Abstract
Early development of the brain’s neural circuitry has been shown to be vulnerable to high levels of circulating steroid hormones such as corticosterone. These steroid hormones are lipophylic and can cross the placental barrier especially during the last week of gestation leading to disturbances in the formation of neural circuits that contain amongst others dopaminergic and serotonergic neurons. The effects of this disruption of neuronal circuit formation during gestation has been shown to manifest in adult offspring as behavioural abnormalities such as anxiety and an abnormal hypothalamic-pituitary-adrenal (HPA) axis. Models of prenatal stress include food deprivation and a model that involves exposure of the pregnant rats to different stressors, commonly referred to as a mild stress model. The objective of this study was to create a mild stress model that did not manifest as anxiety in adult offspring. In the last week of gestation, the pregnant dams were divided into three groups; (1) non-stressed (2) 50% food-deprived and (3) mildly stressed rats that we will refer to as the mildly stressed rats. Following birth, all pups were cross-fostered onto non-stressed dams and on postnatal day 60 (P60), behaviour in the elevated plus maze and the open field box was tested. On P66 the rats were exposed to an acute restraint stress following which trunk blood was collected for HPA axis analysis. The adrenal glands were also dissected and weighed. Results show that the mildly stressed rat model of prenatal stress is even milder than models described in the literature, since we did not find differences in time spent in the open arms of the elevated plus maze or adrenal gland size. In the open field, our model displayed slightly less locomotor activity and also had a slightly blunted adrenocorticotropic hormone (ACTH) response to restraint stress even though the corticosterone response was similar to controls.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Buitelaar JK, Huizink AC, Mulder EJ, de Medina PG, Visser GH (2003) Prenatal stress and cognitive development and temperament in infants. Neurobiol Aging 24:S53–S60
Castro SL, Zigmond MJ (2001) Stress-induced increase in extracellular dopamine in striatum: role of glutaminergic action via N-methyl-D-aspartate receptors in substantia nigra. Brain Res 901:47–54
Dallman MF (2000) Editorial: moments in time–the neonatal rat hypothalamo-pituitary-adrenal axis. Endocrinology 141:1590–1592
Daniels WM, Pietersen CY, Carstens ME, Stein DJ (2004) Maternal separation in rats leads to anxiety-like behavior and a blunted ACTH response and altered neurotransmitter levels in response to a subsequent stressor. Metab Brain Dis 19:3–14
Darnaudéry M, Dutriez I, Viltart O, Morley-Fletcher S, Maccari S (2004) Stress during gestation induces lasting effects on emotional reactivity of the dam rat. Behav Brain Res 153:211–216
de Kloet ER, Oitzl MS (2003) Who cares for a stressed brain? The mother, the kid or both? Neurobiol Aging 24:S61–S65
de Kloet ER, Joëls M, Holsboer F (2005) Stress and the brain: from adaptation to disease. Nat Rev Neurosci 6:463–475
Fujioka T, Fujioka A, Tan N, Chowdhury GMI, Mouri H, Sakata Y, Nakamura S (2001) Mild prenatal stress enhances learning performance in the non-adopted rat offspring. Neuroscience 103:301–307
Griffin WC III, Skinner HD, Salm AK, Birkle DL (2003) Mild prenatal stress in rats is associated with enhanced conditioned fear. Physiol Behav 79:209–215
Ishiwata H, Shiga T, Okado N (2005) Selective serotonin reuptake inhibitor treatment of early postnatal mice reverses their prenatal stress-induced brain dysfunction. Neuroscience 133:893–901
Ježová D, Škultėtyová I, Makatsori A, Monček F, Dunčko R (2002) Hypothalamo-pituitary-adrenocortical axis function and hedonic behavior in adult male and female rats prenatally stressed by maternal food restriction. Stress 5:177–183
Kehoe P, Mallinson K, Bronzino J, McCormick CM (2001) Effects of prenatal protein malnutrition and neonatal stress on CNS responsiveness. Dev Brain Res 132:23–31
Kofman O (2002) The role of prenatal stress in the etiology of development behavioural disorders. Neurosci Biobehav Rev 26:457–470
Lesage J, Dufourny L, Laborie C, Bernet F, Blondeau B, Avril I, Bréant B, Dupouy JP (2002) Perinatal malnutrition programs sympathoadrenal and hypothalamic-pituitary-adrenal axis responsiveness to restraint stress in adult male rats. J Neuroendocrinol 14:135–143
Marcondes FK, Bianchi FJ, Tanno AP (2002) Determination of the estrous cycle phases of rats: some helpful considerations. Braz J Biol 62:609–614
McFadyen-Leussis MP, Lewis SP, Bond TLY, Carrey N, Brown RE (2004) Prenatal exposure to methylphenidate hydrochloride decreases anxiety and increases exploration in mice. Pharmacol Biochem Behav 77:491–500
Nishio H, Kasuga S, Ushijima M, Harada Y (2001) Prenatal stress and postnatal development of neonatal rats—sex-dependent effects on emotional behavior and learning ability of neonatal rats. Int J Dev Neurosci 19:37–45
Olausson H, Uvnäs-Moberg K, Sohlström A (2003) Postnatal oxytocin alleviates adverse effects in adult rat offspring caused by maternal malnutrition. Am J Physiol Endocrinol Metab 284:E475–E480
Ozaki T, Nishina H, Hanson MA, Poston L (2001) Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring. J Physiol (Lond) 530:141–152
Sapolsky RM, Meaney MJ (1986) Maturation of the adrenocortical stress response: neuroendocrine control mechanisms and the stress hyporesponsive period. Brain Res 396:64–76
Smith JW, Seckl JR, Evans AT, Costall B, Smythe JW (2004) Gestational stress induces post-partum depression-like behaviour and alters maternal care in rats. Psychoneuroendocrinology 29:227–244
Sternberg WF, Ridgway CG (2003) Effects of gestational stress and neonatal handling on pain, analgesia, and stress behavior of adult mice. Physiol Behav 78:375–383
Szuran TF, Pliška V, Pokorny J, Welzl H (2000) Prenatal stress in rats: effects on plasma corticosterone, hippocampal glucocorticoid receptors and maze performance. Physiol Behav 71:353–362
Ward HE, Johnson EA, Salm AK, Birkle DL (2000) Effects of prenatal stress on defensive withdrawal behavior and corticotropin releasing factor systems in rat brain. Physiol Behav 70:359–366
Acknowlegements
The authors wish to thank Ms. Thabelo Khoboko and Mrs. Lelanie Marais for technical assistance, Mr. Charles Harris for manufacturing equipment, and Ms. Susan Giegel for assistance with preparation of the manuscript. This work was supported by the Medical Research Council of South Africa, the University of Cape Town, and by NIH Fogarty International Center grant R21DA018087 to Michael J. Zigmond, principal investigator.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mabandla, M.V., Dobson, B., Johnson, S. et al. Development of a mild prenatal stress rat model to study long term effects on neural function and survival. Metab Brain Dis 23, 31–42 (2008). https://doi.org/10.1007/s11011-007-9049-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-007-9049-2