Voluntary exercise ameliorates cognitive performance and long-term potentiation (LTP) impairments in maternally separated adolescent male rats

Document Type : Original Research

Authors
1 Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, IranDepartment of Physiology & pharmacology, school of medicine, Zabol University of Medical Sciences, Zabol, Iran
2 Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, IranNeuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
3 Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
4 Department of Physiology, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
Abstract
Maternal separation (MS) is a model to induce early life stress (CNS) and is related to increased levels of anxiety and cognitive deficiencies. Voluntary exercise has been shown to be associated with learning and memory improvement in behavioral tests and electrophysiological experiments. Since it plays a significant role in learning and memory and enhances synaptic plasticity, the authors hypothesized that voluntary exercise may affect MS-induced changes in synaptic plasticity and cognitive performance.

Rat pups underwent the MS protocol for 180 min/day from postnatal day (PND) 1 to 21. Voluntary exercise was performed in the exercise (Ex and MS + Ex groups from PND 29 to 49. Anxiety-like behavior, learning and memory were measured in adolescent rats. In addition, evoked field excitatory postsynaptic potentials (fEPSP) were recorded from the CA1 region of the hippocampus.

MS induced higher anxiety-like behavior as well as impaired learning and memory, but did not affect locomotor activity. Voluntary exercise improved MS-induced deficits and increased the learning and memory of MS rats. It also decreased anxiety-like behavior in the open field test. The results revealed that long-term potentiation (LTP) was induced in all groups, except for MS. However, voluntary exercise induced LTP and had maintenance in MS + Ex.

Keywords


1. Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology (Berl). 2011;214(1):55–70.
2. Sandi C, Pinelo-Nava MT. Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plast. 2007;2007.
3. Judo C, Matsumoto M, Yamazaki D, Hiraide S, Yanagawa Y, Kimura S, et al. Early stress exposure impairs synaptic potentiation in the rat medial prefrontal cortex underlying contextual fear extinction. Neuroscience. 2010;169(4):1705–14.
4. Solas M, Aisa B, Mugueta MC, Del Río J, Tordera RM, Ramírez MJ. Interactions between age, stress and insulin on cognition: implications for Alzheimer’s disease. Neuropsychopharmacology. 2010;35(8):1664–73.
5. Sousa VC, Vital J, Costenla AR, Batalha VL, Sebastião AM, Ribeiro JA, et al. Maternal separation impairs long term-potentiation in CA1-CA3 synapses and hippocampal-dependent memory in old rats. Neurobiol Aging. 2014;35(7):1680–5.
6. Schwabe L, Joëls M, Roozendaal B, Wolf OT, Oitzl MS. Stress effects on memory: an update and integration. Neurosci Biobehav Rev. 2012;36(7):1740–9.
7. Kosten TA, Kim JJ, Lee HJ. Early life manipulations alter learning and memory in rats. Neurosci Biobehav Rev. 2012;36(9):1985–2006.
8. Lai M-C, Huang L-T. Effects of early life stress on neuroendocrine and neurobehavior: mechanisms and implications. Pediatr Neonatol. 2011;52(3):122–9.
9. Figueiredo ÍL, Frota PB, da Cunha DG, da Silva Raposo R, Canuto KM, de Andrade GM, et al. Prolonged maternal separation induces undernutrition and systemic inflammation with disrupted hippocampal development in mice. Nutrition. 2016;32(9):1019–27.
10. Aguggia JP, Suárez MM, Rivarola MA. Early maternal separation: neurobehavioral consequences in mother rats. Behav Brain Res. 2013;248:25–31.
11. Doreste-Mendez R, Ríos-Ruiz EJ, Rivera-López LL, Gutierrez A, Torres-Reveron A. Effects of environmental enrichment in maternally separated rats: age and sex specific outcomes. Front Behav Neurosci. 2019;13:198.
12. Shin SY, Han SH, Woo R-S, Jang SH, Min SS. Adolescent mice show anxiety-and aggressive-like behavior and the reduction of long-term potentiation in mossy fiber-CA3 synapses after neonatal maternal separation. Neuroscience. 2016;316:221–31.
13. Cao X, Huang S, Cao J, Chen T, Zhu P, Zhu R, et al. The timing of maternal separation affects Morris water maze performance and long‐term potentiation in male rats. Dev Psychobiol. 2014;56(5):1102–9.
