open access

Ahead of Print
ORIGINAL ARTICLES
Published online: 2019-02-25
Submitted: 2018-11-30
Accepted: 2019-01-31
Get Citation

Long-term treadmill exercise upregulated hippocampal learning-related genes without improving cognitive behavior in social isolated rats

Seval Keloglan, Leyla Sahin, Ozge Selin Cevik
DOI: 10.5603/FM.a2019.0018
·
Pubmed: 30816552

open access

Ahead of Print
ORIGINAL ARTICLES
Published online: 2019-02-25
Submitted: 2018-11-30
Accepted: 2019-01-31

Abstract

Background: Some environment enrichments such as exercise has been reported to improve the diminished cognitive functions and related gene expression.  Therefore, we aimed to investigate the effects of prolonged treadmill exercise on long-term learning and hippocampal gene expression, which involves learning and plasticity.

Materials and methods: Male Wistar rats (n=32) randomly assigned into four groups: control (C), social isolation (SI), exercised (E), social isolation+exercise (SE) during postnatal days (PNDs) 21-34. Social isolation protocol was applied during 14 days by placing the rat alone in a cage. Rats were exercised daily, 5 days per week, for overall 4 weeks. Finally, learning performance was evaluated by the novel object recognition test. At the end of learning test, the rats were decapitated to isolate hippocampus tissues for learning related gene expression such as N-methyl-d-aspartate receptor (NMDAR) subunit genes (Grin1, Grin2a, Grin2b) and cyclin dependent kinase 5 (Cdk5), Cdk5 regulatory subunit p35 (Cdk5r), activity-regulated, cytoskeletal-associated protein (Arc), the immediate early gene (c-Fos, a marker of neuronal activation), doublecortin (DCX), Achaete-scute homolog 1 (ASCL1), brain-derived neurotrophic factor (BDNF) by RT-PCR.

Results: Grin1, NMDAR subunit gene expression was increased significantly in E group compared to other groups. Grin2b, NMDAR subunit gene expression was increased in E compared to the SI group. Cdk5 level increased in E compared to the SE group. The ASCL1 gene expression increased in E group compare to the SE group. The DCX gene expression increasing in C compared to SI and SE groups. 

Conclusions: Taken together these findings may point out that long-term social isolation down-regulated learning-related genes. However, treadmill exercise together with social isolation did not restore this down-regulation although treadmill exercise increased learning-related genes without improving cognitive behaviour.

Abstract

Background: Some environment enrichments such as exercise has been reported to improve the diminished cognitive functions and related gene expression.  Therefore, we aimed to investigate the effects of prolonged treadmill exercise on long-term learning and hippocampal gene expression, which involves learning and plasticity.

Materials and methods: Male Wistar rats (n=32) randomly assigned into four groups: control (C), social isolation (SI), exercised (E), social isolation+exercise (SE) during postnatal days (PNDs) 21-34. Social isolation protocol was applied during 14 days by placing the rat alone in a cage. Rats were exercised daily, 5 days per week, for overall 4 weeks. Finally, learning performance was evaluated by the novel object recognition test. At the end of learning test, the rats were decapitated to isolate hippocampus tissues for learning related gene expression such as N-methyl-d-aspartate receptor (NMDAR) subunit genes (Grin1, Grin2a, Grin2b) and cyclin dependent kinase 5 (Cdk5), Cdk5 regulatory subunit p35 (Cdk5r), activity-regulated, cytoskeletal-associated protein (Arc), the immediate early gene (c-Fos, a marker of neuronal activation), doublecortin (DCX), Achaete-scute homolog 1 (ASCL1), brain-derived neurotrophic factor (BDNF) by RT-PCR.

Results: Grin1, NMDAR subunit gene expression was increased significantly in E group compared to other groups. Grin2b, NMDAR subunit gene expression was increased in E compared to the SI group. Cdk5 level increased in E compared to the SE group. The ASCL1 gene expression increased in E group compare to the SE group. The DCX gene expression increasing in C compared to SI and SE groups. 

Conclusions: Taken together these findings may point out that long-term social isolation down-regulated learning-related genes. However, treadmill exercise together with social isolation did not restore this down-regulation although treadmill exercise increased learning-related genes without improving cognitive behaviour.

