Biochemistry (Moscow)

, Volume 84, Issue 11, pp 1306–1328 | Cite as

Biochemical Mechanisms and Translational Relevance of Hippocampal Vulnerability to Distant Focal Brain Injury: The Price of Stress Response

  • N. V. GulyaevaEmail author


Focal brain injuries (in particular, stroke and traumatic brain injury) induce with high probability the development of delayed (months, years) cognitive and depressive disturbances which are frequently comorbid. The association of these complications with hippocampal alterations (in spite of the lack of a primary injury of this structure), as well as the lack of a clear dependence between the probability of depression and dementia development and primary damage severity and localization served as the basis for a new hypothesis on the distant hippocampal damage as a key link in the pathogenesis of cognitive and psychiatric disturbances. According to this hypothesis, the excess of corticosteroids secreted after a focal brain damage, in particular in patients with abnormal stress-response due to hypothalamic-pituitary-adrenal axis (HPAA) dysfunction, interacts with corticosteroid receptors in the hippocampus inducing signaling pathways which stimulate neuroinflammation and subsequent events including disturbances in neurogenesis and hippocampal neurodegeneration. In this article, the molecular and cellular mechanisms associated with the regulatory role of the HPAA and multiple functions of brain corticosteroid receptors in the hippocampus are analyzed. Functional and structural damage to the hippocampus, a brain region selectively vulnerable to external factors and responding to them by increased cytokine secretion, forms the basis for cognitive function disturbances and psychopathology development. This concept is confirmed by our own experimental data, results of other groups and by prospective clinical studies of post-stroke complications. Clinically relevant biochemical approaches to predict the risks and probability of post-stroke/post-trauma cognitive and depressive disturbances are suggested using the evaluation of biochemical markers of patients’ individual stress-response. Pathogenetically justified ways for preventing these consequences of focal brain damage are proposed by targeting key molecular mechanisms underlying hippocampal dysfunction.


hippocampus stress stress response hypothalamic-pituitary-adrenal axis corticosteroids cortisol corticosterone glucocorticoid receptor mineralocorticoid receptor cytokines neuroinflammation neurogenesis BDNF interleukins focal brain injury stroke traumatic brain injury depression cognitive disturbances dementia 



adrenocorticotropic hormone

amyloid β


Alzheimer’s disease


brain derived neurotrophic factor


central nervous system


corticotropin-releasing hormone




glucocorticoid receptor


hypothalamic-pituitary-adrenocortical axis


11β-hydroxysteroid dehydrogenase




mild cognitive impairment


mineralocorticoid receptor


poststroke depression


tumor necrosis factor-α


tropomyosin receptor kinase B


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.



This work was supported by the Russian Foundation for Basic Research, grant no. 18-00-00125 (stress, depression), and the Russian Academy of Sciences Presidium Program “Fundamental bases of physiological adaptation technologies” (remote hippocampal damage).


