Elsevier

Neuroscience

Volume 147, Issue 4, 29 July 2007, Pages 1022-1033
Neuroscience

Developmental neuroscience
Neurodevelopment milestone abnormalities in rats exposed to stress in early life

https://doi.org/10.1016/j.neuroscience.2007.04.007Get rights and content

Abstract

Manipulation of the corticosteroid milieu by interfering with the mother–newborn relationship has received much attention because of its potential bearing on psychopathology later in life. In the present study, infant rats that were deprived of maternal contact between the 2nd and the 15th postnatal days (MS2–15) for 6 h/day were subjected to a systematic assessment of neurodevelopmental milestones between postnatal days 2 and 21. The analyses included measurements of physical growth and maturation and evaluation of neurological reflexes. Although some somatic milestones (e.g. eye opening) were anticipated, MS2–15 animals showed retardation in the acquisition of postural reflex, air righting and surface righting reflexes, and in the wire suspension test; the latter two abnormalities were only found in males. A gender effect was also observed in negative geotaxis, with retardation being observed in females but not males. To better understand the delay of neurological maturation in MS2–15 rats, we determined the levels of various monoamines in different regions of the brain stem, including the vestibular area, the substantia nigra, ventral tegmental area and dorsal raphe nuclei. In the vestibular region of MS2–15 rats the levels of 5-HT were reduced, while 5-HT turnover was increased. There was also a significant increase of the 5-HT turnover in MS2–15 animals in the raphe nuclei, mainly due to increased 5-hydroxyindoleacetic acid (5-HIAA) levels, and an increase of 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the ventral tegmental area (VTA) of stressed females. No significant differences were found in the immunohistochemical sections for tyrosine and tryptophan hydroxylase in these regions of the brain stem. In conclusion, the present results show that postnatal stress induces signs of neurological pathology that may contribute to the genesis of behavioral abnormalities later in life.

Section snippets

Animals

Female primigestous Wistar rats (Charles River, Barcelona, Spain) were maintained under standard laboratory conditions under artificial 12-h light/dark cycle: lights on from 8:00 a.m. to 8:00 p.m., and an ambient temperature of 22 °C; food and water were available ad libitum. The day on which a female rat showed a vaginal plug was designated as embryonic day 0 and the day of delivery as postnatal day (PND) 0. Males were removed from the cage when a vaginal plug was confirmed. Nest material was

Effects of experimental procedures in maternal behavior

Maternal behavior was not significant affected by the separation of the pups as can be observed in Table 1. The only significant difference was related with the feeding time of the pups, which was increased during the observation period in maternal separated groups, probably as a compensation for the 6 h period of maternal separation (36.1 min for MS and 21.7 min for Cont).

Effects of maternal separation on basal corticosterone levels in pups and mothers

Statistical analysis showed that maternal separation significantly increased basal levels of corticosterone in both male (P

Discussion

Neurodevelopmental assessment typically includes analysis/scoring of physical growth and maturation and neurological reflexes (Spear 1990, Sousa et al 2006). Maturational parameters such as timing of ear and eye opening, teeth eruption, body weight and ano-genital distance measure the physical maturation. Dynamic tests of sensorimotor development, such as negative geotaxis, postural and righting reflexes, reflect maturation of vestibular function (Altman and Sudarshan 1975, Khan et al 2004),

Acknowledgments

We acknowledge the Portuguese Foundation for Science and Technology for providing a predoctoral fellowship to A. R. Mesquita (SFRH/BD/11838/2003) and postdoctoral one to T. Summavielle (SFRH/BPD/20997/2004).

References (55)

  • C.R. Pryce et al.

    Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research

    Neurosci Biobehav Rev

    (2005)
  • P. Rosenfeld et al.

    Multifactorial regulation of the hypothalamic-pituitary-adrenal axis during development

    Neurosci Biobehav Rev

    (1992)
  • M.L. Schneider et al.

    The impact of prenatal stress, fetal alcohol exposure, or both on development: perspectives from a primate model

    Psychoneuroendocrinology

    (2002)
  • P.F. Smith et al.

    The effects of vestibular lesions on hippocampal function in rats

    Prog Neurobiol

    (2005)
  • L.P. Spear

    Neurobehavioral assessment during the early postnatal period

    Neurotoxicol Teratol

    (1990)
  • P.N. Velazquez et al.

    Corticosterone therapy during gestation: effects on the development of rat cerebellum

    Int J Dev Neurosci

    (1987)
  • A. Vicentic et al.

    Maternal separation alters serotonergic transporter densities and serotonergic 1A receptors in rat brain

    Neuroscience

    (2006)
  • M. Weinstock

    Alterations induced by gestational stress in brain morphology and behaviour of the offspring

    Prog Neurobiol

    (2001)
  • I. Antonow-Schlorke et al.

    Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain

    J Physiol

    (2003)
  • I. Bellido et al.

    Corticosterone strongly increases the affinity of dorsal raphe 5-HT1A receptors

    Neuroreport

    (2004)
  • T. Brandt et al.

    Vestibular loss causes hippocampal atrophy and impaired spatial memory in humans

    Brain

    (2005)
  • S.A. Cameron et al.

    Lesion-induced plasticity in rat vestibular nucleus neurones dependent on glucocorticoid receptor activation

    J Physiol

    (1999)
  • A. Cintra et al.

    Strongly glucocorticoid receptor immunoreactive neurons in the neonatal rat brain

    Neuroreport

    (1991)
  • J. Crane et al.

    Antenatal corticosteroid therapy for fetal maturation

    J Obstet Gynaecol Can

    (2003)
  • H. Cransac et al.

    Monoamines (norepinephrine, dopamine, serotonin) in the rat medial vestibular nucleus: endogenous levels and turnover

    J Neural Transm

    (1996)
  • E.R. De Kloet et al.

    Brain corticosteroid receptor balance in health and disease

    Endocr Rev

    (1998)
  • S.A. Dunlop et al.

    Repeated prenatal corticosteroids delay myelination in the ovine central nervous system

    J Matern Fetal Med

    (1997)
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      A schematic representation of the experimental model is shown in Fig. 1. On postnatal days (PNDs) 2–15, the pups were separated from their mothers for 360 min (9:00 AM – 3:00 PM) (MS2–15360) as described by Mesquita et al. (2007) who reported the delay of neurological maturation of MS rats. PNDs 2–15 were previously demonstrated to be the “critical” period in early life, when stressful events disrupt the programming of the central and peripheral nervous systems that may increase susceptibility to emotional disorders later in life (Roque et al., 2014).

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