Advertisement

Neurochemical Research

, Volume 44, Issue 4, pp 917–929 | Cite as

Beneficial Effects of Physical Activity and Crocin Against Adolescent Stress Induced Anxiety or Depressive-Like Symptoms and Dendritic Morphology Remodeling in Prefrontal Cortex in Adult Male Rats

  • Mohadeseh Ghalandari-Shamami
  • Shahla Nourizade
  • Behpour Yousefi
  • Abbas Ali Vafaei
  • Roghayeh Pakdel
  • Ali Rashidy-PourEmail author
Original Paper
  • 302 Downloads

Abstract

Increasing evidence suggests that exposure to chronic stress during adolescent period may lead to behavioral and neuronal morphology deficits in adulthood. This study examined whether crocin, the main active saffron constituent, and voluntary exercise, alone or combined, could prevent the detrimental influences of chronic restraint stress during adolescent (postnatal days, PND, 30–40) on behavioral and morphological deficits in adult (PND60) male rats. Results showed that plasma corticosterone levels increased at PND40, but not PND60 in stressed rats. Moreover, stressed rats demonstrated enhanced anxiety levels and depression like behaviors in adulthood. These behavioral abnormalities were accompanied by a decline in apical dendritic length in both infralimbic and prelimbic regions and dendritic branches in infralimbic region of the prefrontal cortex. Treatment with crocin, exposure to wheel running activity, and the combined interventions alleviated both behavioral and morphological deficits induced by adolescent stress. Moreover, these treatments exerted positive neuronal morphological effects in the prefrontal cortex in non-stressed animals. Our findings provide important evidences that exercise as a non-pharmacological intervention and crocin treatment during pre-pubertal period can protect against adolescent stress induced behavioral and morphological abnormalities in adulthood.

Keywords

Adolescent stress Crocin Running wheel exercise Anxiety Depression Dendritic remodeling Prefrontal cortex 

Notes

Acknowledgements

This study was supported by a (Grant No. 984) from Semnan University of Medical Sciences (Semnan, Iran). In addition, Mrs. Mohadeseh Ghalandari carried out this work in partial project fulfillment of the requirements to obtain the Ph.D. in Physiology.

Author Contributions

MG-S and ARP designed the overall study and wrote the paper. MG-S, SN, BY, AAV conducted the research, collected data and carried out the lab work. MG-S and ARP carried out the statistical analysis and mostly drafted the manuscript. ARP coordinated and supervised the study. All authors approved the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors report no biomedical financial interests or potential conflicts of interest regarding this work.

