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Treadmill Exercise Improves Behavioral and Neurobiological Alterations in Restraint-Stressed Rats

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Abstract

Stress is a state that is known to impact an organism’s physiological and psychological balance as well as the morphology and functionality of certain brain areas. In the present work, chronic restraint stress (CRS) model rats treated with treadmill exercise were used to examine anomalies associated to emotion and mood as well as molecular changes in the brain. Forty male Sprague-Dawley rats were divided into control, stress, exercise, and stress+exercise groups. CRS were exposed to stress group rats and exercise group underwent a chronic treadmill exercise. Depressive-like behavior was evaluated with the forced swim test (FST) and tail suspension test (TST). For assessing anxiety-like behavior, the light-dark test (LDT) and the open field test (OFT) were used. The Morris water maze test (MWMT) was used for testing memory and learning. Brain’s monoamine level and the expression of genes related to stress were measured. It was discovered that CRS lengthens latency in the MWMT, increases immobility in the FST and TST, decreases time in the light compartment, and causes hypoactivity in the OFT. CRS reduced the dopamine levels in the nucleus accumbens(NAc). Brain-derived neurotrophic factor (BDNF), dopamine receptors, and serotonin receptor (HTR2A) gene expression in the prefrontal cortex, corpus striatum, and hypothalamus were decreased by CRS. Exercise on a treadmill leads to increase NAc’s dopamine and noradrenaline levels and prevented behavioral alterations. Exercise increased the alterations of BDNF expressions in the brain in addition to improving behavior. As a result, CRS-induced behavioral impairments were effectively reversed by chronic treadmill exercise with molecular alterations in the brain.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  • Akter S, Sasaki H, Uddin KR, Ikeda Y, Miyakawa H, Shibata S (2019) Anxiolytic effects of γ-oryzanol in chronically-stressed mice are related to monoamine levels in the brain. Life Sci 216:119–128

    Article  CAS  PubMed  Google Scholar 

  • Alghasham A, Rasheed N (2014) Stress-mediated modulations in dopaminergic system and their subsequent impact on behavioral and oxidative alterations: an update. Pharm Biol 52:368–377

    Article  CAS  PubMed  Google Scholar 

  • Anderson E, Gomez D, Caccamise A, McPhail D, Hearing M (2019) Chronic unpredictable stress promotes cell-specific plasticity in prefrontal cortex D1 and D2 pyramidal neurons. Neurobiology of Stress 10:100152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnsten AF (2015) Stress weakens prefrontal networks: molecular insults to higher cognition. Nat Neurosci 18:1376–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bakshi VP, Kalin NH (2000) Corticotropin-releasing hormone and animal models of anxiety: gene–environment interactions. Biol Psychiat 48:1175–1198

    Article  CAS  PubMed  Google Scholar 

  • Björklund A, Dunnett SB (2007) Dopamine neuron systems in the brain: an update. Trends Neurosci 30:194–202

    Article  PubMed  Google Scholar 

  • Can A, Dao DT, Terrillion CE, Piantadosi SC, Bhat S, Gould TD (2012) The tail suspension test. J Vis Exp e3769

  • Canteras NS, Graeff FG (2014) Executive and modulatory neural circuits of defensive reactions: implications for panic disorder. Neurosci Biobehav Rev 46:352–364

    Article  PubMed  Google Scholar 

  • Carhart-Harris R, Nutt D (2017) Serotonin and brain function: a tale of two receptors. J Psychopharmacol 31:1091–1120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chaouloff F (1989) Physical exercise and brain monoamines: a review. Acta Physiol Scand 137:1–13

    Article  CAS  PubMed  Google Scholar 

  • Clark PJ, Amat J, McConnell SO, Ghasem PR, Greenwood BN, Maier SF, Fleshner M (2015) Running reduces uncontrollable stress-evoked serotonin and potentiates stress-evoked dopamine concentrations in the rat dorsal striatum. PLoS ONE 10:e0141898

    Article  PubMed  PubMed Central  Google Scholar 

  • De Kloet ER, Joëls M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475

    Article  PubMed  Google Scholar 

  • Dishman RK, Berthoud HR, Booth FW, Cotman CW, Edgerton VR, Fleshner MR, Gandevia SC, Gomez-Pinilla F, Greenwood BN, Hillman CH (2006) Neurobiology of exercise. Obesity 14:345–356

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  CAS  PubMed  Google Scholar 

