Effects of Hippocampal Microinjection of Irisin, an Exercise-Induced Myokine, on Spatial and Passive Avoidance Learning and Memory in Male Rats

  • Saeed Mohammadi
  • Shahrbanoo Oryan
  • Alireza KomakiEmail author
  • Akram Eidi
  • Mohammad Zarei


Irisin is a soluble and exercise-induced myokine and/or adipokine hormone; generated by FNDC5 (a gene precursor) and also, it can ameliorate both motor performance and hippocampal neurogenesis. This study was designed to evaluate the effect of intra-dentate gyrus (DG) microinjection of irisin on both spatial and passive avoidance (PA) learning and memory in male rats. In this study, male Wistar rats were randomly divided into a control group (saline), irisin—receiving group (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide-receiving group (DMSO) Morris Water Maze (MWM) and Shuttle Box (SB) tests were used to evaluate spatial and PA learning and memory, respectively. The results of MWM test showed that treatment with irisin (1 and 1.5 μg/rat) in day 3 and 4 of the training (acquisition) period caused a significant reduction in escape latency of rats in experimental group compared to control group. Subsequently, the results of probe-trial experiment in day 5 showed that treatment with irisin (1.5 μg/rat) enhanced formation of short-term memory compared to control group. In the retention trial, the results of SB test revealed that, all rats treated by irisin (0.5, 1, and 1.5 μg/rat) showed an increase in step-through latency (STLr) compared to control group (p < 0.05, p < 0.001, and p < 0.01, respectively). Also, the administration of irisin caused a decrease in the time spent in the dark box by rats. The results of the present study suggested that microinjection of irisin has led to the enhancement of both spatial and passive avoidance learning and memory. Further studies are needed to investigate how exactly the treatment with irisin influences memory and learning at the molecular level.