Get Citation

Keywords

Learning, Neurogenesis, NMDAR, Plasticity, BDNF, Novel Object Test

About this article
Title

Long-term treadmill exercise upregulated hippocampal learning-related genes without improving cognitive behavior in social isolated rats

Journal

Folia Morphologica

Issue

Ahead of Print

Published online

2019-02-25

DOI

10.5603/FM.a2019.0018

Pubmed

30816552

Keywords

Learning
Neurogenesis
NMDAR
Plasticity
BDNF
Novel Object Test

Authors

Seval Keloglan
Leyla Sahin
Ozge Selin Cevik

References (50)
  1. Albasser MM, Davies M, Futter JE, et al. Magnitude of the object recognition deficit associated with perirhinal cortex damage in rats: Effects of varying the lesion extent and the duration of the sample period. Behav Neurosci. 2009; 123(1): 115–124.
  2. Barbour KA, Edenfield TM, Blumenthal JA. Exercise as a treatment for depression and other psychiatric disorders: a review. J Cardiopulm Rehabil Prev. 2007; 27(6): 359–367.
  3. Bekinschtein P, Cammarota M, Katche C, et al. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A. 2008; 105(7): 2711–2716.
  4. Bekinschtein P, Oomen CA, Saksida LM, et al. Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable? Semin Cell Dev Biol. 2011; 22(5): 536–542.
  5. Benite-Ribeiro SA, Santos JM, Duarte JA. Moderate physical exercise attenuates the alterations of feeding behaviour induced by social stress in female rats. Cell Biochem Funct. 2014; 32(2): 142–149.
  6. Cevik OS, Sahin L, Tamer L. Long term treadmill exercise performed to chronic social isolated rats regulate anxiety behavior without improving learning. Life Sci. 2018; 200: 126–133.
  7. Chen J, Kitanishi T, Ikeda T, et al. Contextual learning induces an increase in the number of hippocampal CA1 neurons expressing high levels of BDNF. Neurobiol Learn Mem. 2007; 88(4): 409–415.
  8. Chen WG, Chang Q, Lin Y, et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science. 2003; 302(5646): 885–889.
  9. Contreras-Vallejos E, Utreras E, Bórquez DA, et al. Searching for novel Cdk5 substrates in brain by comparative phosphoproteomics of wild type and Cdk5-/- mice. PLoS One. 2014; 9(3): e90363.
  10. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007; 30(9): 464–472.
  11. Cull-Candy SG, Leszkiewicz DN. Role of distinct NMDA receptor subtypes at central synapses. Sci STKE. 2004; 2004(255): re16.
  12. D'Alessio L, Konopka H, López EM, et al. Doublecortin (DCX) immunoreactivity in hippocampus of chronic refractory temporal lobe epilepsy patients with hippocampal sclerosis. Seizure. 2010; 19(9): 567–572.
  13. de Bruin N, Pouzet B. Beneficial effects of galantamine on performance in the object recognition task in Swiss mice: deficits induced by scopolamine and by prolonging the retention interval. Pharmacol Biochem Behav. 2006; 85(1): 253–260.
  14. Ennaceur A, Meliani K. A new one-trial test for neurobiological studies of memory in rats. III. Spatial vs. non-spatial working memory. Behav Brain Res. 1992; 51(1): 83–92.
  15. Fone KCF, Porkess MV. Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev. 2008; 32(6): 1087–1102.
  16. Francis F, Koulakoff A, Boucher D, et al. Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron. 1999; 23(2): 247–256.
  17. Gleeson J, Lin P, Flanagan L, et al. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron. 1999; 23(2): 257–271.
  18. Green MR, McCormick CM. Effects of stressors in adolescence on learning and memory in rodent models. Horm Behav. 2013; 64(2): 364–379.
  19. Gubern C, Hurtado O, Rodríguez R, et al. Validation of housekeeping genes for quantitative real-time PCR in in-vivo and in-vitro models of cerebral ischaemia. BMC Mol Biol. 2009; 10: 57.
  20. Hamilton GF, Rhodes JS. Exercise regulation of cognitive function and neuroplasticity in the healthy and diseased brain. Prog Mol Biol Transl Sci. 2015; 135: 381–406.
  21. Hatchard T, Ting JJ, Messier C. Translating the impact of exercise on cognition: methodological issues in animal research. Behav Brain Res. 2014; 273: 177–188.
  22. Heldt SA, Stanek L, Chhatwal JP, et al. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007; 12(7): 656–670.
  23. Hong S, Flashner B, Chiu M, et al. Social isolation in adolescence alters behaviors in the forced swim and sucrose preference tests in female but not in male rats. Physiol Behav. 2012; 105(2): 269–275.
  24. Hong YP, Lee HC, Kim HT. Treadmill exercise after social isolation increases the levels of NGF, BDNF, and synapsin I to induce survival of neurons in the hippocampus, and improves depression-like behavior. J Exerc Nutrition Biochem. 2015; 19: 11–18.
