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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

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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.

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References

  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 106:1–16

    Article  PubMed  Google Scholar 

  2. Brydges NM (2016) Pre-pubertal stress and brain development in rodents. Curr Opin Behav Sci 7:8–14

    Article  Google Scholar 

  3. Herman JP, Cullinan WE (1997) Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis. Trends Neurosci 20:78–84

    Article  CAS  PubMed  Google Scholar 

  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 95:56–64

    Article  CAS  PubMed  Google Scholar 

  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 15:36–48

    Article  CAS  PubMed  Google Scholar 

  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 34:646–653

    Article  PubMed  Google Scholar 

  7. Goldman L, Winget C, Hollingshead G, Levine S (1973) Postweaning development of negative feedback in the pituitary-adrenal system of the rat. Neuroendocrinology 12:199–211

    Article  CAS  PubMed  Google Scholar 

  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 10:434

    Article  CAS  PubMed  Google Scholar 

  9. Holmes A, Wellman CL (2009) Stress-induced prefrontal reorganization and executive dysfunction in rodents. Neurosci Biobehav Rev 33:773–783

    Article  PubMed  Google Scholar 

  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 16:313–320

    Article  PubMed  Google Scholar 

  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 22:6810–6818

    Article  CAS  Google Scholar 

  12. Arnsten AF (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 37:39–47

    Article  CAS  PubMed  Google Scholar 

  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 23:768–774

    Article  CAS  Google Scholar 

  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 435–445

  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 64:24

    Article  CAS  PubMed  Google Scholar 

  17. Ghadami MR, Pourmotabbed A (2009) The effect of Crocin on scopolamine induced spatial learning and memory deficits in rats. Physiol Pharmacol 12:287–295

    Google Scholar 

  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 667:222–229

    Article  CAS  PubMed  Google Scholar 

  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 174:51–56

    Article  CAS  PubMed  Google Scholar 

  20. Swan J, Hyland P (2012) A review of the beneficial mental health effects of exercise and recommendations for future research. Psychol Soc 5:1–15

    Google Scholar 

  21. Cotman CW, Berchtold NC (2002) Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 25:295–301

    Article  CAS  Google Scholar 

  22. Kramer AF, Erickson KI, Colcombe SJ (2006) Exercise, cognition, and the aging brain. J Appl Physiol 101:1237–1242

    Article  PubMed  Google Scholar 

  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 18:189–193

    Article  PubMed  Google Scholar 

  24. Cassilhas RC, Tufik S, de Mello MT (2016) Physical exercise, neuroplasticity, spatial learning and memory. Cell Mol Life Sci 73:975–983

    Article  CAS  Google Scholar 

  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 442:203–207

    Article  CAS  PubMed  Google Scholar 

  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 486:39–47

    Article  PubMed  Google Scholar 

  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 19:988–1001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 133:853–861

    Article  CAS  PubMed  Google Scholar 

  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 7:145

    Article  PubMed  PubMed Central  Google Scholar 

  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 275:297–306

    Article  CAS  PubMed  Google Scholar 

  31. Stranahan AM, Khalil D, Gould E (2007) Running induces widespread structural alterations in the hippocampus and entorhinal cortex. Hippocampus 17:1017–1022

    Article  PubMed  PubMed Central  Google Scholar 

  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 69:405–415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 250:316–325

    Article  CAS  PubMed  Google Scholar 

  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 121:992

    Article  PubMed  Google Scholar 

  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 35:374

    Article  CAS  PubMed  Google Scholar 

  36. Nibuya M, Takahashi M, Russell DS, Duman RS (1999) Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 267:81–84

    Article  CAS  PubMed  Google Scholar 

  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 22:16

    Article  CAS  Google Scholar 

  38. Lister RG (1987) The use of a plus-maze to measure anxiety in the mouse. Psychopharmacology 92:180–185

    CAS  Google Scholar 

  39. Treit D, Menard J, Royan C (1993) Anxiogenic stimuli in the elevated plus-maze. Pharmacol Biochem Behav 44:463–469

    Article  CAS  PubMed  Google Scholar 

  40. Brown SM, Henning S, Wellman CL (2005) Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex. Cereb Cortex 15:1714–1722

    Article  PubMed  Google Scholar 

  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 4:117–125

    Article  CAS  PubMed  Google Scholar 

  42. Sholl DA (1956) The organization of the cerebral cortex. John Wiley, Oxford

    Google Scholar 

  43. Garrett JE, Wellman CL (2009) Chronic stress effects on dendritic morphology in medial prefrontal cortex: sex differences and estrogen dependence. Neuroscience 162:195–207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 50:370–382

    Article  CAS  PubMed  Google Scholar 

  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 21:1216–1227

    Article  CAS  PubMed  Google Scholar 

  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 278:559–562

    Article  PubMed  Google Scholar 

  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 4:4–13

    Article  PubMed  Google Scholar 

  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 17:245–256

    Article  CAS  PubMed  Google Scholar 

  49. Ilin Y, Richter-Levin G (2009) Enriched environment experience overcomes learning deficits and depressive-like behavior induced by juvenile stress. PLoS ONE 4:e4329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 82:338–344

    Article  CAS  PubMed  Google Scholar 

  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 99:11946–11950

    Article  CAS  PubMed  Google Scholar 

  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 21:1304–1314

    Article  PubMed  Google Scholar 

  53. Storkebaum E, Lambrechts D, Carmeliet P (2004) VEGF: once regarded as a specific angiogenic factor, now implicated in neuroprotection. Bioessays 26:943–954

    Article  CAS  PubMed  Google Scholar 

  54. Thakker-Varia S, Alder J (2009) Neuropeptides in depression: role of VGF. Behav Brain Res 197:262–278

    Article  CAS  PubMed  Google Scholar 

  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 22:3251–3261

    Article  CAS  PubMed  Google Scholar 

  56. McCormick C, Green M (2013) From the stressed adolescent to the anxious and depressed adult: investigations in rodent models. Neuroscience 249:242–257

    Article  CAS  Google Scholar 

  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 4:493–499

    PubMed  PubMed Central  Google Scholar 

  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 16:91–100

    PubMed  PubMed Central  Google Scholar 

  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 6:157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 44:83–102

    Article  CAS  PubMed  Google Scholar 

  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 27:2781–2787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 26:7870–7874

    Article  CAS  PubMed  Google Scholar 

  63. McEwen BS, Morrison JH (2013) The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 79:16–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 30:6726–6731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 507:1141–1150

    Article  PubMed  PubMed Central  Google Scholar 

  66. Chao HM, Choo PH, McEwen BS (1989) Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain. Neuroendocrinology 50:365–371

    Article  CAS  PubMed  Google Scholar 

  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 18:2357–2364

    Article  PubMed  Google Scholar 

  68. Martin KP, Wellman CL (2011) NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex. Cereb Cortex 21:2366–2373

    Article  PubMed  PubMed Central  Google Scholar 

  69. McEwen BS, Nasca C, Gray JD (2016) Stress effects on neuronal structure: hippocampus, amygdala, and prefrontal cortex. Neuropsychopharmacology 41:3

    Article  CAS  Google Scholar 

  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 34:3878–3887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 1294:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 194:84–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Anderson EH, Shivakumar G (2013) Effects of exercise and physical activity on anxiety. Front Psychiatry 4:27

    Article  PubMed  PubMed Central  Google Scholar 

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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.

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Authors and Affiliations

  1. Student Research Committee, Semnan University of Medical Sciences, Semnan, Iran

    Mohadeseh Ghalandari-Shamami

  2. Laboratory of Learning and Memory, Research Center of Physiology, Semnan University of Medical Sciences, 15131-38111, Semnan, Iran

    Mohadeseh Ghalandari-Shamami, Shahla Nourizade, Abbas Ali Vafaei, Roghayeh Pakdel & Ali Rashidy-Pour

  3. Department of Anatomical Sciences, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Behpour Yousefi

  4. Department of Physiology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Abbas Ali Vafaei & Ali Rashidy-Pour

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  1. Mohadeseh Ghalandari-Shamami
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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.

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Correspondence to Ali Rashidy-Pour.

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Ghalandari-Shamami, M., Nourizade, S., Yousefi, B. et al. 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. Neurochem Res 44, 917–929 (2019). https://doi.org/10.1007/s11064-019-02727-2

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