, 1–7 (2007).
Hendriksen, H., Korte, S. M., Olivier, B., and Oosting, R. S., “The olfactory bulbectomy model in mice and rat: one story or two tails?” Eur. J. Pharmacol., 753, 105–113 (2015).
Hozumi, S., Nakagawasai, O., Tan-no, K., and Niijima, F., “Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy,” Behav. Brain Res., 138, 9–15 (2003).
Hu, J., Wang, X., Liu, D., et al., “Olfactory deficits induce neurofilament hyperphosphorylation,” Neurosci. Lett., 506, No. 2, 180–183 (2012).
Irle, E. and Markowitsch, H. J., “Basal forebrain-lesioned monkeys are severely impaired in tasks of association and recognition memory,” Ann. Neurol., 22, No. 6, 735–743 (1987).
Jin, J., Cheng, J., Lee, K., et al., “Cholinergic neurons of the medial septum are crucial for sensorimotor gating,” J. Neurosci., 39, No. 26, 5234–5242 (2019).
Kang, H.-M., Jin, J., Lee, S., et al., “A novel method for olfactory bulbectomy using photochemically induced lesion,” Neuroreport, 21, No. 3, 179–184 (2010).
Kelly, J. P., Wrynn, A. S., and Leonard, B. E., “The olfactory bulbectomized rat as a model of depression: an update,” Pharmacol. Ther., 74, No. 3, 299–316 (1997).
Koliatsos, V., Dawson, T., Kesojevic, A., et al., “Cortical interneurons become activated by deafferentation and instruct the apoptosis of pyramidal neurons,” Proc. Natl. Acad. Sci. USA, 101, No. 39, 14264–14269 (2004).
Lazo, O. M., Mauna, J. C., Pissani, C. A., et al., “Axotomy-induced neurotrophic withdrawal causes the loss of phenotypic differentiation and downregulation of NGF signalling, but not death of septal cholinergic neurons,” Mol. Neurodegener., 5, 5 (2010).
Leanza, G., Mu, J., Nissonl, G., et al., “Selective immunolesioning of the basal forebrain cholinergic system disrupts short-term memory in rats,” Eur. J. Neurosci., 8, 1535–1544 (1996).
Liu, A., Lim, E., Ahmed, I., et al., “Review: Revisiting the human cholinergic nucleus of the diagonal band of Broca,” Neuropath. Appl. Neurobiol., 44, No. 7, 647–662 (2018).
Lopez-Coviella, I., Mellott, T. J., Schnitzler, A. C., and Blusztajn, J. K., “BMP9 protects septal neurons from axotomy-evoked loss of cholinergic phenotype,” PLoS One, 6, No. 6, e21166 (2011).
Machado, D. G., Cunha, M. P., Neis, V. B., et al., “Rosmarinus officinalis L. hydroalcoholic extract, similar to fluoxetine, reverses depressive-like behavior without altering learning deficit in olfactory bulbectomized mice,” J. Ethnopharmacol., 143, No. 1, 158–169 (2012).
McDiarmid, T. A., Bernardos, A. C., and Rankin, C. H., “Habituation is altered in neuropsychiatric disorders a comprehensive review with recommendations for experimental design and analysis,” Neurosci. Biobehav. Rev., 80, 286–305 (2017).
Meola, D. M., Huang, Z., King, M., and Petitto, J. M., “Loss of cholinergic phenotype in septohippocampal projection neurons: relation to brain versus peripheral IL-2 deficiency,” Neurosci. Lett., 539, 60–64 (2013).
Mucignat-Caretta, C., Bondí, M., and Caretta, A., “Time course of alterations after olfactory bulbectomy in mice,” Physiol. Behav., 89, No. 5, 637–643 (2006).
Müller, C. and Remy, S., “Septo-hippocampal interaction,” Cell Tissue Res., 373, No. 3, 565–575 (2018).
Nedogreeva, O. A., Evtushenko, N. A., Manolova, A. O., et al., “Oxidative modification of proteins and nucleic acids in the mouse brain after olfactory bulbectomy,” Asimmetriya, 12, 346–350 (2018).
Nedogreeva, O. A., Stepanichev, M. Yu., and Gulyaeva, N. V., “Olfactory bulbectomy in mice leads to changes in emotional behavior,” Zh. Vyssh. Nerv. Deyat., 70, No. 1, 104–114 (2020).
Papouin, T., Dunphy, J., Tolman, M., et al., “Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness,” Neuron, 94, No. 4, 840–854 (2017).
Platel, A. and Porsolt, R. D., “Habituation of exploratory activity in mice: a screening test for memory enhancing drugs,” Psychopharmacology, 78, 346–352 (1982).
Platel, A., Jalfre, M., Pawelec, C., et al., “Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes,” Pharmacol. Biochem. Behav., 21, 209–212 (1984).
Schliebs, R. and Arendt, T., “The cholinergic system in aging and neuronal degeneration,” Behav. Brain Res., 221, No. 2, 555–563 (2011).
Schliebs, R. and Arendt, T., “The significance of the cholinergic system in the brain during aging and in Alzheimer’s disease,” J. Neural Transm. (Vienna), 113, No. 11, 1625–1644 (2006).
Solari, N. and Hangya, B., “Cholinergic modulation of spatial learning, memory and navigation,” Eur. J. Neurosci., 48, No. 5, 2199–2230 (2018).
Song, C. and Leonard, B. E., “The olfactory bulbectomised rat as a model of depression,” Neurosci. Biobehav. Rev., 29, No. 4–5, 627–647 (2005).
Stepanichev, M., Lazareva, N., Tukhbatova, G., et al., “Transient disturbances in contextual fear memory induced by Aβ(25–35) in rats are accompanied by cholinergic dysfunction,” Behav. Brain Res., 259, 152–157 (2014).
Stepanichev, M., Nedogreeva, O., and Gulyaeva, N., “Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?” Alzheimers Dementia Cogn. Neurol., 1, No. 2, 1–7 (2017).
Tasset, I., Medina, F. J., Peña, J., et al., “Olfactory bulbectomy induced oxidative and cell damage in rat: protective effect of melatonin,” Physiol. Res., 59, No. 1, 105–112 (2010).
Vorhees, C. V. and Williams, M. T., “Morris water maze: procedures for assessing spatial and related forms of learning and memory,” Nat. Protoc., 1, No. 2, 848–858 (2006).
Yoshimura, H., Gomita, Y., and Ueki, S., “Changes in acetylcholine content in rat brain after bilateral olfactory bulbectomy in relation to mouse-killing behavior,” Pharmacol. Biochem. Behav., 2, No. 5, 703–705 (1974).
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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 70, No. 6, pp. 794–806, November–December, 2020.
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Nedogreeva, O.A., Lazareva, N.A., Stepanichev, M.Y. et al. Impaired Memory Formation and the Development of Transient Cholinergic Deficit in Mice after Olfactory Bulbectomy. Neurosci Behav Physi 51, 748–756 (2021). https://doi.org/10.1007/s11055-021-01131-0
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DOI: https://doi.org/10.1007/s11055-021-01131-0