References

  1. 1.
    Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ (2013) Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106:1–16CrossRefPubMedGoogle Scholar
  2. 2.
    Brydges NM (2016) Pre-pubertal stress and brain development in rodents. Curr Opin Behav Sci 7:8–14CrossRefGoogle Scholar
  3. 3.
    Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84CrossRefPubMedGoogle Scholar
  4. 4.
    Horovitz O, Tsoory M, Hall J, Jacobson-Pick S, Richter-Levin G (2012) Post-weaning to pre-pubertal (‘juvenile’) stress: a model of induced predisposition to stress-related disorders. Neuroendocrinology 95:56–64CrossRefPubMedGoogle Scholar
  5. 5.
    Horovitz O, Tsoory M, Yovell Y, Richter-Levin G (2014) A rat model of pre-puberty (juvenile) stress-induced predisposition to stress-related disorders: sex similarities and sex differences in effects and symptoms. World J Biol Psychiatry 15:36–48CrossRefPubMedGoogle Scholar
  6. 6.
    Vázquez DM, Akil H (1993) Pituitary-adrenal response to ether vapor in the weanling animal: characterization of the inhibitory effect of glucocorticoids on adrenocorticotropin secretion. Pediatr Res 34:646–653CrossRefPubMedGoogle Scholar
  7. 7.
    Goldman L, Winget C, Hollingshead G, Levine S (1973) Postweaning development of negative feedback in the pituitary-adrenal system of the rat. Neuroendocrinology 12:199–211CrossRefPubMedGoogle Scholar
  8. 8.
    Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434CrossRefPubMedGoogle Scholar
  9. 9.
    Holmes A, Wellman CL (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33:773–783CrossRefPubMedGoogle Scholar
  10. 10.
    Radley JJ, Rocher AB, Miller M, Janssen WG, Liston C, Hof PR, McEwen BS, Morrison JH (2005) Repeated stress induces dendritic spine loss in the rat medial prefrontal cortex. Cereb Cortex 16:313–320CrossRefPubMedGoogle Scholar
  11. 11.
    Vyas A, Mitra R, Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818CrossRefGoogle Scholar
  12. 12.
    Arnsten AF (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eiland L, Ramroop J, Hill MN, Manley J, McEwen BS (2012) Chronic juvenile stress produces corticolimbic dendritic architectural remodeling and modulates emotional behavior in male and female rats. Psychoneuroendocrinology 37:39–47CrossRefPubMedGoogle Scholar
  14. 14.
    Hosseinzadeh H, Noraei NB (2009) Anxiolytic and hypnotic effect of Crocus sativus aqueous extract and its constituents, crocin and safranal, in mice. Phytother Res 23:768–774CrossRefGoogle Scholar
  15. 15.
    Hosseinzadeh H, Karimi G, Niapoor M (2003) Antidepressant effect of Crocus sativus L. stigma extracts and their constituents, crocin and safranal, in mice. In: I international symposium on saffron biology and biotechnology 650. pp 435–445Google Scholar
  16. 16.
    Wang Y, Han T, Zhu Y, Zheng C-J, Ming Q-L, Rahman K, Qin L-P (2010) Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. J Nat Med 64:24CrossRefPubMedGoogle Scholar
  17. 17.
    Ghadami MR, Pourmotabbed A (2009) The effect of Crocin on scopolamine induced spatial learning and memory deficits in rats. Physiol Pharmacol 12:287–295Google Scholar
  18. 18.
    Ghadrdoost B, Vafaei AA, Rashidy-Pour A, Hajisoltani R, Bandegi AR, Motamedi F, Haghighi S, Sameni HR, Pahlvan S (2011) Protective effects of saffron extract and its active constituent crocin against oxidative stress and spatial learning and memory deficits induced by chronic stress in rats. Eur J Pharmacol 667:222–229CrossRefPubMedGoogle Scholar
  19. 19.
    Talaei A, Moghadam MH, Tabassi SAS, Mohajeri SA (2015) Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double-blind, placebo-controlled, pilot clinical trial. J Affect Disord 174:51–56CrossRefPubMedGoogle Scholar
  20. 20.
    Swan J, Hyland P (2012) A review of the beneficial mental health effects of exercise and recommendations for future research. Psychol Soc 5:1–15Google Scholar
  21. 21.
    Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301CrossRefGoogle Scholar
  22. 22.
    Kramer AF, Erickson KI, Colcombe SJ (2006) Exercise, cognition, and the aging brain. J Appl Physiol 101:1237–1242CrossRefPubMedGoogle Scholar
  23. 23.
    Penedo FJ, Dahn JR (2005) Exercise and well-being: a review of mental and physical health benefits associated with physical activity. Curr Opin Psychiatry 18:189–193CrossRefPubMedGoogle Scholar
  24. 24.
    Cassilhas RC, Tufik S, de Mello MT (2016) Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci 73:975–983CrossRefGoogle Scholar
  25. 25.
    Ekstrand J, Hellsten J, Tingström A (2008) Environmental enrichment, exercise and corticosterone affect endothelial cell proliferation in adult rat hippocampus and prefrontal cortex. Neurosci Lett 442:203–207CrossRefPubMedGoogle Scholar
  26. 26.
    Eadie BD, Redila VA, Christie BR (2005) Voluntary exercise alters the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. J Comp Neurol 486:39–47CrossRefPubMedGoogle Scholar
  27. 27.