  • Foley TE, Fleshner M (2008) Neuroplasticity of dopamine circuits after exercise: implications for central fatigue. NeuroMol Med 10:67–80

    Article  CAS  Google Scholar 

  • Godsil BP, Kiss JP, Spedding M, Jay TM (2013) The hippocampal–prefrontal pathway: the weak link in psychiatric disorders? Eur Neuropsychopharmacol 23:1165–1181

    Article  CAS  PubMed  Google Scholar 

  • Goekint M, Bos I, Heyman E, Meeusen R, Michotte Y, Sarre S (2012) Acute running stimulates hippocampal dopaminergic neurotransmission in rats, but has no influence on brain-derived neurotrophic factor. J Appl Physiol

  • Greenwood BN, Fleshner M (2008) Exercise, learned helplessness, and the stress-resistant brain. NeuroMol Med 10:81–98

    Article  CAS  Google Scholar 

  • Greenwood BN, Fleshner M (2011) Exercise, stress resistance, and central serotonergic systems. Exerc Sport Sci Rev 39:140

    Article  PubMed  PubMed Central  Google Scholar 

  • Greenwood BN, Foley TE, Day HE, Burhans D, Brooks L, Campeau S, Fleshner M (2005) Wheel running alters serotonin (5-HT) transporter, 5-HT1A, 5-HT1B, and alpha1b-adrenergic receptor mRNA in the rat raphe nuclei. Biol Psychiat 57:559–568

    Article  CAS  PubMed  Google Scholar 

  • Greenwood BN, Foley TE, Day HE, Campisi J, Hammack SH, Campeau S, Maier SF, Fleshner M (2003) Freewheel running prevents learned helplessness/behavioral depression: role of dorsal raphe serotonergic neurons. J Neurosci 23:2889–2898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwood BN, Strong PV, Loughridge AB, Day HE, Clark PJ, Mika A, Hellwinkel JE, Spence KG, Fleshner M (2012) 5-HT2C receptors in the basolateral amygdala and dorsal striatum are a novel target for the anxiolytic and antidepressant effects of exercise.

  • Heijnen S, Hommel B, Kibele A, Colzato LS (2015) Neuromodulation of aerobic exercise-a review. Front Psychol 6:1890

    PubMed  Google Scholar 

  • Heninger G, Delgado P, Charney D (1996) The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry 29:2–11

    Article  CAS  PubMed  Google Scholar 

  • Inoue T, Tsuchiya K, Koyama T (1994) Regional changes in dopamine and serotonin activation with various intensity of physical and psychological stress in the rat brain. Pharmacol Biochem Behav 49:911–920

    Article  CAS  PubMed  Google Scholar 

  • Jiang X, Xing G, Yang C, Verma A, Zhang L, Li H (2009) Stress impairs 5-HT2A receptor-mediated serotonergic facilitation of GABA release in juvenile rat basolateral amygdala. Neuropsychopharmacology 34:410–423

    Article  CAS  PubMed  Google Scholar 

  • Joëls M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10:459–466

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim T-K, Han P-L (2016) Physical exercise counteracts stress-induced upregulation of melanin-concentrating hormone in the brain and stress-induced persisting anxiety-like behaviors. Exp Neurobiol 25:163

    Article  PubMed  PubMed Central  Google Scholar 

  • Lapmanee S, Charoenphandhu J, Teerapornpuntakit J, Krishnamra N, Charoenphandhu N (2017) Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats. PLoS ONE 12:e0187671

    Article  PubMed  PubMed Central  Google Scholar 

  • Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10:434–445

    Article  CAS  PubMed  Google Scholar 

  • Mahar I, Bambico FR, Mechawar N, Nobrega JN (2014) Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects. Neurosci Biobehav Rev 38:173–192

    Article  CAS  PubMed  Google Scholar 

  • Marcinkiewcz CA, Mazzone CM, D’Agostino G, Halladay LR, Hardaway JA, DiBerto JF, Navarro M, Burnham N, Cristiano C, Dorrier CE, Tipton GJ, Ramakrishnan C, Kozicz T, Deisseroth K, Thiele TE, McElligott ZA, Holmes A, Heisler LK, Kash TL (2016) Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature 537:97–101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martin CB, Hamon M, Lanfumey L, Mongeau R (2014) Controversies on the role of 5-HT2C receptors in the mechanisms of action of antidepressant drugs. Neurosci Biobehav Rev 42:208–223

    Article  CAS  PubMed  Google Scholar 

  • Martin CB, Ramond F, Farrington DT, Aguiar AS Jr, Chevarin C, Berthiau AS, Caussanel S, Lanfumey L, Herrick-Davis K, Hamon M, Madjar JJ, Mongeau R (2013) RNA splicing and editing modulation of 5-HT(2C) receptor function: relevance to anxiety and aggression in VGV mice. Mol Psychiatry 18:656–665

    Article  CAS  PubMed  Google Scholar 

  • Martin JR, Ballard TM, Higgins GA (2002) Influence of the 5-HT2C receptor antagonist, SB-242084, in tests of anxiety. Pharmacol Biochem Behav 71:615–625

    Article  CAS  PubMed  Google Scholar 

  • McEwen BS (2012) The ever-changing brain: cellular and molecular mechanisms for the effects of stressful experiences. Dev Neurobiol 72:878–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moraska A, Deak T, Spencer RL, Roth D, Fleshner M (2000) Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol 279:R1321–R1329

    Article  CAS  PubMed  Google Scholar 

  • Murnane KS (2019) Serotonin 2A receptors are a stress response system: implications for post-traumatic stress disorder. Behav Pharmacol 30:151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oh D-R, Yoo J-S, Kim Y, Kang H, Lee H, Lm SJ, Choi E-j, Jung M-A, Bae D, Oh K-N (2018) Vaccinium bracteatum leaf extract reverses chronic restraint stress-induced depression-like behavior in mice: regulation of hypothalamic-pituitary-adrenal axis, serotonin turnover systems, and ERK/Akt phosphorylation. Front Pharmacol 9:604

    Article  PubMed  PubMed Central  Google Scholar 

  • Paxinos G, Watson C (2006) The rat brain in stereotaxic coordinates sixth edition by. Acad Press 170(10):1016

  • Pietrelli A, Di Nardo M, Masucci A, Brusco A, Basso N, Matkovic L (2018) Lifelong aerobic exercise reduces the stress response in rats. Neuroscience 376:94–107

    Article  CAS  PubMed  Google Scholar 

  • Prut L, Belzung C (2003) The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: a review. Eur J Pharmacol 463:3–33

    Article  CAS  PubMed  Google Scholar 

  • Rock EM, Limebeer CL, Petrie GN, Williams LA, Mechoulam R, Parker LA (2017) Effect of prior foot shock stress and Δ 9-tetrahydrocannabinol, cannabidiolic acid, and cannabidiol on anxiety-like responding in the light-dark emergence test in rats. Psychopharmacology 234:2207–2217

    Article  CAS  PubMed  Google Scholar 

  • Shin M-S, Park S-S, Lee J-M, Kim T-W, Kim Y-P (2017) Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats. J Exerc Rehabil 13:36

    Article  PubMed  PubMed Central  Google Scholar 

  • Shinohara R, Taniguchi M, Ehrlich AT, Yokogawa K, Deguchi Y, Cherasse Y, Lazarus M, Urade Y, Ogawa A, Kitaoka S (2018) Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice. Mol Psychiatry 23:1717–1730

    Article  CAS  PubMed  Google Scholar 

  • Sousa FSS, Birmann PT, Balaguez R, Alves D, Brüning CA, Savegnago L (2018) α-(Phenylselanyl) acetophenone abolishes acute restraint stress induced-comorbid pain, depression and anxiety-related behaviors in mice. Neurochem Int 120:112–120

    Article  CAS  PubMed  Google Scholar 

  • Sousa N, Almeida OF (2012) Disconnection and reconnection: the morphological basis of (mal) adaptation to stress. Trends Neurosci 35:742–751

    Article  CAS  PubMed  Google Scholar 

  • Suwabe K, Byun K, Hyodo K, Reagh ZM, Roberts JM, Matsushita A, Saotome K, Ochi G, Fukuie T, Suzuki K (2018) Rapid stimulation of human dentate gyrus function with acute mild exercise. Proc Natl Acad Sci 115:10487–10492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Torres I, Gamaro G, Vasconcellos A, Silveira R, Dalmaz C (2002) Effects of chronic restraint stress on feeding behavior and on monoamine levels in different brain structures in rats. Neurochem Res 27:519–525

    Article  CAS  PubMed  Google Scholar 

  • Tuzcu M, Baydas G (2006) Effect of melatonin and vitamin E on diabetes-induced learning and memory impairment in rats. Eur J Pharmacol 537:106–110

