Skip to main content
    • Aa
    • Aa

Prenatal stress produces sex-specific changes in depression-like behavior in rats: implications for increased vulnerability in females

  • H. M. Sickmann (a1) (a2) (a3), T. S. Arentzen (a2), T. B. Dyrby (a3), N. Plath (a2) and M. P. Kristensen (a1)...

Stress during rat gestation can elicit depression-like physiological and behavioral responses in the offspring. However, human clinical depression is more prevalent among females than males. Accordingly, we examined how repeated variable prenatal stress (PS) alters rat anxiety- and depression-like behavior as well as circadian patterning of motor activity in both male and female offspring. For this purpose, we exposed pregnant Sprague–Dawley rats to multiple stressors during gestational days 13–21. Subsequently, we monitored locomotor and rearing/climbing activities in home-like cages for 24 h and measured anxiety- (elevated plus maze, EPM) and depression-like (forced swim test, FST) behaviors in the offspring at a young adult age. As a stressful event later in life (in addition to PS) may be needed to actually trigger an episode of clinical depression, half of the animals were exposed to an acute stressor (elevated platform) before EPM testing. Dams exposed to the stressor battery had increased plasma corticosterone levels compared with controls. Male PS offspring displayed changes in locomotor and rearing/climbing activity relative to controls. Additionally, anxiety measures in the EPM were affected in control animals after acute stressor exposure, however, this response was blunted in PS offspring. Moreover, FST immobility, as an indicator of depressive-like behavior, was increased in female but not male PS rats. Altogether, our results identify both sex- and circadian phase-specific effects of PS. These findings indicate that the PS rat model reflects multiple clinical depression characteristics, including elevated female vulnerability.

Corresponding author
*Address for correspondence: H. M. Sickmann, Department of Drug Design and Pharmacology, Jagtvej 160, DK-2100 Copenhagen Ø, Denmark. (Email
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1. K Kleinhaus , S Harlap , M Perrin , et al. Prenatal stress and affective disorders in a population birth cohort. Bipolar Disord. 2013; 15, 9299.

2. AC Huizink , PG Robles de Medina , EJ Mulder , GH Visser , JK Buitelaar . Stress during pregnancy is associated with developmental outcome in infancy. J Child Psychol Psychiatry. 2003; 44, 810818.

7. S Morley-Fletcher , J Mairesse , A Soumier , et al. Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats. Psychopharmacology (Berl). 2011; 217, 301313.

11. JA Markham , AR Taylor , SB Taylor , DB Bell , JI Koenig . Characterization of the cognitive impairments induced by prenatal exposure to stress in the rat. Front Behav Neurosci. 2010; 4, 173.

14. A Armario . The hypothalamic-pituitary-adrenal axis: what can it tell us about stressors? CNS Neurol Disord Drug Targets. 2006; 5, 485501.

15. N Daviu , C Rabasa , R Nadal , A Armario . Comparison of the effects of single and daily repeated immobilization stress on resting activity and heterotypic sensitization of the hypothalamic-pituitary-adrenal axis. Stress. 2014; 17, 176185.

18. M Weinstock . Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem Res. 2007; 32, 17301740.

19. M Darnaudery , S Maccari . Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev. 2008; 57, 571585.

20. S Baker , C Bielajew . Influence of housing on the consequences of chronic mild stress in female rats. Stress. 2007; 10, 283293.

21. PS Brocardo , F Boehme , AR Patten , et al. Anxiety- and depression-like behaviors are accompanied by an increase in oxidative stress in a rat model of fetal alcohol spectrum disorders: protective effects of voluntary physical exercise. Neuropharmacology. 2012; 62, 16071608.

23. AA Walf , CA Frye . The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc. 2007; 2, 322328.

24. MJ Detke , M Rickels , I Lucki . Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl). 1995; 121, 6672.

25. F Borsini , A Meli . Is the forced swimming test a suitable model for revealing antidepressant activity? Psychopharmacology (Berl). 1988; 94, 147160.

26. C Bielajew , ATM Konkle , AC Kentner , et al. Strain and gender specific effects in the forced swim test: effects of previous stress exposure. Stress. 2003; 6, 269280.

27. T Szuran , E Zimmerman , V Pliska , HP Pfister , H Welzl . Prenatal stress effects on exploratory activity and stress-induced analgesia in rats. Dev Psychobiol. 1991; 24, 361372.

30. A Guo , RE Nappi , M Criscuolo , et al. Effect of chronic intermittent stress on rat pregnancy and postnatal development. Eur J Obstet Gynecol Reprod Biol. 1993; 51, 4145.

31. MA Berger , VG Barros , MI Sarchi , FI Tarazi , MC Antonelli . Long-term effects of prenatal stress on dopamine and glutamate recptors in the adult rat brain. Neurochem Res. 2002; 27, 15251533.

34. AC Volker , JHM Tulen , WW Van den Broek , et al. Motor activity and autonomic cardiac functioning in major depressive disorder. J Affective Dis. 2003; 76, 2330.

35. DT Fullerton , FJ Wenzel , FN Lohrenz , H Fahs . Circadian rhythm of adrenal cortical activity in depression. I. A comparison of depressed patients with normal subjects. Arch Gen Psychiatry. 1968; 19, 674681.

36. N Tsuno , A Besset , K Ritchie . Sleep and depression. J Clin Psychiatry. 2005; 66, 12541269.

37. AS Urrila , L Karlsson , O Kiviruusu , et al. Sleep complaints among adolescent outpatients with major depressive disorder. Sleep Med. 2012; 13, 816823.

40. H Abe , N Hidaka , C Kawagoe , et al. Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis. Neurosci Res. 2007; 59, 145151.

41. E Fride , Y Dan , J Feldon , G Halevy , M Weinstock . Effects of prenatal stress on vulnerability to stress in prepubertal and adult rats. Physiol Behav. 1986; 37, 681687.

43. Y Huang , S Chen , H Xu , et al. Pre-gestational stress alters stress-response of pubertal offspring rat in sexually dimorphic and hemispherically asymmetric manner. BMC Neurosci. 2013; 14, 67.

44. N Mendez , L Abarzua-Catalan , N Vilches , et al. Timed maternal melatonin treatment reverses circadian disruption of the fetal adrenal clock imposed by exposure to constant light. PLoS One. 2012; 7, e42713.

46. TE Moffitt , H Harrington , A Caspi , et al. Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. Arch Gen Psychiatry. 2007; 64, 651660.

47. A Wakshlak , M Weinstock . Neonatal handling reverses behavioral abnormalities induced in rats by prenatal stress. Physiol Behav. 1990; 48, 289292.

48. L Guan , N Jia , X Zhao , et al. The involvement of ERK/CREB/Bcl-2 in depression-like behavior in prenatally stressed offspring rats. Brain Res Bull. 2013; 99, 18.

49. IQ Whishaw , OA Gharbawie , BJ Clark , H Lehmann . The exploratory behavior of rats in an open environment optimizes security. Behav Brain Res. 2006; 171, 230239.

50. VG Barros , P Rodriguez , ID Martijena , et al. Prenatal stress and early adoption effects on benzodiazepine receptors and anxiogenic behavior in the adult rat brain. Synapse. 2006; 60, 609618.

54. A Russel . Relationships between exploratory behavior and fear: a review. Br J Psychol. 1973; 64, 417433.

55. JC Joshi , A Ray , K Gulati . Differential modulatory effects of morphine on acute and chronic stress induced neurobehavioral and cellular markers in rats. Eur J Pharmacol. 2014; 729, 1721.

57. RD Porsolt , PM Le , M Jalfre . Depression: a new animal model sensitive to antidepressant treatments. Nature. 1977; 266, 730732.

58. Y Kitada , T Miyauchi , A Satoh , S Satoh . Effects of antidepressants in the rats forced swimming test. Eur J Pharmacol. 1981; 72, 145152.

61. DL Van den Hove , G Kenis , A Brass , et al. Vulnerability versus resilience to prenatal stress in male and female rats; implications from gene expression profiles in the hippocampus and frontal cortex. Eur Neuropsychopharmacol. 2013; 23, 12261246.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 4
Total number of PDF views: 43 *
Loading metrics...

Abstract views

Total abstract views: 203 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 25th June 2017. This data will be updated every 24 hours.