    Greenwood BN, Strong PV, Foley TE, Fleshner M (2009) A behavioral analysis of the impact of voluntary physical activity on hippocampus-dependent contextual conditioning. Hippocampus 19:988–1001CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Berchtold N, Chinn G, Chou M, Kesslak J, Cotman C (2005) Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus. Neuroscience 133:853–861CrossRefPubMedGoogle Scholar
  29. 29.
    Gebara EG, Sultan S, Kocher-Braissant J, Toni N (2013) Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging. Front Neurosci 7:145CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bechara RG, Lyne R, Kelly ÁM (2014) BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat. Behav Brain Res 275:297–306CrossRefPubMedGoogle Scholar
  31. 31.
    Stranahan AM, Khalil D, Gould E (2007) Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17:1017–1022CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hamilton G, Criss K, Klintsova A (2015) Voluntary exercise partially reverses neonatal alcohol-induced deficits in mPFC layer II/III dendritic morphology of male adolescent rats. Synapse 69:405–415CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lapmanee S, Charoenphandhu J, Charoenphandhu N (2013) Beneficial effects of fluoxetine, reboxetine, venlafaxine, and voluntary running exercise in stressed male rats with anxiety-and depression-like behaviors. Behav Brain Res 250:316–325CrossRefPubMedGoogle Scholar
  34. 34.
    Greenwood BN, Strong PV, Dorey AA, Fleshner M (2007) Therapeutic effects of exercise: wheel running reverses stress-induced interference with shuttle box escape. Behav Neurosci 121:992CrossRefPubMedGoogle Scholar
  35. 35.
    De Chiara V, Errico F, Musella A, Rossi S, Mataluni G, Sacchetti L, Siracusano A, Castelli M, Cavasinni F, Bernardi G (2010) Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum. Neuropsychopharmacology 35:374CrossRefPubMedGoogle Scholar
  36. 36.
    Nibuya M, Takahashi M, Russell DS, Duman RS (1999) Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 267:81–84CrossRefPubMedGoogle Scholar
  37. 37.
    Hassani FV, Naseri V, Razavi BM, Mehri S, Abnous K, Hosseinzadeh H (2014) Antidepressant effects of crocin and its effects on transcript and protein levels of CREB, BDNF, and VGF in rat hippocampus. DARU J Pharm Sci 22:16CrossRefGoogle Scholar
  38. 38.
    Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185Google Scholar
  39. 39.
    Treit D, Menard J, Royan C (1993) Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 44:463–469CrossRefPubMedGoogle Scholar
  40. 40.
    Brown SM, Henning S, Wellman CL (2005) Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex 15:1714–1722CrossRefPubMedGoogle Scholar
  41. 41.
    Glaser EM, Van der Loos H (1981) Analysis of thick brain sections by obverse—reverse computer microscopy: application of a new, high clarity Golgi—Nissl stain. J Neurosci Methods 4:117–125CrossRefPubMedGoogle Scholar
  42. 42.
    Sholl DA (1956) The organization of the cerebral cortex. John Wiley, OxfordGoogle Scholar
  43. 43.
    Garrett JE, Wellman CL (2009) Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience 162:195–207CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Brummelte S, Pawluski JL, Galea LA (2006) High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: a model of post-partum stress and possible depression. Horm Behav 50:370–382CrossRefPubMedGoogle Scholar
  45. 45.
    Barha CK, Brummelte S, Lieblich SE, Galea LA (2011) Chronic restraint stress in adolescence differentially influences hypothalamic-pituitary-adrenal axis function and adult hippocampal neurogenesis in male and female rats. Hippocampus 21:1216–1227CrossRefPubMedGoogle Scholar
  46. 46.
    Grigoryan G, Ardi Z, Albrecht A, Richter-Levin G, Segal M (2015) Juvenile stress alters LTP in ventral hippocampal slices: involvement of noradrenergic mechanisms. Behav Brain Res 278:559–562CrossRefPubMedGoogle Scholar
  47. 47.
    Brydges NM, Jin R, Seckl J, Holmes MC, Drake AJ, Hall J (2014) Juvenile stress enhances anxiety and alters corticosteroid receptor expression in adulthood. Brain Behav 4:4–13CrossRefPubMedGoogle Scholar
  48. 48.
    Tsoory M, Cohen H, Richter-Levin G (2007) Juvenile stress induces a predisposition to either anxiety or depressive-like symptoms following stress in adulthood. Eur Neuropsychopharmacol 17:245–256CrossRefPubMedGoogle Scholar
  49. 49.
    Ilin Y, Richter-Levin G (2009) Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress. PLoS ONE 4:e4329CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Gameiro GH, da Silva Andrade A, de Castro M, Pereira LF, Tambeli CH, de Arruda Veiga MCF (2005) The effects of restraint stress on nociceptive responses induced by formalin injected in rat’s TMJ. Pharmacol Biochem Behav 82:338–344CrossRefPubMedGoogle Scholar
  51. 51.
    Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci USA 99:11946–11950CrossRefPubMedGoogle Scholar
  52. 52.
    Heine VM, Zareno J, Maslam S, Joëls M, Lucassen PJ (2005) Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression. Eur J Neurosci 21:1304–1314CrossRefPubMedGoogle Scholar
