Reproductive experience alters the involvement of N-methyl-D-aspartate receptors in fear extinction, but not fear conditioning, in female Sprague Dawley rats
- 90 Downloads
Recently, evidence has emerged showing that the behavioural and hormonal features of fear extinction are altered as a result of reproductive experience in both rats and humans. The current set of experiments sought to determine whether reproductive experience also alters the molecular features of fear extinction. In adult male rats, it has been widely demonstrated that the activation of N-methyl-d-aspartate receptors (NMDAR) is essential for fear extinction. We therefore compared the involvement of NMDAR in fear extinction between nulliparous (virgin) and primiparous (reproductively experienced) female rats. Nulliparous and primiparous females received systemic administrations of either MK-801 (a non-competitive NMDAR antagonist) or saline prior to extinction training. MK-801 was found to impair extinction recall in nulliparous females, but not primiparous females. When the same dose of MK-801 was administered prior to conditioning, both groups of rats showed impaired recall of conditioning the following day. The results of these experiments indicate that the extinction, but not the acquisition of fear, may become NMDAR-independent following reproductive experience.
KeywordsAnxiety disorders Fear extinction Fear conditioning NMDA receptors Reproductive experience
This work was supported by grants from the Australian Research Council (DE140100243 and DP180101563) to BMG and an Australian Postgraduate Award to ST.
Compliance with ethical standards
All rats were treated according to The Australian Code of Practice for the Care and Use of Animals for Scientific Purposes (8th edition), and all procedures were approved by the Animal Care and Ethics Committee at The University of New South Wales.
Conflicts of interest
The authors declare that they have no conflict of interest.
- Barha CK, Dalton GL, Galea LAM (2010) Low doses of 17 alpha-estradiol and 17 bold italic beta-estradiol facilitate, whereas higher doses of estrone and 17 alpha-and 17 bold italic beta-estradiol impair, contextual fear conditioning in adult female rats. Neuropsychopharmacology 35:547–559. https://doi.org/10.1038/npp.2009.161 CrossRefPubMedGoogle Scholar
- Fanselow MS (1980) Conditional and unconditional components of post-shock freezing. Pavlovian J Biol Sci 15:177–182Google Scholar
- Kinsley CH, Trainer R, Stafisso-Sandoz G, Quadros P, Marcus LK, Hearon C, Meyer EA, Hester N, Morgan M, Kozub FJ, Lambert KG (2006) Motherhood and the hormones of pregnancy modify concentrations of hippocampal neuronal dendritic spines. Horm Behav 49:131–142. https://doi.org/10.1016/j.yhbeh.2005.05.017 CrossRefPubMedGoogle Scholar
- Lemaire V, Billard JM, Dutar P, George O, Piazza PV, Epelbaum J, le Moal M, Mayo W (2006) Motherhood-induced memory improvement persists across lifespan in rats but is abolished by a gestational stress. Eur J Neurosci 23:3368–3374. https://doi.org/10.1111/j.1460-9568.2006.04870.x CrossRefPubMedGoogle Scholar
- Lewis MC, Kerr KM, Orr PT, Frick KM (2008) Estradiol-induced enhancement of object memory consolidation involves NMDA receptors and protein kinase A in the dorsal hippocampus of female C57BL/6 mice. Behav Neurosci 122:716–721. https://doi.org/10.1037/0735-7044.122.3.716 CrossRefPubMedPubMedCentralGoogle Scholar
- Liu IYC, Lyons WE, Mamounas LA, Thompson RF (2004) Brain-derived neurotrophic factor plays a critical role in contextual fear conditioning J Neurosci 24:7958–7963. doi: https://doi.org/10.1037/h0042199
- Liu JL, Li M, Dang XR, Wang ZH, Rao ZR, Wu SX, Li YQ, Wang W (2009) A NMDA receptor antagonist, MK-801 impairs consolidating extinction of auditory conditioned fear responses in a Pavlovian model. PLoS One 4:e7548. https://doi.org/10.1371/journal.pone.0007548 CrossRefPubMedPubMedCentralGoogle Scholar
- Markus EJ, Zecevic M (1997) Sex differences and estrous cycle changes in hippocampus-dependent fear conditioning. Psychobiol 25:246–252Google Scholar
- Milad MR, Igoe SA, Lebron-Milad K, Novales JE (2009) Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 164:887–895. https://doi.org/10.1016/j.neuroscience.2009.09.011 CrossRefPubMedPubMedCentralGoogle Scholar
- Milligan-Saville JS, Graham BG (2016) Mothers do it differently: reproductive experience alters fear extinction in female rats and women. Transl Psychiatry 6:e928Google Scholar
- Monte LM, Ellis RR (2014) Fertility of women in the United States: 2012. Econ 24:1071–1100Google Scholar
- Pawluski JL, Vanderbyl BL, Ragan K, Galea LA (2006) First reproductive experience persistently affects spatial reference and working memory in the mother and these effects are not due to pregnancy or ‘mothering’ alone. Behav Brain Res 175:157–165. https://doi.org/10.1016/j.bbr.2006.08.017 CrossRefPubMedGoogle Scholar
- Rasia-Filho AA, Fabian C, Rigoti KM, Achaval M (2004) Influence of sex, estrous cycle and motherhood on dendritic spine density in the rat medial amygdala revealed by the Golgi method. Neuroscience 126:839–847. https://doi.org/10.1016/j.neuroscience.2004.04.009 CrossRefPubMedGoogle Scholar