14. Gruss M, Braun K, Frey JU, Korz V. Maternal separation during a specific postnatal time window prevents reinforcement of hippocampal long-term potentiation in adolescent rats. Neuroscience. 2008;152(1):1–7.
15. Cao X, Huang S, Ruan D. Enriched environment restores impaired hippocampal long‐term potentiation and water maze performance induced by developmental lead exposure in rats. Dev Psychobiol J Int Soc Dev Psychobiol. 2008;50(3):307–13.
16. Bliss TVP, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31–9.
17. Herpfer I, Hezel H, Reichardt W, Clark K, Geiger J, Gross CM, et al. Early life stress differentially modulates distinct forms of brain plasticity in young and adult mice. PLoS One. 2012;7(10):e46004.
18. Baudin A, Blot K, Verney C, Estevez L, Santamaria J, Gressens P, et al. Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex. Neurobiol Learn Mem. 2012;98(3):207–14.
19. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci. 2002;25(6):295–301.
20. Griffin EW, Bechara RG, Birch AM, Kelly ÁM. Exercise enhances hippocampal‐dependent learning in the rat: evidence for a BDNF‐related mechanism. Hippocampus. 2009;19(10):973–80.
21. Liu H, Zhao G, Cai K, Zhao H. Treadmill exercise prevents decline in spatial learning and memory in APP/PS1 transgenic mice through improvement of hippocampal long-term potentiation. Behav Brain Res. 2011;218(2):308–14.
22. Landers MR, Kinney JW, Allen DN, van Breukelen F. A comparison of voluntary and forced exercise in protecting against behavioral asymmetry in a juvenile hemiparkinsonian rat model. Behav Brain Res. 2013;248:121–8.
23. Leasure JL, Jones M. Forced and voluntary exercise differentially affect brain and behavior. Neuroscience. 2008;156(3):456–65.
24. Vaynman S, Ying Z, Gomez‐Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci. 2004;20(10):2580–90.
25. Zheng S, Zhang F, Liu Q, Jian R, Yang M. Exercise training increases spatial memory via reducing contralateral hippocampal NMDAR subunits expression in intracerebral hemorrhage rats. Neuropsychiatr Dis Treat. 2019;15:1921.
26. Ji E-S, Kim Y-M, Shin M-S, Kim C-J, Lee K-S, Kim K, et al. Treadmill exercise enhances spatial learning ability through suppressing hippocampal apoptosis in Huntington’s disease rats. J Exerc Rehabil. 2015;11(3):133.
27. Jacotte-Simancas A, Costa-Miserachs D, Torras-Garcia M, Coll-Andreu M, Portell-Cortés I. Effect of voluntary physical exercise and post-training epinephrine on acquisition of a spatial task in the barnes maze. Behav Brain Res. 2013;247:178–81.
28. Zhang L, Feng Y, Ji W, Liu J, Liu K. Effect of voluntary wheel running on striatal dopamine level and neurocognitive behaviors after molar loss in rats. Behav Neurol. 2017;2017.
29. Ang E-T, Dawe GS, Wong PTH, Moochhala S, Ng Y-K. Alterations in spatial learning and memory after forced exercise. Brain Res. 2006;1113(1):186–93.
30. Mabandla MV, Russell VA. Voluntary exercise reduces the neurotoxic effects of 6-hydroxydopamine in maternally separated rats. Behav Brain Res. 2010;211(1):16–22.
31. Grace L, Hescham S, Kellaway LA, Bugarith K, Russell VA. Effect of exercise on learning and memory in a rat model of developmental stress. Metab Brain Dis. 2009;24(4):643.
32. Li M, Xue X, Shao S, Shao F, Wang W. Cognitive, emotional and neurochemical effects of repeated maternal separation in adolescent rats. brain Res. 2013;1518:82–90.
33. Mustard JF. Experience-based brain development: scientific underpinnings of the importance of early child development in a global world. Early child Dev from Meas to action Washingt DC, World Bank. 2007;43–86.
34. Rajizadeh MA, Esmaeilpour K, Haghparast E, Ebrahimi MN, Sheibani V. Voluntary exercise modulates learning & memory and synaptic plasticity impairments in sleep deprived female rats. Brain Res. 2020;1729:146598.