  53. 53.
    Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954CrossRefPubMedGoogle Scholar
  54. 54.
    Thakker-Varia S, Alder J (2009) Neuropeptides in depression: role of VGF. Behav Brain Res 197:262–278CrossRefPubMedGoogle Scholar
  55. 55.
    Shirayama Y, Chen AC-H, Nakagawa S, Russell DS, Duman RS (2002) Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22:3251–3261CrossRefPubMedGoogle Scholar
  56. 56.
    McCormick C, Green M (2013) From the stressed adolescent to the anxious and depressed adult: investigations in rodent models. Neuroscience 249:242–257CrossRefGoogle Scholar
  57. 57.
    Bandegi AR, Rashidy-Pour A, Vafaei AA, Ghadrdoost B (2014) Protective effects of Crocus sativus L. extract and crocin against chronic-stress induced oxidative damage of brain, liver and kidneys in rats. Adv Pharm Bull 4:493–499PubMedPubMedCentralGoogle Scholar
  58. 58.
    Tamaddonfard E, Farshid AA, Asri-Rezaee S, Javadi S, Khosravi V, Rahman B, Mirfakhraee Z (2013) Crocin improved learning and memory impairments in streptozotocin-induced diabetic rats. Iran J Basic Med Sci 16:91–100PubMedPubMedCentralGoogle Scholar
  59. 59.
    Dastgerdi AH, Radahmadi M, Pourshanazari AA, Dastgerdi HH (2017) Effects of crocin on learning and memory in rats under chronic restraint stress with special focus on the hippocampal and frontal cortex corticosterone levels. Adv Biomed Res 6:157CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Chen C, Nakagawa S, An Y, Ito K, Kitaichi Y, Kusumi I (2017) The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels. Front Neuroendocrinol 44:83–102CrossRefPubMedGoogle Scholar
  61. 61.
    Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N (2007) The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 27:2781–2787CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Liston C, Miller MM, Goldwater DS, Radley JJ, Rocher AB, Hof PR, Morrison JH, McEwen BS (2006) Stress-induced alterations in prefrontal cortical dendritic morphology predict selective impairments in perceptual attentional set-shifting. J Neurosci 26:7870–7874CrossRefPubMedGoogle Scholar
  63. 63.
    McEwen BS, Morrison JH (2013) The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79:16–29CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Bloss EB, Janssen WG, McEwen BS, Morrison JH (2010) Interactive effects of stress and aging on structural plasticity in the prefrontal cortex. J Neurosci 30:6726–6731CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Radley JJ, Rocher AB, Rodriguez A, Ehlenberger DB, Dammann M, McEwen BS, Morrison JH, Wearne SL, Hof PR (2008) Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol 507:1141–1150CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Chao HM, Choo PH, McEwen BS (1989) Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain. Neuroendocrinology 50:365–371CrossRefPubMedGoogle Scholar
  67. 67.
    Figueiredo HF, Bruestle A, Bodie B, Dolgas CM, Herman JP (2003) The medial prefrontal cortex differentially regulates stress-induced c-fos expression in the forebrain depending on type of stressor. Eur J Neurosci 18:2357–2364CrossRefPubMedGoogle Scholar
  68. 68.
    Martin KP, Wellman CL (2011) NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex. Cereb Cortex 21:2366–2373CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41:3CrossRefGoogle Scholar
  70. 70.
    Vialou V, Bagot RC, Cahill ME, Ferguson D, Robison AJ, Dietz DM, Fallon B, Mazei-Robison M, Ku SM, Harrigan E (2014) Prefrontal cortical circuit for depression-and anxiety-related behaviors mediated by cholecystokinin: role of ∆FosB. J Neurosci 34:3878–3887CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Helfer JL, Goodlett CR, Greenough WT, Klintsova AY (2009) The effects of exercise on adolescent hippocampal neurogenesis in a rat model of binge alcohol exposure during the brain growth spurt. Brain Res 1294:1–11CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Hopkins ME, Nitecki R, Bucci DJ (2011) Physical exercise during adolescence versus adulthood: differential effects on object recognition memory and brain-derived neurotrophic factor levels. Neuroscience 194:84–94CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Anderson EH, Shivakumar G (2013) Effects of exercise and physical activity on anxiety. Front Psychiatry 4:27CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mohadeseh Ghalandari-Shamami
    • 1
    • 2
  • Shahla Nourizade
    • 2
  • Behpour Yousefi
    • 3
  • Abbas Ali Vafaei
    • 2
    • 4
  • Roghayeh Pakdel
    • 2
  • Ali Rashidy-Pour
    • 2
    • 4
    Email author
  1. 1.Student Research CommitteeSemnan University of Medical SciencesSemnanIran
  2. 2.Laboratory of Learning and Memory, Research Center of PhysiologySemnan University of Medical SciencesSemnanIran
  3. 3.Department of Anatomical Sciences, School of MedicineSemnan University of Medical SciencesSemnanIran
  4. 4.Department of Physiology, School of MedicineSemnan University of Medical SciencesSemnanIran

Personalised recommendations