  1. 1.
    McEwen, B. S. (1996) Gonadal and adrenal steroids regulate neurochemical and structural plasticity of the hippocampus via cellular mechanisms involving NMDA receptors, Cell. Mol. Neurobiol., 16, 103–116.PubMedCrossRefGoogle Scholar
  2. 2.
    De Kloet, E. R., Han, F., and Meijer, O. C. (2008) From the stalk to down under about brain glucocorticoid receptors, stress and development, Neurochem. Res., 33, 637–642.PubMedCrossRefGoogle Scholar
  3. 3.
    Uchoa, E. T., Aguilera, G., Herman, J. P., Fiedler, J. L., Deak, T., and de Sousa, M. B. (2014) Novel aspects of glucocorticoid actions, J. Neuroendocrinol., 26, 557–572.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Gulyaeva, N. V. (2019) Functional neurochemistry of the ventral and dorsal hippocampus: stress, depression, dementia and remote hippocampal damage, Neurochem. Res., 44, 1306–1322.PubMedCrossRefGoogle Scholar
  5. 5.
    De Kloet, E. R. (2000) Stress in the brain, Eur. J. Pharmacol., 405, 187–198.PubMedCrossRefGoogle Scholar
  6. 6.
    De Kloet, E. R., Vreugdenhil, E., Oitzl, M. S., and Joels, M. (1998) Brain corticosteroid receptor balance in health and disease, Endocr. Rev., 19, 269–301.PubMedGoogle Scholar
  7. 7.
    Meijer, O. C., Buurstede, J. C., and Schaaf, M. J. M. (2019) Corticosteroid receptors in the brain: transcriptional mechanisms for specificity and context-dependent effects, Cell. Mol. Neurobiol., 39, 539–549.PubMedCrossRefGoogle Scholar
  8. 8.
    Joels, M. (2018) Corticosteroids and the brain, J. Endocrinol., 238, R121–R130.PubMedCrossRefGoogle Scholar
  9. 9.
    Groeneweg, F. L., Karst, H., de Kloet, E. R., and Joels, M. (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response, J. Endocrinol., 209, 153–167.PubMedCrossRefGoogle Scholar
  10. 10.
    Nishi, M., and Kawata, M. (2006) Brain corticosteroid receptor dynamics and trafficking: implications from live cell imaging, Neuroscientist, 12, 119–133.PubMedCrossRefGoogle Scholar
  11. 11.
    De Kloet, E. R., Oitzl, M. S., and Schobitz, B. (1994) Cytokines and the brain corticosteroid receptor balance: relevance to pathophysiology of neuroendocrine-immune communication, Psychoneuroendocrinology, 19, 121–134.PubMedCrossRefGoogle Scholar
  12. 12.
    De Kloet, E. R., Meijer, O. C., de Nicola, A. F., de Rijk, R. H., and Joels, M. (2018) Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation, Front. Neuroendocrinol., 49, 124–145.PubMedCrossRefGoogle Scholar
  13. 13.
    Murakami, G., Hojo, Y., Kato, A., Komatsuzaki, Y., Horie, S., Soma, M., Kim, J., and Kawato, S. (2018) Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: androgen, oestrogen and corticosteroid, J. Neuroendocrinol., 30, doi: Scholar
  14. 14.
    Giordano, R., Pellegrino, M., Picu, A., Bonelli, L., Balbo, M., Berardelli, R., Lanfranco, F., Ghigo, E., and Arvat, E. (2006) Neuroregulation of the hypothalamus-pituitary-adrenal (HPA) axis in humans: effects of GABA-, miner-alocorticoid-, and GH-secretagogue-receptor modulation, Sci. World J., 6, 1–11.CrossRefGoogle Scholar
  15. 15.
    Joels, M., and de Kloet, E. R. (2017) 30 years of the min-eralocorticoid receptor: the brain mineralocorticoid receptor: a saga in three episodes, J. Endocrinol., 234, T49–T66.PubMedCrossRefGoogle Scholar
  16. 16.
    Le Menuet, D., and Lombes, M. (2014) The neuronal min-eralocorticoid receptor: from cell survival to neurogenesis, Steroids, 91, 11–19.PubMedCrossRefGoogle Scholar
  17. 17.
    Odermatt, A., and Kratschmar, D. V. (2012) Tissue-specific modulation of mineralocorticoid receptor function by 11β-hydroxysteroid dehydrogenases: an overview, Mol. Cell. Endocrinol., 350, 168–186.PubMedCrossRefGoogle Scholar