  25. Imayoshi I, Kageyama R. bHLH factors in self-renewal, multipotency, and fate choice of neural progenitor cells. Neuron. 2014; 82(1): 9–23.
  26. Kuruba R, Hattiangady B, Shetty AK. Hippocampal neurogenesis and neural stem cells in temporal lobe epilepsy. Epilepsy Behav. 2009; 14 Suppl 1: 65–73.
  27. Lander SS, Linder-Shacham D, Gaisler-Salomon I. Differential effects of social isolation in adolescent and adult mice on behavior and cortical gene expression. Behav Brain Res. 2017; 316: 245–254.
  28. Li S, Luo J, Wang Xi, et al. Effects of Ginkgo biloba extracts on NMDA-activated currents in acutely isolated hippocampal neurons of the rat. Phytother Res. 2011; 25(1): 137–141.
  29. McCormick CM, Thomas CM, Sheridan CS, et al. Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus. 2012; 22(6): 1300–1312.
  30. Mishiba T, Tanaka M, Mita N, et al. Cdk5/p35 functions as a crucial regulator of spatial learning and memory. Mol Brain. 2014; 7: 82.
  31. Murakami S, Imbe H, Morikawa Y, et al. Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly. Neurosci Res. 2005; 53(2): 129–139.
  32. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013; 14(6): 383–400.
  33. Papa FT, Mancardi MM, Frullanti E, et al. Personalized therapy in a GRIN1 mutated girl with intellectual disability and epilepsy. Clin Dysmorphol. 2018; 27(1): 18–20.
  34. Pleasure SJ, Collins AE, Lowenstein DH. Unique expression patterns of cell fate molecules delineate sequential stages of dentate gyrus development. J Neurosci. 2000; 20(16): 6095–6105.
  35. Peebles CL, Yoo J, Thwin MT, et al. Arc regulates spine morphology and maintains network stability in vivo. Proc Natl Acad Sci U S A. 2010; 107(42): 18173–18178.
  36. Plath N, Ohana O, Dammermann B, et al. Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Neuron. 2006; 52(3): 437–444.
  37. Plattner F, Hernández A, Kistler TM, et al. Memory enhancement by targeting Cdk5 regulation of NR2B. Neuron. 2014; 81(5): 1070–1083.
  38. Quan MN, Tian YT, Xu KH, et al. Post weaning social isolation influences spatial cognition, prefrontal cortical synaptic plasticity and hippocampal potassium ion channels in Wistar rats. Neuroscience. 2010; 169(1): 214–222.
  39. Raineki C, Cortés MR, Belnoue L, et al. Effects of early-life abuse differ across development: infant social behavior deficits are followed by adolescent depressive-like behaviors mediated by the amygdala. J Neurosci. 2012; 32(22): 7758–7765.
  40. Sandstrom NJ, Hart SR. Isolation stress during the third postnatal week alters radial arm maze performance and corticosterone levels in adulthood. Brain. Res. 2005; 156(22): 289–296.
  41. Schöfl C, Waring M, Bergwitz C, et al. Cyclic-adenosine 3',5'-monophosphate-stimulated c-fos gene transcription involves distinct calcium pathways in single beta-cells. Mol Cell Endocrinol. 2002; 186(1): 121–131.
  42. Sik A, van Nieuwehuyzen P, Prickaerts J, et al. Performance of different mouse strains in an object recognition task. Behav Brain Res. 2003; 147(1-2): 49–54.
  43. Stranahan AM, Khalil D, Gould E. Social isolation delays the positive effects of running on adult neurogenesis. Nat Neurosci. 2006; 9(4): 526–533.
  44. Tao X, Finkbeiner S, Arnold DB, et al. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998; 20(4): 709–726.
  45. Taylor H, Jaimee TJ, Claude M. Translating the impact of exercise on cognition: methodological issues in animal research. Behav Brain Res. 2014; 273: 177–188.
  46. van den Buuse M, Ruimschotel E, Martin S, et al. Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT(1A) receptor knockout mice: implications for schizophrenia. Neuropharmacology. 2011; 61(1-2): 209–216.
  47. Winters BD, Bussey TJ. Glutamate receptors in perirhinal cortex mediate encoding, retrieval, and consolidation of object recognition memory. J Neurosci. 2005; 25(17): 4243–4251.
  48. Xu H, Luo C, Richardson JS, et al. Recovery of hippocampal cell proliferation and BDNF levels, both of which are reduced by repeated restraint stress, is accelerated by chronic venlafaxine. Pharmacogenomics J. 2004; 4: 322–331.
  49. Yuzaki M. Cerebellar LTD vs. motor learning-lessons learned from studying GluD2. Neural Netw. 2013; 47: 36–41.
  50. Zhao X, Sun L, Jia H, et al. Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33(7): 1173–1177.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By  "Via Medica sp. z o.o." sp.k., Świętokrzyska 73, 80–180 Gdańsk, Poland

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl