Abstract
To investigate the effect of stress before pregnancy on memory function and serum corticosterone (COR) levels, as well as the expression of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate (NMDA) 2A (NR2A) and 2B (NR2B) receptors in the hippocampus of the offspring rats when they were 2 months postnatally. Adult female Sprague-Dawley (SD) rats were divided randomly into two groups: control group (n = 8) and chronic unpredictable stress (CUS) group (n = 12). All rats were tested in the open field test and sucrose intake test before and after CUS. The memory function of their offspring were tested in the Morris water maze. Serum COR levels were determined by using a standard radioimmunoassay kit. The expression of BDNF, NR2A and NR2B in the hippocampus of the offspring rats were studied by immunoreactivity quantitative analysis and real-time RT-PCR. (1) Following CUS, reduced open field test activity and decreased sucrose consumption were observed relative to controls. (2) The Morris water maze task demonstrated increased escape latency in the offspring rats of CUS group relative to controls (P < 0.01). No-platform probe testing showed reduced crossings for offspring of CUS relative to controls (P < 0.05). (3) CUS induced a significant increase in serum COR levels of the offspring rats (P < 0.01), but no difference was observed in the body or brain weight between the offspring of the two groups. (4) Immunoreactivity quantitative analysis shows that BDNF and NR2B in the offspring of CUS group was decreased in the CA3 and DG regions of the hippocampus compared to the control group offspring, but NR2A levels were not altered between the offspring of the two groups. (5) Real-time RT-PCR demonstrated that BDNF and NR2B mRNAs were significantly decreased in the offspring of the CUS group compared with the control group (P < 0.01). No significant difference in the levels of NR2A mRNA was detected between offspring of CUS and offspring of control groups. In our study, pregestational stress can increase serum corticosterone levels and reduce the expression of BDNF and NR2B in the hippocampus of offspring. These alterations are associated with impairment of memory in the adult offspring. These data suggest that, stress before pregnancy might have a profound influence on brain development of offspring, that may persist into and be manifested in adulthood.
Similar content being viewed by others
Abbreviations
- ANOVA:
-
Analysis of variance
- BDNF:
-
Brain-derived neurotrophic factor
- COR:
-
Corticosterone
- CUS:
-
Chronic unpredictable stress
- CRH:
-
Corticotropin-releasing hormone
- E:
-
Embryonic
- EL:
-
Escape latency
- GCs:
-
Glucocorticoids
- GR:
-
Glucocorticoid receptors
- HPA:
-
Hypothalamic-pituitary-adrenal
- LTP:
-
Long-term potentiation
- NMDA:
-
N-methyl-D-aspartate
- NR:
-
N-methyl-D-aspartate receptor
- PND:
-
Postnatal day
- RT-PCR:
-
Reverse-transcriptase polymerase chain reaction
References
Beversdorf DQ, Manning SE, Hillier A (2005) Timing of prenatal stressors and autism. J Autism Dev Disord 35:471–478
Li ZY, Yan CH, Xu J (2008) Effects of prenatal exposure to stress and lead on spatial learning and memory development in rats. Zhonghua Yu Fang Yi Xue Za Zhi 42(10):717–721
Kapoor A, Kostaki A, Janus C (2009) The effects of prenatal stress on learning in adult offspring is dependent on the timing of the stressor. Behav Brain Res 197(1):144–149
Binder EB, Bradley RG, Liu W et al (2008) Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 299(11):1291–1305
Stratakis CA, Chrousos GP (1995) Neuroendocrinology and pathophysiology of the stress system. In: Chrousos GP, McCarty R, Pacak K, Cizza G, Sternberg E, Gold PW, Kvetnansky R (eds) Stress: basic mechanisms and clinical implications. The New York Academy Science, New York, pp 1–18
Barbazanges A, Piazza PV, Le Moal M et al (1996) Maternal glucocorticoid secretion mediates long-term effects of prenatal stress. J Neurosci 16:3943–3949
Welberg LA, Seckl JR (2001) Prenatal stress, glucocorticoids and the programming of the brain. J Neuroendocrinol 13:113–128
Martínez-Téllez RI, Hernández-Torres E, Gamboa C (2009) Prenatal stress alters spine density and dendritic length of nucleus accumbens and hippocampus neurons in rat offspring. Synapse 63(9):794–804
Lemaire V, Koehl M, Le Moal M et al (2000) Prenatal stress produces learning deficits associated with an inhibition of neurogenesis in the hippocampus. Proc Natl Acad Sci USA 97:11032–11037
Yang J, Han H, Cao J (2006) Prenatal stress modifies hippocampal synaptic plasticity and spatial learning in young rat offspring. Hippocampus 16:431–436
Meunier J, Gue M, Recasens M (2004) Attenuation by a sigma1 (sigma1) receptor agonist of the learning and memory deficits induced by a prenatal restraint stress in juvenile rats. Br J Pharmacol 142:689–700
Zagron G, Weinstock M (2006) Maternal adrenal hormone secretion mediates behavioural alterations induced by prenatal stress in male and female rats. Behav Brain Res 175:323–328
Cannizzaro C, Plescia F, Martire M (2006) Single, intense prenatal stress decreases emotionality and enhances learning performance in the adolescent rat offspring: interaction with a brief, daily maternal separation. Behav Brain Res 169:128–136
Fujioka T, Fujioka A, Tan N (2001) Mild prenatal stress enhances learning performance in the non-adopted rat offspring. Neuroscience 103:301–307
Li H, Zhang L, Fang Z (2009) Behavioral and neurobiological studies on the male progeny of maternal rats exposed to chronic unpredictable stress before pregnancy. Neurosci Lett. Epub ahead of print
Gomez-Pinilla F, Vaynman S, Ying Z (2008) Brain-derived neurotrophic factor functions as a metabotrophin to mediate the effects of exercise on cognition. Eur J Neurosci 28(11):2278–2287
Mizuno M, Yamada K, Olariu A et al (2000) Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci 20:7116–7121
Poo MM (2001) Neurotrophins as synaptic modulators [Review]. Nat Rev Neurosci 2:24–32
Seeburg PH (1993) The molecular biology of mammalian glutamate receptor channels. Trends Neurosci 16:359–365
Gao XM, Sakai K, Roberts RC et al (2000) Ionotropic glutamate receptors and expression of N-methyl-Daspartate receptor subunits in subregions of human hippocampus: effects of schizophrenia. Am J Psychiatry 157:1141–1149
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39
Katz RJ, Schmaltz K (1980) Dopaminergic involvement in attention. A novel animal model. Prog Neuropsychopharmacol 4:585–590
Willner P (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl) 134:319–329
Sfikakis A, Galanopoulou P, Konstandi M et al (1996) Stress through handling for vaginal screening, serotonin, and ACTH response to ether. Pharmacol Biochem Behav 53:965–970
Rossato JI, Bevilaqua LRM, Myskiw JC (2007) On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory. Learn Mem 14:36–46
Frick KM, Stillner ET, Berger-Sweeney J (2000) Mice are not little rats: species differences in a one-day water maze task. Neuro Report 11:3461–3465
Ang ET, Dawe GS, Wong PTH (2006) Alterations in spatial learning and memory after forced exercise. Brain Res 1113:186–193
Rossato JI, Bevilaqua LRM, Lima RH (2006) On the participation of hippocampal p38 mitogen-activated protein kinase in extinction and reacquisition of inhibitory avoidance memory. Neuroscience 143:15–23
Loeliger MM, Briscoe T, Ree SM (2008) BDNF increases survival of retinal dopaminergic neurons after prenatal compromise. Invest Ophthalmol Vis Sci 49:1282–1289
Bilbo SD, Newsum NJ, Sprunger DB (2007) Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood. Brain Behav Immun 21:332–342
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction. Anal Biochem 162:156–159
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(_△△C(T)) method. Methods 25:402–408
Willner P, Muscat R, Papp M (1992) Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci Biobehav Rev 16:525–534
Glynn LM, Schetter CD, Wadhwa PD (2004) Pregnancy affects appraisal of negative life events. J Psychoso Res 56(1):47–52