Irisin Hippocampus Learning Memory Dentate gyrus 



This research was supported by Islamic Azad University of Tehran, Science and Research Branch, Iran, which was extracted from the Ph.D. thesis of Saeed Mohammadi. The authors would like to express their gratitude to the staff of the Neurophysiology Research Center of Hamadan University of Medical Sciences for helping us to carry out this project.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Akbari E, Naghdi N, Motamedi F (2006) Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav Brain Res 173:47–52CrossRefGoogle Scholar
  2. Ardeshiri MR, Hosseinmardi N, Akbari E (2017) The effect of orexin 1 and orexin 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task. Physiol Behav 174:42–48CrossRefGoogle Scholar
  3. Asadbegi M, Yaghmaei P, Salehi I, Komaki A, Ebrahim-Habibi A (2017) Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet-fed rats. Metab Brain Dis 32:827–839CrossRefGoogle Scholar
  4. Asadbegi M et al (2018) Effects of thymol on amyloid-β-induced impairments in hippocampal synaptic plasticity in rats fed a high-fat diet. Brain Res Bull 137:338CrossRefGoogle Scholar
  5. Bailey CH, Kandel ER, Si K (2004) The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 44:49–57CrossRefGoogle Scholar
  6. Boström P et al (2012) A PGC1-[agr]-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468CrossRefGoogle Scholar
  7. Brynskikh A, Warren T, Zhu J, Kipnis J (2008) Adaptive immunity affects learning behavior in mice. Brain Behav Immun 22:861–869CrossRefGoogle Scholar
  8. Butt ZD, Hackett JD, Volkoff H (2017) Irisin in goldfish (Carassius auratus): effects of irisin injections on feeding behavior and expression of appetite regulators, uncoupling proteins and lipoprotein lipase, and fasting-induced changes in FNDC5 expression. Peptides 90:27–36CrossRefGoogle Scholar
  9. Carlini VP, Monzón MaE, Varas MM, Cragnolini AB, Schiöth HB, Scimonelli TN, de Barioglio SR (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun 299:739–743CrossRefGoogle Scholar
  10. Carobrez AP, Kincheski GC, Bertoglio LJ (2015) Elevated plus maze. In: Encyclopedia of psychopharmacology. Springer, New York, pp 603–606Google Scholar
  11. Cheng A et al (2012) Involvement of PGC-1α in the formation and maintenance of neuronal dendritic spines. Nat Commun 3:1250CrossRefGoogle Scholar
  12. Chiavaroli A et al (2017) Effects of central fibroblast growth factor 21 and irisin in anxiety-like behavior. J Biol Regul Homeostat Agents 31:797Google Scholar
  13. Chieffi S et al (2017) Exercise influence on hippocampal function: possible involvement of orexin-A. Front Physiol 8:85Google Scholar
  14. Dameni S, Janzadeh A, Yousefifard M, Nasirinezhad F (2018) The effect of intrathecal injection of irisin on pain threshold and expression rate of GABAB receptors in peripheral neuropathic pain model. J Chem Neuroanat 91:17–26CrossRefGoogle Scholar
  15. Daumas S et al (2017) The kinase function of MSK1 regulates BDNF signaling to CREB and basal synaptic transmission, but is not required for hippocampal long-term potentiation or spatial memory. eNeuro 4:0212–0216CrossRefGoogle Scholar
  16. de Almeida AA, Da Silva SG, Lopim GM, Campos DV, Fernandes J, Cabral FR, Arida RM (2017) Resistance exercise reduces seizure occurrence, attenuates memory deficits and restores BDNF signaling in rats with chronic epilepsy. Neurochem Res 42:1230–1239CrossRefGoogle Scholar
  17. Devan BD, Pistell PJ, Duffy KB, Kelley-Bell B, Spangler EL, Ingram DK (2014) Phosphodiesterase inhibition facilitates cognitive restoration in rodent models of age-related memory decline. NeuroRehabilitation 34:101–111Google Scholar
  18. Dun SL, Lyu R-M, Chen Y-H, Chang J-K, Luo JJ, Dun NJ (2013) Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience 240:155–162CrossRefGoogle Scholar
  19. Erickson KI et al (2011) Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci 108:3017–3022CrossRefGoogle Scholar
  20. Farmer J, Zhao Xv, Van Praag H, Wodtke K, Gage F, Christie B (2004) Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience 124:71–79CrossRefGoogle Scholar
  21. Ferrante C et al (2016) Central inhibitory effects on feeding induced by the adipo-myokine irisin. Eur J Pharmacol 791:389–394CrossRefGoogle Scholar
  22. Flynn KM, Newbold RR, Ferguson SA (2002) Multigenerational exposure to dietary nonylphenol has no severe effects on spatial learning in female rats. Neurotoxicology 23:87–94CrossRefGoogle Scholar
  23. Gamal MM, Tork OM, Eshra MA, Magdy S, Rashed LA (2016) Role of endogenous irisin, a novel myokine, in cognitive functions and insulin sensitivity in exercised diabetic rats Kasr Al Ainy. Med J 22:136Google Scholar
  24. Ghosh A, Carnahan J, Greenberg ME (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263:1618–1623CrossRefGoogle Scholar
  25. Kee N, Teixeira CM, Wang AH, Frankland PW (2007) Preferential incorporation of adult-generated granule cells into spatial memory networks in the dentate gyrus. Nat Neurosci 10:355CrossRefGoogle Scholar
  26. Khodamoradi N, Komaki A, Salehi I, Shahidi S, Sarihi A (2015) Effect of vitamin E on lead exposure-induced learning and memory impairment in rats. Physiol Behav 144:90–94CrossRefGoogle Scholar
  27. Komaki A, Esteky H (2005) Effects of neonatal C-fiber depletion on neocortical long-term potentiation and depression. Brain Res 1054:135–142CrossRefGoogle Scholar
  28. Komaki A, Shahidi S, Lashgari R, Haghparast A, Malakouti SM, Noorbakhsh SM (2007) Effects of GABAergic inhibition on neocortical long-term potentiation in the chronically prepared rat. Neurosci Lett 422:181–186CrossRefGoogle Scholar
  29. Laursen SE, Belknap J (1986) Intracerebroventricular injections in mice: some methodological refinements. J Pharmacol Methods 16:355–357CrossRefGoogle Scholar