35. Rajizadeh MA, Sheibani V, Bejeshk MA, Mohtashami Borzadaran F, Saghari H, Esmaeilpour K. The effects of high intensity exercise on learning and memory impairments followed by combination of sleep deprivation and demyelination induced by etidium bromide. Int J Neurosci. 2019;129(12):1166–78.
36. Esmaeilpour K, Sheibani V, Shabani M, Mirnajafi-Zadeh J. Effect of low frequency electrical stimulation on seizure-induced short-and long-term impairments in learning and memory in rats. Physiol Behav. 2017;168:112–21.
37. Sivakumaran MH, Mackenzie AK, Callan IR, Ainge JA, O’Connor AR. The discrimination ratio derived from novel object recognition tasks as a measure of recognition memory sensitivity, not bias. Sci Rep. 2018;8(1):1–12.
38. Joushi S, Esmaeilpour K, Masoumi-Ardakani Y, Esmaeili-Mahani S, Sheibani V. Intranasal oxytocin administration facilitates the induction of long-term potentiation and promotes cognitive performance of maternally separated rats. Psychoneuroendocrinology. 2021;123:105044.
39. Mohammadi F, Ahmadi-Zeidabadi M, Nazeri M, Ghasemi A, Shabani M. Nitric oxide modulates cognitive, nociceptive and motor functions in a rat model of empathy. Int J Neurosci. 2020;1–10.
40. Herman JP, Watson SJ. The rat brain in stereotaxic coordinates (2nd edn): by George Paxinos and Charles Watson, Academic Press, 1986.£ 40.00/$80.00 (264 pages) ISBN 012 547 6213. Elsevier Current Trends; 1987.
41. Luby JL, Belden A, Harms MP, Tillman R, Barch DM. Preschool is a sensitive period for the influence of maternal support on the trajectory of hippocampal development. Proc Natl Acad Sci. 2016;113(20):5742–7.
42. Nylander I, Roman E. Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption? Psychopharmacology (Berl). 2013;229(4):555–69.
43. Banqueri M, Méndez M, Arias JL. Spatial memory-related brain activity in normally reared and different maternal separation models in rats. Physiol Behav. 2017;181:80–5.
44. Huot RL, Thrivikraman K, Meaney MJ, Plotsky PM. Development of adult ethanol preference and anxiety as a consequence of neonatal maternal separation in Long Evans rats and reversal with antidepressant treatment. Psychopharmacology (Berl). 2001;158(4):366–73.
45. Salm AK, Pavelko M, Krouse EM, Webster W, Kraszpulski M, Birkle DL. Lateral amygdaloid nucleus expansion in adult rats is associated with exposure to prenatal stress. Dev brain Res. 2004;148(2):159–67.
46. Meaney MJ, Plotsky PM. Long-term behavioral and neuroendocrine adaptations to adverse early experience. Biol basis mind body Interact. 2000;122:81.
47. Garcia VA, Hirotsu C, Matos G, Alvarenga T, Pires GN, Kapczinski F, et al. Modafinil ameliorates cognitive deficits induced by maternal separation and sleep deprivation. Behav Brain Res. 2013;253:274–9.
48. Kambali MY, Anshu K, Kutty BM, Muddashetty RS, Laxmi TR. Effect of early maternal separation stress on attention, spatial learning and social interaction behaviour. Exp brain Res. 2019;237(8):1993–2010.
49. Yang S, Li J, Han L, Zhu G. Early maternal separation promotes apoptosis in dentate gyrus and alters neurological behaviors in adolescent rats. Int J Clin Exp Pathol. 2017;10(11):10812.
50. Aisa B, Elizalde N, Tordera R, Lasheras B, Del Río J, Ramírez MJ. Effects of neonatal stress on markers of synaptic plasticity in the hippocampus: implications for spatial memory. Hippocampus. 2009;19(12):1222–31.
51. Korosi A, Naninck EFG, Oomen CA, Schouten M, Krugers H, Fitzsimons C, et al. Early-life stress mediated modulation of adult neurogenesis and behavior. Behav Brain Res. 2012;227(2):400–9.
