Comparison of high-intensity interval training and moderate-intensity continuous training in their effects on behavioral functions and CORT levels in streptozotocin-induced diabetic mice


Neurodegenerative disorders, such as deficits in cognition and motor coordination, are associated with diabetes mellitus (DM). It is believed that Corticosterone (CORT) has a role in behavioral functions. Exercise is beneficial on neurobehavioral impairment in DM; however, the debate about the value of high-intensity interval training (HIIT) vs. moderate-intensity continuous training (MICT) has been long-lasting. In the present study, we evaluated the effects of HIIT and MICT on cognitive performance, motor coordination, and serum CORT level using streptozotocin (STZ)–induced diabetes mice. We used STZ (50 mg/kg, i.p.) for five consecutive days to induce diabetes, followed by treatment with MICT and HIIT for 8 weeks. STZ-induced chronic diabetes significantly induced cognitive deficiency and motor coordination impairment in mice (p < 0.001). In addition, chronic diabetes significantly up-regulated CORT compared to controlled mice (p < 0.001). Chronic treatment with MICT and HIIT significantly reversed the diabetes-mediated motor coordination impairment and cognitive deficiency (p = 0.04 and p < 0.001 vs. STZ, respectively) by the adjustment of serum CORT level in diabetes mice (p = 0.037 and p = 0.001 vs. STZ, respectively). Also, it was found that HIIT significantly improved motor coordination compared to MICT (p = 0.043). There was also a significant negative correlation between serum CORT level and inhibitory avoidance (p = 0.012( and rotarod (p = 0.037) tests. Diabetes-mediated neurobehavioral impairment and the up-regulation of CORT substantially attenuated following MICT and HIIT treatment. However, HIIT might be more effective in diabetes-induced neurobehavioral impairment.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ et al (2011) National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: Systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2.7 million participants. Lancet 2 378(9785):31–40.

    CAS  Article  Google Scholar 

  2. 2.

    Patel SS, Udayabanu M (2017) Effect of natural products on diabetes associated neurological disorders. Rev Neurosci 1 28(3):271–293.

    Article  Google Scholar 

  3. 3.

    Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93(1):137–188.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tripathi BK, Srivastava AK (2006) Diabetes mellitus: complications and therapeutics. Med Sci Monit 12(7):130–147

    Google Scholar 

  5. 5.

    McCarthy AM, Lindgren S, Mengeling MA, Tsalikian E, Engvall JC (2002) Effects of diabetes on learning in children. Pediatrics 109(1):E9.

    Article  PubMed  Google Scholar 

  6. 6.

    Fan YC, Hsu JL, Tung HY, Chou CC, Bai CH (2017) Increased dementia risk predominantly in diabetes mellitus rather than in hypertension or hyperlipidemia: a population-based cohort study. Alzheimers Res Ther 9(1):7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Biessels GJ, Despa F (2018) Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol 14(10):591–604.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Albai O, Frandes M, Timar R, Roman D, Timar B (2019) Risk factors for developing dementia in type 2 diabetes mellitus patients with mild cognitive impairment. Neuropsychiatr Dis Treat 15:167–175.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Ites KI, Anderson EJ, Cahill ML, Kearney JA, Post EC, Gilchrist LS (2011) Balance interventions for diabetic peripheral neuropathy: a systematic review. J Geriatr Phys Ther 34(3):109–116.

    Article  PubMed  Google Scholar 

  10. 10.

    Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ et al (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86(1):32–38.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Lieberman D, Friger M, Lieberman D (2007) Rehabilitation outcome following hip fracture surgery in elderly diabetics: a prospective cohort study of 224 patients. Disabil Rehabil 28 29(4):339–345.

    Article  Google Scholar 

  12. 12.

    Pijpers E, Ferreira I, de Jongh RT, Deeg DJ, Lips P, Stehouwer CD et al (2012) Older individuals with diabetes have an increased risk of recurrent falls: analysis of potential mediating factors: the longitudinal ageing study Amsterdam. Age Ageing 41(3):358–365.

    Article  PubMed  Google Scholar 

  13. 13.

    Walley M, Anderson EG, Pippen MW, Maitland G (2014) Dizziness and loss of balance in individuals with diabetes: relative contribution of vestibular versus somatosensory dysfunction. Clinical 32(2):76–77.

    Article  Google Scholar 

  14. 14.