Entringer S, Kumsta R, Hellhammer DH (2009) Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Horm Behav 55(2):292–298
Magarinos AM, Verdugo JM, McEwen BS (1997) Chronic stress alters synaptic terminal structure in hippocampus. Proc Natl Acad Sci USA 94:14002–14008
McEwen BS (1998) Protective and damaging effects of stress mediators. N Engl J Med 338:171–179
Romberg C, Raffel J, Martin L (2009) Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus. Eur J Neurosci 29(6):1141–1152
Fumagalli F, Bedogni F, Slotkin TA (2005) Prenatal stress elicits regionally selective changes in basal FGF-2gene expression in adulthood and alters the adult response to acute or chronic stress. Neurobiol Dis 20(3):731–737
Kang H, Schuman EM (1995) Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science 267:1658–1662
Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog Brain Res 128:183–191
Kealy J, Commins S (2009) Antagonism of glutamate receptors in the CA1 to perirhinal cortex projection prevents long-term potentiation and attenuates levels of brain-derived neurotrophic factor. Brain Res 1265:53–64
Pozzo-Miller LD, Gottschalk W, Zhang L (1999) Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci 19:4972–4983
Siegel GJ, Chauhan NB (2000) Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev 33:199–227
Batchelor PE, Liberatore GT, Porritt MJ (2000) Inhibition of brain-derived neurotrophic factor and glial cell linederived neurotrophic factor expression reduces dopaminergic sprouting in the injured striatum. Eur J Neurosci 12:3462–3468
Song DK, Choe B, Bae JH (1998) Brainderived neurotrophic factor rapidly potentiates synaptic transmission through NMDA, but suppresses it through non-NMDA receptors in rat hippocampal neuron. Brain Res 799:176–179
Bhave SV, Ghoda L, Hoffman PL (1999) Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascades and site of ethanol action. J Neurosci 19:3277–3286
Kovalchuk Y, Hanse E, Kafitz KW et al (2002) Postsynaptic induction of BDNF-mediated long-term potentiation. Science 295:1729–1734
Jiang X, Tian F, Mearow K et al (2005) The excitoprotective effect of N-methyl-d-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampus neurons. J Neurochem 94:713–722
Lu B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10:86–98
Nagappan G, Lu B (2005) Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Trends Neurosci 28:464–471
Yamada K, Nabeshima T (2004) Interaction of BDNF/TrkB signaling with NMDA receptor in learning and memory. Drug News Perspect 17:435–438
Barria A, Malinow R (2002) Subunit-specific NMDA receptor trafficking to synapses. Neuron 35:345–353
Fukaya M, Kato A, Lovett C et al (2003) Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice. Proc Natl Acad Sci USA 100:4855–4860
Wyllie DJ, Behe P, Colquhoun D (1998) Single-channel activations and concentration jumps: comparison of recombinant NR1a/NR2A and NR1a/NR2D NMDA receptors. J Physiol (Lond) 510:1–18
Clayton DA, Mesches MH, Alvarez E et al (2002) A hippocampal NR2B deficit can mimic age-related changes in long-term potentiation and spatial learning in the Fischer 344 rat. J Neurosci 22:3628–3637
Kamphuis PJ, Gardoni F, Kamal A et al (2003) Long-lasting effects of neonatal dexamethasone treatment on spatial learning and hippocampal synaptic plasticity: involvement of the NMDA receptor complex. FASEB J 17:911–913
Dunah AW, Wang Y, Yasuda RP et al (2000) Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson’s disease. Mol Pharmacol 57:342–352
Acknowledgments
The authors would like to thank Professor Shi XC for his critical comments on the experiments and manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huang, Y., Shi, X., Xu, H. et al. Chronic Unpredictable Stress Before Pregnancy Reduce the Expression of Brain-Derived Neurotrophic Factor and N-Methyl-D-Aspartate Receptor in Hippocampus of Offspring Rats Associated with Impairment of Memory. Neurochem Res 35, 1038–1049 (2010). https://doi.org/10.1007/s11064-010-0152-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-010-0152-0