52. Sachs BD, Rodriguiz RM, Siesser WB, Kenan A, Royer EL, Jacobsen JPR, et al. The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress. Int J Neuropsychopharmacol. 2013;16(9):2081–94.
53. Ognibene E, Adriani W, Caprioli A, Ghirardi O, Ali SF, Aloe L, et al. The effect of early maternal separation on brain derived neurotrophic factor and monoamine levels in adult heterozygous reeler mice. Prog Neuro-Psychopharmacology Biol Psychiatry. 2008;32(5):1269–76.
54. Klug M, van den Buuse M. Chronic cannabinoid treatment during young adulthood induces sex-specific behavioural deficits in maternally separated rats. Behav Brain Res. 2012;233(2):305–13.
55. Pinheiro RMC, de Lima MNM, Portal BCD, Busato SB, Falavigna L, Ferreira RDP, et al. Long-lasting recognition memory impairment and alterations in brain levels of cytokines and BDNF induced by maternal deprivation: effects of valproic acid and topiramate. J Neural Transm. 2015;122(5):709–19.
56. Danielewicz J, Hess G. Early life stress alters synaptic modification range in the rat lateral amygdala. Behav Brain Res. 2014;265:32–7.
57. Hannesson DK, Howland JG, Pollock M, Mohapel P, Wallace AE, Corcoran ME. Anterior perirhinal cortex kindling produces long‐lasting effects on anxiety and object recognition memory. Eur J Neurosci. 2005;21(4):1081–90.
58. Hulshof HJ, Novati A, Sgoifo A, Luiten PGM, den Boer JA, Meerlo P. Maternal separation decreases adult hippocampal cell proliferation and impairs cognitive performance but has little effect on stress sensitivity and anxiety in adult Wistar rats. Behav Brain Res. 2011;216(2):552–60.
59. Benetti F, Mello PB, Bonini JS, Monteiro S, Cammarota M, Izquierdo I. Early postnatal maternal deprivation in rats induces memory deficits in adult life that can be reversed by donepezil and galantamine. Int J Dev Neurosci. 2009;27(1):59–64.
60. Delavari F, Sheibani V, Esmaeilpour K, Esmaeili-Mahani S, Nakhaee N. Effects of maternal separation on nicotine-induced conditioned place preference and later spatial learning and memory function in adolescent male rats. Addict Heal. 2016;8(4):261.
61. Wang Q, Li M, Du W, Shao F, Wang W. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res. 2015;280:16–23.
62. Hui J, Zhang Z, Liu S, Xi G, Zhang X, Teng G-J, et al. Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study. Behav Brain Res. 2011;217(1):122–7.
63. Hill RA, Klug M, Kiss Von Soly S, Binder MD, Hannan AJ, van Den Buuse M. Sex‐specific disruptions in spatial memory and anhedonia in a “two hit” rat model correspond with alterations in hippocampal brain‐derived neurotrophic factor expression and signaling. Hippocampus. 2014;24(10):1197–211.
64. Banqueri M, Méndez M, Arias JL. Behavioral effects in adolescence and early adulthood in two length models of maternal separation in male rats. Behav Brain Res. 2017;324:77–86.
65. Tchenio A, Lecca S, Valentinova K, Mameli M. Limiting habenular hyperactivity ameliorates maternal separation-driven depressive-like symptoms. Nat Commun. 2017;8(1):1–8.
66. Soztutar E, Colak E, Ulupinar E. Gender-and anxiety level-dependent effects of perinatal stress exposure on medial prefrontal cortex. Exp Neurol. 2016;275:274–84.
67. heydari A, Esmaeilpour K, Sheibani V. Maternal separation impairs long term-potentiation in CA3-CA1 synapses in adolescent female rats. Behav Brain Res [Internet]. 2019;376:112239. Available from: https://doi.org/10.1016/j.bbr.2019.112239
68. Spear LP. The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev. 2000;24(4):417–63.
69. Uysal N, Dayi A, ÖZBAL S, Cetin F, Aksu I, Yalaz G, et al. Development of spatial memory during adolescent period in rats. J Neurol Sci Turk. 2010;27(4):407–13.
70. Rajizadeh MA, Esmaeilpour K, Masoumi-Ardakani Y, Bejeshk MA, Shabani M, Nakhaee N, et al. Voluntary exercise impact on cognitive impairments in sleep-deprived intact female rats. Physiol Behav. 2018;188:58–66.