    Afrazi S, Esmaeili-Mahani S (2014) Allopregnanolone suppresses diabetes-induced neuropathic pain and motor deficit through inhibition of GABAA receptor down-regulation in the spinal cord of diabetic rats. Iran J Basic Med Sci 17(5):312–317.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Palleria C, Leoa A, Andreozzib F, Citraroa R, Iannonec M, Spigab R et al (2017) Liraglutide prevents cognitive decline in a rat model of streptozotocin-induced diabetes independently from its peripheral metabolic effects Behav. Brain Res 15(321):157–169.

    CAS  Article  Google Scholar 

  16. 16.

    Wang J, Wanag L, Zhou J, Qin A, Chen Z (2018) The protective effect of formononetin on cognitive impairment in streptozotocin (STZ)-induced diabetic mice. Biomed Pharmacother 106:1250–1257.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11(3):309–317.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    ElBatsh MM (2015) Antidepressant-like effect of simvastatin in diabetic rats. Can J Physiol Pharmacol 93(8):649–656.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Groeneweg FL, Karst H, de Kloet ER, Joëls M (2011) Rapid non-genomic effects of corticosteroids and their role in the central stress response. J Endocrinol 209(2):153–167.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Kurek A, Kucharczyk M, Detka J, Ślusarczyk J, Trojan E, Głombik K et al (2016) Pro-apoptotic action of corticosterone in hippocampal organotypic cultures. Neurotox Res 30(2):225–238.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Kott JM, Mooney-Leber SM, Shoubah FA, Brummelte S (2016) Effectiveness of different corticosterone administration methods to elevate corticosterone serum levels, induce depressive-like behavior, and affect neurogenesis levels in female rats. Neuroscience 312:201–214

    CAS  Article  Google Scholar 

  22. 22.

    Zhang H, Zhao Y, Wang Z (2015) Chronic corticosterone exposure reduces hippocampal astrocyte structural plasticity and induces hippocampal atrophy in mice. Neurosci Lett 10(592):76–81

    CAS  Article  Google Scholar 

  23. 23.

    Miyake H, Mori D, Katayama T, Fujiwara S, Sato Y, Azuma K, Kubo KY (2016) Novel stress increases hypothalamic-pituitary-adrenal activity in mice with a raised bite. Arch Oral Biol 68:55–60

    CAS  Article  Google Scholar 

  24. 24.

    Mori D, Miyake H, Mizutani K, Shimpo K, Sonoda S, Yamamoto T, Fujiwara S, Kubo KY (2016) Effects of occlusal disharmony on the hippocampal dentate gyrus in aged senescence-accelerated mouse prone 8 (SAMP8). Arch Oral Biol 65:95–101

    Article  Google Scholar 

  25. 25.

    Pandya CD, Crider A, Pillai A (2014) Glucocorticoid regulates parkin expression in mouse frontal cortex: implications in schizophrenia. Curr Neuropharmacol 12:100–107

    CAS  Article  Google Scholar 

  26. 26.

    Selvan PK, Malathi M, Rajan RR (2016) Effect of 4-Allyl-2-methoxyphenol (eugenol) on motor co-ordination in subacute restraint stress Induced wistar albino rats. J App Pharm Sci 6(11):120–125.

    CAS  Article  Google Scholar 

  27. 27.

    Heo YM, Shin MS, Lee JM, Kim CJ, Baek SB, Kim KH, Baek SS (2014) Treadmill exercise ameliorates short-term memory disturbance in scopolamine-induced amnesia rats. Int Neurourol J 18(1):16–22.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Lee J, Shin ME, Ji E, Kim TW, Cho H, Kim CJ et al (2014) Treadmill exercise improves motor coordination through ameliorating Purkinje cell loss in amyloid beta23-35-induced Alzheimer’s disease rats. J Exerc Rehabil 10(5):258–264.

    Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lee JM, Kim TW, Park SS, Han JH, Shin MS, Lim BV et al (2018) Treadmill exercise improves motor function by suppressing Purkinje cell loss in Parkinson disease rats. Int Neurourol J 22(Suppl 3):S147–155.

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Sim YJ (2014) Treadmill exercise alleviates impairment of spatial learning ability through enhancing cell proliferation in the streptozotocin-induced Alzheimer's disease rats. J Exerc Rehabil 30 10(2):81–88.

    Article  Google Scholar 

  31. 31.

    Kang EB, Cho JY (2014) Effects of treadmill exercise on brain insulin signaling and β-amyloid in intracerebroventricular streptozotocin induced-memory impairment in rats. J Exerc Nutrition Biochem 18(1):89–96.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Shen Y, Huang G, McCormick BP, Song T, Xu X (2017) Effects of high-intensity interval versus mild-intensity endurance training on metabolic phenotype and corticosterone response in rats fed a high-fat or control diet. PLoS ONE 12(7):e0181684.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Jiménez-Maldonado A, Rentería I, García-Suárez PC, Moncada-Jiménez J, Freire-Royes LF (2018) The impact of high-Intensity Interval training on Brain Derived Neurotrophic Factor in brain: a mini-review. Front Neurosci 12:839.

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Patel SS, Ray RS, Sharma A, Mehta V, Katyal A, Udayabanu M (2018) Antidepressant and anxiolytic like effects of Urtica dioicaleaves in streptozotocin induced diabetic mice. Metab Brain Dis 33(4):1281–1292.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Wang N, Liu Y, Ma Y, Wen D (2017) High-intensity interval versus moderate-intensity continuous training: Superior metabolic benefits in diet-induced obesity mice. Life Sci 15(191):122–131.

    CAS  Article  Google Scholar 

  36. 36.

    Kemi OJ, Loennechen JP, Wisløff U, Ellingsen Ø (2002) Intensitycontrolled treadmill running in mice: cardiac and skeletal muscle hypertrophy. J Appl Physiol 93(4):1301–1309.

    Article  PubMed  Google Scholar 

  37. 37.

    de Almeida AA, Gomes da Silva S, Lopim GM, Vannucci Campos D, Fernandes J, Cabral FR (2017) Resistance exercise reduces seizure occurrence, attenuates memory deficits and restores BDNF signaling in rats with chronic epilepsy. Neurochem Res 42(4):1230–1239.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Wagner JM, Sichler ME, Schleicher EM, Franke TN, Irwin C, Löw MJ et al (2019) Analysis of motor function in the Tg4–42 mouse model of Alzheimer’s disease. Front Behav Neurosci 13:107.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Liu P, Li Y, Yang W, Liu D, Ji X, Chi T et al (2019) Prevention of Huntington’s disease-like behavioral deficits in R6/1 mouse by tolfenamic acid is associated with decreases in mutant huntingtin and oxidative stress. Oxid Med Cell Longev 26(2019):4032428.

    CAS  Article  Google Scholar 

  40. 40.

    Mätlik K, Võikar V, Vilenius C, Kulesskaya N, Andressoo J (2018) Two-fold elevation of endogenous GDNF levels in mice improves motor coordination without causing side-effects. Sci Rep 8:11861.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Robinson SA, Brookshire BR, Lucki I (2016) Corticosterone exposure augments sensitivity to the behavioral and neuroplastic effects of fluoxetine in C57BL/6 mice. Neurobiol Stress 30(3):34–42

    Article  Google Scholar 

  42. 42.

    Dranovsky A, Hen R (2014) Hippocampal neurogenesis: regulation by stress and antidepressants. Biol Psychiatry 59(12):1136–1143

    Article  Google Scholar 

  43. 43.

    Grigoryan G, Lonnemann N, Korte M (2019) Immune challenge alters reactivity of hippocampal noradrenergic system in prenatally stressed aged mice. Neural Plasticity 2019:3152129.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Ngoupaye GT, Yassi FB, Bahane DAN, Bum EN (2018) Combined corticosterone treatment and chronic restraint stress lead to depression associated with early cognitive deficits in mice. Metab Brain Dis 33(2):421–431.

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Olescowicz G, Neis VB, Fraga DB, Rosa PB, Azevedo DP, Melleu FF et al (2018) Antidepressant and pro-neurogenic effects of agmatine in a mouse model of stress induced by chronic exposure to corticosterone. Prog Neuropsychopharmacol Biol Psychiatry 2(81):395–407.

    CAS  Article  Google Scholar 

  46. 46.

    Horowitz JM, Pastor DM, Kar S, Arinsburg SA, Hallas BH, Torres G (2003) Regulation of hippocampal parkin protein by corticosteroids. NeuroReport 14:2327–2330

    CAS  Article  Google Scholar 

  47. 47.

    Srivastava A, Tang MX, Mejia-Santana H, Rosado L, Louis ED, Caccappolo E et al (2011) The relation between depression and parkin genotype: the CORE-PD study. Parkinsonism Relat Disord 17:740–744

    CAS  Article  Google Scholar 

  48. 48.

    Shen JD, Ma LG, Hu CY, Pei YY, Jin SL, Fang XY et al (2016) Berberine up-regulates the BDNF expression in hippocampus and attenuates corticosterone-induced depressive-like behavior in mice. Neurosci Lett 12(614):77–82

    Article  Google Scholar 

  49. 49.

    Li YC, Liu YM, Shen JD, Chen JJ, Pei YY, Fang XY (2016) Resveratrol ameliorates the depressive-like behaviors and metabolic abnormalities induced by chronic corticosterone Injection. Molecules 13 21(10):pii: E1341

    Article  Google Scholar 

  50. 50.

    Beheshti F, Hosseini M, Hashemzehi M, Soukhtanloo M, Khazaei M, Shafei M (2019) The effects of PPAR-γ agonist pioglitazone on hippocampal cytokines, brain-derived neurotrophic factor, memory impairment, and oxidative stress status in lipopolysaccharide-treated rats. Iran J Basic Med Sci 22(8):940–948.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Eskandari-Roozbahani N, Shomali T, Taherianfard M (2019) Neuroprotective effect of zataria multiflora essential oil on rats with Alzheimer disease: a mechanistic study. Basic Clin Neurosci 10(1):85–97.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Bosman LWJ, Hartmann J, Barski JJ, Lepier A, Noll-Hussong M, Reichardt LF (2006) Requirement of TrkB for synapse elimination in developing cerebellar Purkinje cells. Brain Cell Biol 35(1):87–101.

    CAS  Article  PubMed  Google Scholar 

  53. 53.

    Sherrard RM, Dixon KJ, Bakouche J, Rodger J, Lemaigre-dubreuil Y, Mariani J (2009) Differential expression of TrkB isoforms switches climbing fiber-purkinje cell synaptogenesis to selective synapse elimination. Dev Neurobiol 69(10):647–662.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Choo M, Miyazaki T, Yamazaki M, Kawamura M, Nakazawa T, Zhang J et al (2017) Retrograde BDNF to TrkB signaling promotes synapse elimination in the developing cerebellum. Nature Commun 8(1):195.

    CAS  Article  Google Scholar 

  55. 55.

    Mellesmoen A, Sheeler C, Ferro A, Rainwater O, Cvetanovic M (2019) Brain Derived Neurotrophic Factor (BDNF) delays onset of pathogenesis in transgenic mouse model of spinocerebellar ataxia Type 1 (SCA1). Front Cell Neurosci 12:509.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Razgado-Hernandez LF, Espadas-Alvarez AJ, Reyna-Velazquez P, Sierra-Sanchez A, Anaya-Martinez V, Jimenez-Estrada I et al (2015) The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease. PLoS ONE 10(2):e0117391

    Article  Google Scholar 

  57. 57.

    Rose AJ, Vegiopoulos A, Herzig S (2010) Role of glucocorticoids and the glucocorticoid receptor in metabolism: insights from genetic manipulations. J Steroid Biochem Mol Biol 122(1–3):10–20.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Weston KS, Wisløff U, Coombes JS (2014) High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. Br J Sports Med 48:1227–1234.

    Article  PubMed  Google Scholar 

  59. 59.

    Fisher G, Brown AW, Bohan Brown MM, Alcorn A, Noles C, Winwood L et al (2015) High intensity interval- vs moderate intensity- training for improving cardiometabolic health in overweight or obese males: a randomized controlled trial. PLoS ONE 10:e0138853.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Wewege MA, Ahn D, Yu J, Liou K, Keech A (2018) High-intensity interval training for patients with cardiovascular disease-Is It safe? A systematic review. J Am Heart Associat 7(21):e009305.

    Article  Google Scholar 

Download references


This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information



Corresponding author

Correspondence to Ayoob Sabaghi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical approval

This article does not contain any studies with human participant performed by any of the authors.

Informed consent

For this type of study, formal consent is not required.


Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sabaghi, A., Heirani, A., Yousofvand, N. et al. Comparison of high-intensity interval training and moderate-intensity continuous training in their effects on behavioral functions and CORT levels in streptozotocin-induced diabetic mice. Sport Sci Health (2020).

Download citation


  • Neurobehavioral
  • Exercise
  • Diabetes
  • CORT
  • Mice