    Article  CAS  PubMed  Google Scholar 

  • Uysal N, Kiray M, Sisman A, Camsari U, Gencoglu C, Baykara B, Cetinkaya C, Aksu I (2015) Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotech Histochem 90:55–68

    Article  CAS  PubMed  Google Scholar 

  • Vaidya VA, Terwilliger RMZ, Duman RS (1999) Role of 5-HT2A receptors in the stress-induced down-regulation of brain-derived neurotrophic factor expression in rat hippocampus. Neurosci Lett 262:1–4

    Article  CAS  PubMed  Google Scholar 

  • Van Praag H, Fleshner M, Schwartz MW, Mattson MP (2014) Exercise, energy intake, glucose homeostasis, and the brain. J Neurosci 34:15139–15149

    Article  PubMed  PubMed Central  Google Scholar 

  • Vicente MA, Zangrossi H Jr (2012) Serotonin-2C receptors in the basolateral nucleus of the amygdala mediate the anxiogenic effect of acute imipramine and fluoxetine administration. Int J Neuropsychopharmacol 15:389–400

    Article  CAS  PubMed  Google Scholar 

  • Voss MW, Vivar C, Kramer AF, van Praag H (2013) Bridging animal and human models of exercise-induced brain plasticity. Trends Cogn Sci 17:525–544

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang J, Cheng C, Xin C, Wang Z (2019) The antidepressant-like effect of flavonoids from Trigonella foenum-graecum seeds in chronic restraint stress mice via modulation of monoamine regulatory pathways. Molecules 24:1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wood MD, Reavill C, Trail B, Wilson A, Stean T, Kennett GA, Lightowler S, Blackburn TP, Thomas D, Gager TL, Riley G, Holland V, Bromidge SM, Forbes IT, Middlemiss DN (2001) SB-243213; a selective 5-HT2C receptor inverse agonist with improved anxiolytic profile: lack of tolerance and withdrawal anxiety. Neuropharmacology 41:186–199

    Article  CAS  PubMed  Google Scholar 

  • Yankelevitch-Yahav R, Franko M, Huly A, Doron R (2015) The forced swim test as a model of depressive-like behavior. J Vis Exp

  • Zhang R, Peng Z, Wang H, Xue F, Chen Y, Wang Y, Wang H, Tan Q (2014) Gastrodin ameliorates depressive-like behaviors and up-regulates the expression of BDNF in the hippocampus and hippocampal-derived astrocyte of rats. Neurochem Res 39:172–179

    Article  CAS  PubMed  Google Scholar 

  • Zou J, Yuan J, Lv S, Tu J (2010) Effects of exercise on behavior and peripheral blood lymphocyte apoptosis in a rat model of chronic fatigue syndrome. J Huazhong Univ Sci Technol Med Sci 30:258–264

    Article  PubMed  Google Scholar 

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Funding

This project was supported by TUBITAK (The Scientific and Technological Research Council of Turkey) (Grant no: 114S179).

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Authors and Affiliations

  1. Department of Physiotherapy and Rehabilitation, Faculty of Health Sciences, Firat University, Elazig, Turkey

    Zubeyde Ercan

  2. Department of Physiology, Faculty of Medicine, Balikesir University, Balikesir, Turkey

    Ozgur Bulmus

  3. Department of Physiology, Faculty of Medicine, Firat University, Elazig, Turkey

    Emine Kacar

  4. Department of Biophysics, Faculty of Medicine, Firat University, Elazig, Turkey

    Ihsan Serhatlioglu & Gokhan Zorlu

  5. Department of Physiology, Faculty of Medicine, Istanbul Okan University, Istanbul, Turkey

    Haluk Kelestimur

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  1. Zubeyde Ercan
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Conception, design of research, acquisition, analysis or interpretation of data; and drafting of the work or revising it critically for important intellectual content: all authors. Supervision: H.K. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Correspondence to Zubeyde Ercan.

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All experimental procedures were approved by the Local Ethics Committee for the Experimental Animal Research of Firat University (Approval no: 2014/34).

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Ercan, Z., Bulmus, O., Kacar, E. et al. Treadmill Exercise Improves Behavioral and Neurobiological Alterations in Restraint-Stressed Rats. J Mol Neurosci 73, 831–842 (2023). https://doi.org/10.1007/s12031-023-02159-2

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