71. Patten AR, Sickmann H, Hryciw BN, Kucharsky T, Parton R, Kernick A, et al. Long-term exercise is needed to enhance synaptic plasticity in the hippocampus. Learn Mem. 2013;20(11):642–7.
72. Titterness AK, Wiebe E, Kwasnica A, Keyes G, Christie BR. Voluntary exercise does not enhance long-term potentiation in the adolescent female dentate gyrus. Neuroscience. 2011;183:25–31.
73. Rajizadeh MA, Afarinesh MR, Zarif M, Mirasadi A, Esmaeilpour K. Does caffeine therapy improve cognitive impairments in valproic acid rat model of autism? Toxin Rev. 2019;1–11.
74. Segal-Gavish H, Barzilay R, Rimoni O, Offen D. Voluntary exercise improves cognitive deficits in female dominant-negative DISC1 transgenic mouse model of neuropsychiatric disorders. World J Biol Psychiatry. 2019;20(3):243–52.
75. Aguiar Jr AS, Castro AA, Moreira EL, Glaser V, Santos ARS, Tasca CI, et al. Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: involvement of hippocampal plasticity via AKT, CREB and BDNF signaling. Mech Ageing Dev. 2011;132(11–12):560–7.
76. Saadati H, Babri S, Ahmadiasl N, Mashhadi M. Effects of exercise on memory consolidation and retrieval of passive avoidance learning in young male rats. Asian J Sports Med. 2010;1(3):137.
77. Fordyce DE, Farrar RP. Enhancement of spatial learning in F344 rats by physical activity and related learning-associated alterations in hippocampal and cortical cholinergic functioning. Behav Brain Res. 1991;46(2):123–33.
78. Howells FM, Russell VA, Mabandla M V, Kellaway LA. Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson’s disease. Behav Brain Res. 2005;165(2):210–20.
79. Liu Y, Chen H, Wu C, Kuo Y, Yu L, Huang A, et al. Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: roles of amygdalar brain‐derived neurotrophic factor and synaptotagmin I. J Physiol. 2009;587(13):3221–31.
80. O’dell SJ, Gross NB, Fricks AN, Casiano BD, Nguyen TB, Marshall JF. Running wheel exercise enhances recovery from nigrostriatal dopamine injury without inducing neuroprotection. Neuroscience. 2007;144(3):1141–51.
81. Duman CH, Schlesinger L, Russell DS, Duman RS. Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice. Brain Res. 2008;1199:148–58.
82. Uysal N, Kiray M, Sisman AR, Camsari UM, Gencoglu C, Baykara B, et al. Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotech Histochem. 2015;90(1):55–68.
83. Cetinkaya C, Sisman AR, Kiray M, Camsari UM, Gencoglu C, Baykara B, et al. Positive effects of aerobic exercise on learning and memory functioning, which correlate with hippocampal IGF-1 increase in adolescent rats. Neurosci Lett. 2013;549:177–81.
84. Sosa PM, Neves B-HS, Carrazoni GS, Gomes GM, Del Rosso G, Ramborger BP, et al. Maternal Deprivation Induces Memory Deficits That Are Reduced by One Aerobic Exercise Shot Performed after the Learning Session. Neural Plast. 2019;2019.
85. Sadeghi M, Peeri M, Hosseini M-J. Adolescent voluntary exercise attenuated hippocampal innate immunity responses and depressive-like behaviors following maternal separation stress in male rats. Physiol Behav. 2016;163:177–83.
86. Park S-S, Kim T-W, Park H-S, Seo T-B, Kim Y-P. Effects of treadmill exercise on activity, short-term memory, vascular dysfunction in maternal separation rats. J Exerc Rehabil. 2020;16(2):118.
87. Zagaar M, Alhaider I, Dao A, Levine A, Alkarawi A, Alzubaidy M, et al. The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiol Dis. 2012;45(3):1153–62.
88. Ravassard P, Pachoud B, Comte J-C, Mejia-Perez C, Scoté-Blachon C, Gay N, et al. Paradoxical (REM) sleep deprivation causes a large and rapidly reversible decrease in long-term potentiation, synaptic transmission, glutamate receptor protein levels, and ERK/MAPK activation in the dorsal hippocampus. Sleep. 2009;32(2):227–40.