  30. Leal G, Comprido D, Duarte CB (2014) BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology 76:639–656CrossRefGoogle Scholar
  31. Lewis S (2017) Learning and memory: holding the space. Nat Rev Neurosci 18:711CrossRefGoogle Scholar
  32. Li H, Liang A, Guan F, Fan R, Chi L, Yang B (2013) Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. Brain Res 1531:1–8CrossRefGoogle Scholar
  33. Lisman J, Buzsáki G, Eichenbaum H, Nadel L, Rangananth C, Redish AD (2017) Viewpoints: how the hippocampus contributes to memory navigation cognition. Nature 20:1Google Scholar
  34. Liu YF et al (2009) Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain-derived neurotrophic factor and synaptotagmin. J Physiol 587:3221–3231CrossRefGoogle Scholar
  35. Luo CX et al (2007) Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke. J Neurosci Res 85:1637–1646CrossRefGoogle Scholar
  36. Messina G et al (2016) Exercise increases the level of plasma orexin A in humans. J Basic Clin Physiol Pharmacol 27:611–616CrossRefGoogle Scholar
  37. Michalak A, Biala G (2017) Calcium homeostasis and protein kinase/phosphatase balance participate in nicotine-induced memory improvement in passive avoidance task in mice. Behav Brain Res 317:27–36CrossRefGoogle Scholar
  38. Moon H-S, Dincer F, Mantzoros CS (2013) Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. Metabolism 62:1131–1136CrossRefGoogle Scholar
  39. Moon HY et al (2016) Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24:332–340CrossRefGoogle Scholar
  40. Moradkhani S, Salehi I, Abdolmaleki S, Komaki A (2015) Effect of Calendula officinalis hydroalcoholic extract on passive avoidance learning and memory in streptozotocin-induced diabetic rats. Ancient Sci Life 34:156CrossRefGoogle Scholar
  41. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11:47CrossRefGoogle Scholar
  42. Naghdi N, Nafisy N, Majlessi N (2001) The effects of intrahippocampal testosterone and flutamide on spatial localization in the Morris water maze. Brain Res 897:44–51CrossRefGoogle Scholar
  43. Nakagawa S et al (2002) Regulation of neurogenesis in adult mouse hippocampus by cAMP and the cAMP response element-binding protein. J Neurosci 22:3673–3682CrossRefGoogle Scholar
  44. Navarro A, Gomez C, López-Cepero JM, Boveris A (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol-Regul Integr Compar Physiol 286:R505–Rr511CrossRefGoogle Scholar
  45. Paxinos G, Watson C (2017) The rat brain in stereotaxic coordinates: compact 7th Edition. Academic press, CambridgeGoogle Scholar
  46. Perakakis N, Triantafyllou GA, Fernández-Real JM, Huh JY, Park KH, Seufert J, Mantzoros CS (2017) Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol 13:324–337CrossRefGoogle Scholar
  47. Piya MK et al (2014) The identification of irisin in human cerebrospinal fluid: influence of adiposity, metabolic markers, and gestational diabetes. Am J Physiol-Endocrinol Metab 306:E512–E518CrossRefGoogle Scholar
  48. Silveira APC et al (2018) Continuous and not continuous 2-week treadmill training enhances the performance in the passive avoidance test in ischemic gerbils. Neurosci Lett 665:170–175CrossRefGoogle Scholar
  49. Sumsuzzman DM, Hong Y (2017) The novel exercise-induced factor irisin exerts neuroprotection and regulates microglial polarization and oxidative stress in a streptozotocin-induced rat model of sporadic alzheimer’s disease. Apoptosis 2:7Google Scholar
  50. Suzuki WA (2016) How Body Affects Brain Cell metabolism 24:192–193Google Scholar
  51. Tamura M, Spellman TJ, Rosen AM, Gogos JA, Gordon JA (2017) Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. Nat Commun 8:2182CrossRefGoogle Scholar
  52. Teufel A, Malik N, Mukhopadhyay M, Westphal H (2002) Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 297:79–83CrossRefGoogle Scholar
  53. Uysal N et al (2018) Regular aerobic exercise correlates with reduced anxiety and incresed levels of irisin in brain and white adipose tissue. Neurosci Lett 676:92CrossRefGoogle Scholar
  54. Vaynman S, Ying Z, Gomez-Pinilla F (2004) Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 20:2580–2590CrossRefGoogle Scholar
  55. Wang S, Pan J (2016) Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism. Biochem Biophys Res Commun 474:22CrossRefGoogle Scholar
  56. Wrann CD (2015) FNDC5/Irisin–their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast 1:55–61CrossRefGoogle Scholar
  57. Wrann CD et al (2013) Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 18:649–659CrossRefGoogle Scholar
  58. Wu J et al (2012) Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150:366–376CrossRefGoogle Scholar
  59. Yin K et al (2017) CART modulates beta-amyloid metabolism-associated enzymes and attenuates memory deficits in APP/PS1 mice. Neurol Res 39:885–894CrossRefGoogle Scholar
  60. Zarrinkalam E, Ranjbar K, Salehi I, Kheiripour N, Komaki A (2018) Resistance training and hawthorn extract ameliorate cognitive deficits in streptozotocin-induced diabetic rats. Biomed Pharmacother 97:503–510CrossRefGoogle Scholar
  61. Zhang W et al (2015) Irisin: a myokine with locomotor activity. Neurosci Lett 595:7–11CrossRefGoogle Scholar
  62. Zhao W et al (2011) Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis. Mol Neurodegenerat 6:51CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Saeed Mohammadi
    • 1
  • Shahrbanoo Oryan
    • 1
    • 3
  • Alireza Komaki
    • 2
    Email author
  • Akram Eidi
    • 1
  • Mohammad Zarei
    • 2
  1. 1.Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
  2. 2.Neurophysiology Research CenterHamadan University of Medical SciencesHamadanIran
  3. 3.Department of Biology, Faculty of ScienceKharazmy UniversityTehranIran

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