  18. 18.
    Kellendonk, C., Gass, P., Kretz, O., Schutz, G., and Tronche, F. (2002) Corticosteroid receptors in the brain: gene targeting studies, Brain Res. Bull., 57, 73–83.PubMedCrossRefGoogle Scholar
  19. 19.
    Saaltink, D. J., and Vreugdenhil, E. (2014) Stress, glucocorticoid receptors, and adult neurogenesis: a balance between excitation and inhibition? Cell. Mol. Life Sci., 71, 2499–2515.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Vitellius, G., Trabado, S., Bouligand, J., Delemer, B., and Lombes, M. (2018) Pathophysiology of glucocorticoid signaling, Ann. Endocrinol. (Paris), 79, 98–106.CrossRefGoogle Scholar
  21. 21.
    Van Weert, L. T. C. M., Buurstede, J. C., Sips, H. C. M., Mol, I. M., Puri, T., Damsteegt, R., Roozendaal, B., Sarabdjitsingh, R. A., and Meijer, O. C. (2019) Mechanistic insights in NeuroD potentiation of mineralocorticoid receptor signaling, Int. J. Mol. Sci., 20, doi: Scholar
  22. 22.
    Joels, M., and Karst, H. (2012) Corticosteroid effects on calcium signaling in limbic neurons, Cell. Calcium, 51, 277–283.PubMedCrossRefGoogle Scholar
  23. 23.
    Lapp, H. E., Bartlett, A. A., and Hunter, R. G. (2019) Stress and glucocorticoid receptor regulation of mitochondrial gene expression, J. Mol. Endocrinol., 62, R121–R128.PubMedCrossRefGoogle Scholar
  24. 24.
    Reul, J. M. (2014) Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways, Front. Psychiatry, 5, 5.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Mifsud, K. R., Gutierrez-Mecinas, M., Trollope, A. F., Collins, A., Saunderson, E. A., and Reul, J. M. (2011) Epigenetic mechanisms in stress and adaptation, Brain Behav. Immun., 25, 1305–1315.PubMedCrossRefGoogle Scholar
  26. 26.
    Bennett, M. R., and Lagopoulos, J. (2014) Stress and trauma: BDNF control of dendritic-spine formation and regression, Prog. Neurobiol., 112, 80–99.PubMedCrossRefGoogle Scholar
  27. 27.
    Gulyaeva, N. V. (2017) Interplay between brain BDNF and glutamatergic systems: a brief state of the evidence and association with the pathogenesis of depression, Biochemistry (Moscow), 82, 301–307.CrossRefGoogle Scholar
  28. 28.
    Leal, G., Bramham, C. R., and Duarte, C. B. (2017) BDNF and hippocampal synaptic plasticity, Vitam. Horm., 104, 153–195.PubMedCrossRefGoogle Scholar
  29. 29.
    Suri, D., and Vaidya, V. A. (2013) Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity, Neuroscience, 239, 196–213.PubMedCrossRefGoogle Scholar
  30. 30.
    Linz, R., Puhlmann, L. M. C., Apostolakou, F., Mantzou, E., Papassotiriou, I., Chrousos, G. P., Engert, V., and Singer, T. (2019) Acute psychosocial stress increases serum BDNF levels: an antagonistic relation to cortisol but no group differences after mental training, Neuropsychopharmacology, 44, 1797–1804, doi: Scholar
  31. 31.
    Daskalakis, N. P., De Kloet, E. R., Yehuda, R., Malaspina, D., and Kranz, T. M. (2015) Early life stress effects on glucocorticoid—BDNF interplay in the hippocampus, Front. Mol. Neurosci., 8, 68.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Finsterwald, C., and Alberini, C. M. (2014) Stress and glucocorticoid receptor-dependent mechanisms in long-term memory: from adaptive responses to psychopathologies, Neurobiol. Learn. Mem., 112, 17–29.PubMedCrossRefGoogle Scholar
  33. 33.
    Sapolsky, R. M. (1990) Glucocorticoids, hippocampal damage and the glutamatergic synapse, Prog. Brain Res., 86, 13–23.PubMedCrossRefGoogle Scholar
  34. 34.
    Popoli, M., Yan, Z., McEwen, B. S., and Sanacora, G. (2011) The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission, Nat. Rev. Neurosci., 13, 22–37.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Chaouloff, F., and Groc, L. (2011) Temporal modulation of hippocampal excitatory transmission by corticosteroids and stress, Front. Neuroendocrinol., 32, 25–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Goujon, E., Lay E. S., Parnet, P., and Dantzer, R. (1997) Regulation of cytokine gene expression in the central nervous system by glucocorticoids: mechanisms and functional consequences, Psychoneuroendocrinology, 22(Suppl. 1), S75–S80.PubMedCrossRefGoogle Scholar
  37. 37.
    Duque Ede, A., and Munhoz, C. D. (2016) The proinflammatory effects of glucocorticoids in the brain, Front. Endocrinol. (Lausanne), 7, 78.Google Scholar
  38. 38.
    Pariante, C. M. (2017) Why are depressed patients inflamed? A reflection on 20 years of research on depression, glucocorticoid resistance and inflammation, Eur. Neuropsychopharmacol., 27, 554–559.PubMedCrossRefGoogle Scholar
  39. 39.
    Walker, F. R., Nilsson, M., and Jones, K. (2013) Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function, Curr. Drug Targets, 14, 1262–1276.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Gadek-Michalska, A., Tadeusz, J., Rachwalska, P., and Bugajski, J. (2013) Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems, Pharmacol. Rep., 65, 1655–1662.PubMedCrossRefGoogle Scholar
  41. 41.
    Johnson, J. D., Barnard, D. F., Kulp, A. C., and Mehta, D. M. (2019) Neuroendocrine regulation of brain cytokines after psychological stress, J. Endocr. Soc., 3, 1302–1320.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Deak, T., Quinn, M., Cidlowski, J. A., Victoria, N. C., Murphy, A. Z., and Sheridan, J. F. (2015). Neuroimmune mechanisms of stress: sex differences, developmental plasticity, and implications for pharmacotherapy of stress-related disease, Stress, 18, 367–380.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Bekhbat, M., Rowson, S. A., and Neigh, G. N. (2017) Checks and balances: the glucocorticoid receptor and NFkB in good times and bad, Front. Neuroendocrinol., 46, 15–31.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    De Kloet, E. R., and Joels, M. (2017) Brain mineralocorticoid receptor function in control of salt balance and stress-adaptation, Physiol. Behav., 178, 13–20.PubMedCrossRefGoogle Scholar
  45. 45.
    Brocca, M. E., Pietranera, L., de Kloet, E. R., and De Nicola, A. F. (2019) Mineralocorticoid receptors, neuroinflammation and hypertensive encephalopathy, Cell. Mol. Neurobiol., 39, 483–492.PubMedCrossRefGoogle Scholar
  46. 46.
    Frank, M. G., Weber, M. D., Watkins, L. R., and Maier, S. F. (2015) Stress sounds the alarmin: the role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming, Brain Behav. Immun., 48, 1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Pearson-Leary, J., Osborne, D. M., and McNay, E. C. (2016) Role of glia in stress-induced enhancement and impairment of memory, Front. Integr. Neurosci., 9, 63.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Van Olst, L., Bielefeld, P., Fitzsimons, C. P., de Vries, H. E., and Schouten, M. (2018) Glucocorticoid-mediated modulation of morphological changes associated with aging in microglia, Aging Cell, 17, e12790.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    McEwen, B. S. (1997) Possible mechanisms for atrophy of the human hippocampus, Mol. Psychiatry, 2, 255–262.PubMedCrossRefGoogle Scholar
  50. 50.
    Vyas, S., Rodrigues, A. J., Silva, J. M., Tronche, F., Almeida, O. F., Sousa, N., and Sotiropoulos, I. (2016) Chronic stress and glucocorticoids: from neuronal plasticity to neurodegeneration, Neural Plast., 2016, 6391686.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Libro, R., Bramanti, P., and Mazzon, E. (2017) Endogenous glucocorticoids: role in the etiopathogenesis of Alzheimer’s disease, Neuro Endocrinol. Lett., 38, 1–12.PubMedGoogle Scholar
  52. 52.
    Vyas, S., and Maatouk, L. (2013) Contribution of glucocorticoids and glucocorticoid receptors to the regulation of neurodegenerative processes, CNS Neurol. Disord. Drug Targets, 12, 1175–1193.PubMedGoogle Scholar
  53. 53.
    Ouanes, S., and Popp, J. (2019) High cortisol and the risk of dementia and Alzheimer’s disease: a review of the literature, Front. Aging Neurosci., 11, 43.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Paul, S., Jeon, W. K., Bizon, J. L., and Han, J. S. (2015) Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment, Front. Aging Neurosci., 7, 43.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Kootar, S., Frandemiche, M. L., Dhib, G., Mouska, X., Lorivel, T., Poupon-Silvestre, G., Hunt, H., Tronche, F., Bethus, I., Barik, J., and Marie, H. (2018) Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses, Neurobiol. Dis., 118, 117–128.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Bisht, K., Sharma, K., and Tremblay, M. E. (2018) Chronic stress as a risk factor for Alzheimer’s disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress, Neurobiol. Stress, 9, 9–21.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Pomara, N., Greenberg, W. M., Branford, M. D., and Doraiswamy, P. M. (2003) Therapeutic implications of HPA axis abnormalities in Alzheimer’s disease: review and update, Psychopharmacol. Bull., 37, 120–134.PubMedGoogle Scholar
  58. 58.
    Numakawa, T., Odaka, H., and Adachi, N. (2017) Actions of brain-derived neurotrophic factor and glucocorticoid stress in neurogenesis, Int. J. Mol. Sci., 18, E2312, doi: Scholar
  59. 59.
    Fitzsimons, C. P., Herbert, J., Schouten, M., Meijer, O. C., Lucassen, P. J., and Lightman, S. (2016) Circadian and ultradian glucocorticoid rhythmicity: implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis, Front. Neuroendocrinol., 41, 44–58.PubMedCrossRefGoogle Scholar
  60. 60.
    Lucassen, P. J., Oomen, C. A., Naninck, E. F., Fitzsimons, C. P., van Dam, A. M., Czeh, B., and Korosi, A. (2015) Regulation of adult neurogenesis and plasticity by (early) stress, glucocorticoids, and inflammation, Cold Spring Harb. Perspect. Biol., 7, a021303.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Schoenfeld, T. J., and Gould, E. (2012). Stress, stress hormones, and adult neurogenesis, Exp. Neurol., 233, 12–21.PubMedCrossRefGoogle Scholar
  62. 62.
    Lupien, S. J., and Lepage, M. (2001) Stress, memory, and the hippocampus: can’t live with it, can’t live without it, Behav. Brain Res., 127, 137–158.PubMedCrossRefGoogle Scholar
  63. 63.
    Herman, J. P., Ostrander, M. M., Mueller, N. K., and Figueiredo, H. (2005) Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis, Prog. Neuropsychopharmacol. Biol. Psychiatry, 29, 1201–1213.PubMedCrossRefGoogle Scholar
  64. 64.
    Joels, M., Pasricha, N., and Karst, H. (2013) The interplay between rapid and slow corticosteroid actions in brain, Eur. J. Pharmacol., 719, 44–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Zunszain, P. A., Anacker, C., Cattaneo, A., Carvalho, L. A., and Pariante, C. M. (2011) Glucocorticoids, cytokines and brain abnormalities in depression, Prog. Neuropsychopharmacol. Biol. Psychiatry, 35, 722–729.PubMedCrossRefGoogle Scholar
  66. 66.
    Leonard, B. (2000) Stress, depression and the activation of the immune system, World J. Biol. Psychiatry, 1, 17–25.PubMedCrossRefGoogle Scholar
  67. 67.
    Oglodek, E., Szota, A., Just, M., Mos, D., and Araszkiewicz, A. (2014) The role of the neuroendocrine and immune systems in the pathogenesis of depression, Pharmacol. Rep., 66, 776–781.PubMedCrossRefGoogle Scholar
  68. 68.
    Silverman, M. N., and Sternberg, E. M. (2012) Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction, Ann. N. Y. Acad. Sci., 1261, 55–63.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Leonard, B. E. (2018) Inflammation and depression: a causal or coincidental link to the pathophysiology? Acta Neuropsychiatr., 30, 1–16.PubMedCrossRefGoogle Scholar
  70. 70.
    Makhija, K., and Karunakaran, S. (2013) The role of inflammatory cytokines on the etiopathogenesis of depression, Aust. N. Z. J. Psychiatry, 47, 828–839.PubMedCrossRefGoogle Scholar
  71. 71.
    Bauer, M. E., and Teixeira, A. L. (2019) Inflammation in psychiatric disorders: what comes first? Ann. N. Y. Acad. Sci., 437, 57–67.CrossRefGoogle Scholar
  72. 72.
    Maes, M., Yirmyia, R., Noraberg, J., Brene, S., Hibbeln, J., Perini, G., Kubera, M., Bob, P., Lerer, B., and Maj, M. (2009) The inflammatory and neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression, Metab. Brain Dis., 24, 27–53.PubMedCrossRefGoogle Scholar
  73. 73.
    Kim, Y. K., Na, K. S., Myint, A. M., and Leonard, B. E. (2016) The role of pro-inflammatory cytokines in neuroinflammation, neurogenesis and the neuroendocrine system in major depression, Prog. Neuropsychopharmacol. Biol. Psychiatry, 64, 277–284.PubMedCrossRefGoogle Scholar
  74. 74.
    Barnard, D. F., Gabella, K. M., Kulp, A. C., Parker, A. D., Dugan, P. B., and Johnson, J. D. (2019) Sex differences in the regulation of brain IL-1β in response to chronic stress, Psychoneuroendocrinology, 103, 203–211.PubMedCrossRefGoogle Scholar
  75. 75.
    Cattaneo, A., and Riva, M. A. (2016) Stress-induced mechanisms in mental illness: a role for glucocorticoid signaling, J. Steroid Biochem. Mol. Biol., 160, 169–174.PubMedCrossRefGoogle Scholar
  76. 76.
    Zimmermann, C. A., Arloth, J., Santarelli, S., Loschner, A., Webe, P., Schmidt, M. V., Spengler, D., and Binder, E. B. (2019) Stress dynamically regulates co-expression networks of glucocorticoid receptor-dependent MDD and SCZ risk genes, Transl. Psychiatry, 9, 41, doi: Scholar
  77. 77.
    Gray, J. D., Kogan, J. F., Marrocco, J., and McEwen, B. S. (2017) Genomic and epigenomic mechanisms of glucocorticoids in the brain, Nat. Rev. Endocrinol., 13, 661–673.PubMedCrossRefGoogle Scholar
  78. 78.
    Sousa, N., and Almeida, O. F. (2002) Corticosteroids: sculptors of the hippocampal formation, Rev. Neurosci., 13, 59–84.PubMedCrossRefGoogle Scholar
  79. 79.
    Chen, J., Wang, Z. Z., Zhang, S., Chu, S. F., Mou, Z., and Chen, N. H. (2019) The effects of glucocorticoids on depressive and anxiety-like behaviors, mineralocorticoid receptor-dependent cell proliferation regulates anxiety-like behaviors, Behav. Brain Res., 362, 288–298.PubMedCrossRefGoogle Scholar
  80. 80.
    Li, Y., Qin, J., Yan, J., Zhang, N., Xu, Y., Zhu, Y., Sheng, L., Zhu, X., and Ju, S. (2018) Differences of physical vs. psychological stress: evidences from glucocorticoid receptor expression, hippocampal subfields injury, and behavioral abnormalities, Brain Imaging Behav., doi: [Epub ahead of print].
  81. 81.
    Leonard, B. E. (2007) Inflammation, depression and dementia: are they connected? Neurochem. Res., 32, 1749–1756.PubMedCrossRefGoogle Scholar
  82. 82.
    Herbert, J., and Lucassen, P. J. (2016) Depression as a risk factor for Alzheimer’s disease: genes, steroids, cytokines and neurogenesis — what do we need to know? Front. Neuroendocrinol., 41, 153–171.PubMedCrossRefGoogle Scholar
  83. 83.
    Kino, T. (2015) Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders, Front. Physiol., 6, 230.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Levada, O. A., and Troyan, A. S. (2018) Poststroke depression biomarkers: a narrative review, Front. Neurol., 16, 577.CrossRefGoogle Scholar
  85. 85.
    Ben Assayag, E., Korczyn, A. D., Giladi, N., Goldbourt, U., Berliner, A. S., Shenhar-Tsarfaty, S., Kliper, E., Hallevi, H., Shopin, L., Hendler, T., Baashat, D. B., Aizenstein, O., Soreq, H., Katz, N., Solomon, Z., Mike, A., Usher, S., Hausdorff, J. M., Auriel, E., Shapira, I., and Bornstein, N. M. (2012) Predictors for poststroke outcomes: the Tel Aviv Brain Acute Stroke Cohort (TABASCO) study protocol, Int. J. Stroke, 7, 341–347.PubMedCrossRefGoogle Scholar
  86. 86.
    Molad, J., Hallevi, H., Korczyn, A. D., Kliper, E., Auriel, E., Bornstein, N. M., and Ben Assayag, E. (2019) Vascular and neurodegenerative markers for the prediction of post-stroke cognitive impairment: results from the TABASCO study, J. Alzheimer’s Dis., 70, 889–898, doi: Scholar
  87. 87.
    Molad, J., Ben-Assayag, E., Korczyn, A. D., Kliper, E., Bornstein, N. M., Hallevi, H., and Auriel, E. (2018) Clinical and radiological determinants of transient symptoms associated with infarction (TSI), J. Neurol. Sci., 390, 195–199.PubMedCrossRefGoogle Scholar
  88. 88.
    Kliper, E., Ben Assayag, E., Tarrasch, R., Artzi, M., Korczyn, A. D., Shenhar-Tsarfaty, S., Aizenstein, O., Hallevi, H., Mike, A., Shopin, L., Bornstein, N. M., and Ben Bashat, D. (2014) Cognitive state following stroke: the predominant role of preexisting white matter lesions, PLoS One, 9, e105461.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Ben Assayag, E., Tene, O., Korczyn, A. D., Shopin, L., Auriel, E., Molad, J., Hallevi, H., Kirschbaum, C., Bornstein, N. M., Shenhar-Tsarfaty, S., Kliper, E., and Stalder, T. (2017) High hair cortisol concentrations predict worse cognitive outcome after stroke: results from the TABASCO prospective cohort study, Psychoneuroendocrinology, 82, 133–139.PubMedCrossRefGoogle Scholar
  90. 90.
    Tene, O., Hallevi, H., Korczyn, A. D., Shopin, L., Molad, J., Kirschbaum, C., Bornstein, N. M., Shenhar-Tsarfaty, S., Kliper, E., Auriel, E., Usher, S., Stalder, T., and Ben Assayag, E. (2018) The price of stress: high bedtime salivary cortisol levels are associated with brain atrophy and cognitive decline in stroke survivors. Results from the TABASCO prospective cohort study, J. Alzheimer’s Dis., 65, 1365–1375.CrossRefGoogle Scholar
  91. 91.
    Tene, O., Shenhar-Tsarfaty, S., Korczyn, A. D., Kliper, E., Hallevi, H., Shopin, L., Auriel, E., Mike, A., Bornstein, N. M., and Assayag, E. B. (2016) Depressive symptoms following stroke and transient ischemic attack: is it time for a more intensive treatment approach? Results from the TABASCO cohort study, J. Clin. Psychiatry, 77, 673–680.PubMedCrossRefGoogle Scholar
  92. 92.
    Kliper, E., Ben Assayag, E., Korczyn, A. D., Auriel, E., Shopin, L., Hallevi, H., Shenhar-Tsarfaty, S., Mike, A., Artzi, M., Klovatch, I., Bornstein, N. M., and Ben Bashat, D. (2016) Cognitive state following mild stroke: a matter of hippocampal mean diffusivity, Hippocampus, 26, 161–169.PubMedCrossRefGoogle Scholar
  93. 93.
    Herman, J. P., McKlveen, J. M., Ghosal, S., Kopp, B., Wulsin, A., Makinson, R., Scheimann, J., and Myers, B. (2016) Regulation of the hypothalamic-pituitary-adrenocortical stress response, Compr. Physiol., 6, 603–621.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Pochigaeva, K., Druzhkova, T., Yakovlev, A., Onufriev, M., Grishkina, M., Chepelev, A., Guekht, A., and Gulyaeva, N. (2017) Hair cortisol as a marker of hypothalamic-pituitary-adrenal axis activity in female patients with major depressive disorder, Metab. Brain Dis., 32, 577–583.PubMedCrossRefGoogle Scholar
  95. 95.
    Druzhkova, T., Pochigaeva, K., Yakovlev, A., Kazimirova, E., Grishkina, M., Chepelev, A., Guekht, A., and Gulyaeva, N. (2019) Acute stress response to a cognitive task in patients with major depressive disorder: potential metabolic and proinflammatory biomarkers, Metab. Brain Dis., 34, 621–629.PubMedCrossRefGoogle Scholar
  96. 96.
    Joels, M., Karst, H., and Sarabdjitsingh, R. A. (2018) The stressed brain of humans and rodents, Acta Physiol. (Oxf.), 223, e13066.CrossRefGoogle Scholar
  97. 97.
    De Kloet, E. R., Otte, C., Kumsta, R., Kok, L., Hillegers, M. H., Hasselmann, H., Kliegel, D., and Joels, M. (2016) Stress and depression: a crucial role of the mineralocorticoid receptor, J. Neuroendocrinol., 28, doi:
  98. 98.
    Martocchia, A., Curto, M., Toussan, L., Stefanelli, M., and Falaschi, P. (2011) Pharmacological strategies against glucocorticoid-mediated brain damage during chronic disorders, Recent Pat. CNS Drug Discov., 6, 196–204.PubMedCrossRefGoogle Scholar
  99. 99.
    Muller, M., Holsboer, F., and Keck, M. E. (2002) Genetic modification of corticosteroid receptor signaling: novel insights into pathophysiology and treatment strategies of human affective disorders, Neuropeptides, 36, 117–131.PubMedCrossRefGoogle Scholar
  100. 100.
    Sutanto, W., and de Kloet, E. R. (1991) Mineralocorticoid receptor ligands: biochemical, pharmacological, and clinical aspects, Med. Res. Rev., 11, 617–639.PubMedCrossRefGoogle Scholar
  101. 101.
    Gomez-Sanchez, E. P. (2016) Third-generation mineralocorticoid receptor antagonists: why do we need a fourth? J. Cardiovasc. Pharmacol., 67, 26–38.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Wang, W., Liu, L., Yang, X., Gao, H., Tang, Q. K., Yin, L. Y., Yin, X. Y., Hao, J. R., Geng, D. Q., and Gao, C. (2019) Ketamine improved depressive-like behaviors via hippocampal glucocorticoid receptor in chronic stress induced-susceptible mice, Behav. Brain Res., 364, 75–84.PubMedCrossRefGoogle Scholar
  103. 103.
    Scheimann, J. R., Mahbod, P., Morano, R., Frantz, L., Packard, B., Campbell, K., and Herman, J. P. (2018) Deletion of glucocorticoid receptors in forebrain GABAergic neurons alters acute stress responding and passive avoidance behavior in female mice, Front. Behav. Neurosci., 12, 325.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Stepanichev, M., Onufriev, M., Aniol, V., Freiman, S., Brandstaetter, H., Winter, S., Lazareva, N., Guekht, A., and Gulyaeva, N. (2017) Effects of Cerebrolysin on nerve growth factor system in the aging rat brain, Restor. Neurol. Neurosci., 35, 571–581.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Joels, M. (2008) Functional actions of corticosteroids in the hippocampus, Eur. J. Pharmacol., 583, 312–321.PubMedCrossRefGoogle Scholar
  106. 106.
    Gulyaeva, N. V. (2017) Molecular mechanisms of neuroplasticity: an expanding universe, Biochemistry (Moscow), 82, 237–242.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2019

Authors and Affiliations

  1. 1.Institute of Higher Nervous Activity and NeurophysiologyRussian Academy of SciencesMoscowRussia
  2. 2.Healthcare Department of MoscowMoscow Research and Clinical Center for NeuropsychiatryMoscowRussia

Personalised recommendations