89. Hagewoud R, Havekes R, Novati A, Keijser JN, Van der Zee EA, Meerlo P. Sleep deprivation impairs spatial working memory and reduces hippocampal AMPA receptor phosphorylation. J Sleep Res. 2010;19(2):280–8.
90. Miller RM, Marriott D, Trotter J, Hammond T, Lyman D, Call T, et al. Running exercise mitigates the negative consequences of chronic stress on dorsal hippocampal long-term potentiation in male mice. Neurobiol Learn Mem. 2018;149:28–38.
91. Farmer J, Zhao X V, Van Praag H, Wodtke K, Gage FH, Christie BR. Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience. 2004;124(1):71–9.
92. Niwa A, Nishibori M, Hamasaki S, Kobori T, Liu K, Wake H, et al. Voluntary exercise induces neurogenesis in the hypothalamus and ependymal lining of the third ventricle. Brain Struct Funct. 2016;221(3):1653–66.
93. Babri S, Reisi P, Alaei H, Sharifi MR, Mohades G. Effect of forced treadmill exercise on long-term potentiation (LTP) in the dentate gyrus of hippocampus in male rats. Physiol Pharmacol. 2008;12(1):39–45.
94. Droste SK, Chandramohan Y, Hill LE, Linthorst ACE, Reul JMHM. Voluntary exercise impacts on the rat hypothalamic-pituitary-adrenocortical axis mainly at the adrenal level. Neuroendocrinology. 2007;86(1):26–37.
95. Timmermans W, Xiong H, Hoogenraad CC, Krugers HJ. Stress and excitatory synapses: from health to disease. Neuroscience. 2013;248:626–36.
96. De Kloet ER, Joëls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6(6):463–75.
97. Zhang H, Etherington LA, Hafner AS, Belelli D, Coussen F, Delagrange P, et al. Regulation of AMPA receptor surface trafficking and synaptic plasticity by a cognitive enhancer and antidepressant molecule. Mol Psychiatry. 2013;18(4):471–84.
98. Tse YC, Bagot RC, Hutter JA, Wong AS, Wong TP. Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus. PLoS One. 2011;6(11):e27215.
99. Sun H, Guan L, Zhu Z, Li H. Reduced levels of NR1 and NR2A with depression-like behavior in different brain regions in prenatally stressed juvenile offspring. PLoS One. 2013;8(11):e81775.
100. Hu H, Real E, Takamiya K, Kang M-G, Ledoux J, Huganir RL, et al. Emotion enhances learning via norepinephrine regulation of AMPA-receptor trafficking. Cell. 2007;131(1):160–73.
101. Whitehead G, Jo J, Hogg EL, Piers T, Kim D-H, Seaton G, et al. Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus. Brain. 2013;136(12):3753–65.
102. Mabandla M V, Kellaway LA, Daniels WMU, Russell VA. Effect of exercise on dopamine neuron survival in prenatally stressed rats. Metab Brain Dis. 2009;24(4):525–39.
103. Wosiski‐Kuhn M, Stranahan AM. Transient increases in dendritic spine density contribute to dentate gyrus long‐term potentiation. Synapse. 2012;66(7):661–4.
104. Makena N, Bugarith K, Russell VA. Maternal separation enhances object location memory and prevents exercise-induced MAPK/ERK signalling in adult Sprague–Dawley rats. Metab Brain Dis. 2012;27(3):377–85.
105. Dimatelis JJ, Stein DJ, Russell VA. Chronic exposure to light reverses the effect of maternal separation on proteins in the prefrontal cortex. J Mol Neurosci. 2013;51(3):835–43.
106. Faure J, Uys JDK, Marais L, Stein DJ, Daniels WMU. Early maternal separation alters the response to traumatization: resulting in increased levels of hippocampal neurotrophic factors. Metab Brain Dis. 2007;22(2):183–95.
107. Marais L, Van Rensburg SJ, Van Zyl JM, Stein DJ, Daniels WMU. Maternal separation of rat pups increases the risk of developing depressive-like behavior after subsequent chronic stress by altering corticosterone and neurotrophin levels in the hippocampus. Neurosci Res. 2008;61(1):106–12.