Periodic Maternal Deprivation Induces Gender-Dependent Alterations in Behavioral and Neuroendocrine Responses to Emotional Stress in Adult Rats

doi:10.1016/S0031-9384(98)00300-X

Physiology & Behavior

Volume 66, Issue 2, April 1999, Pages 293-302

https://doi.org/10.1016/S0031-9384(98)00300-X Get rights and content

Abstract

There is evidence that stressful events during the neonatal “stress hyporesponsive period” may influence both emotional behavior and the maturation of the hypothalamic–pituitary–adrenal (HPA) axis in rats. We tested whether periodic maternal deprivation (180 min daily on postnatal days 3–10, PMD) caused chronic changes in emotional behavior and HPA axis activity in either male or female adult rats, or both. In addition, HPA secretory responses to human/rat corticotropin-releasing factor (CRH, 50 ng/kg i.v.) were determined in the adult males. In the elevated plus-maze test, adult (4–5 months of age) PMD-treated animals of both sexes displayed increased anxiety-related behavior compared to control rats. This was indicated by a reduction in the number of entries (male: 70% reduction, p < 0.01; female: 31% reduction, p < 0.01) and amount of time spent on the open arms (male: 86% reduction, p < 0.01; female: 40% reduction, NS). Neuroendocrine parameters were also altered in PMD-treated rats in a gender-dependent manner. Whereas basal plasma adrenocorticotropin (ACTH) and corticosterone levels did not differ significantly between PMD and control groups of either sex, the ACTH response to elevated plus-maze exposure, a predominantly emotional stressor, was higher in male (p < 0.01), but not female, PMD animals than in the respective controls. In contrast, PMD had no effect on behavioral (duration of struggling) or HPA axis responses to forced swimming (90 s, 19°C), a complex and predominantly physical stressor, in either male or female rats. In response to CRH stimulation, PMD-treated males did not show differences in the ACTH secretion compared to controls, indicating alterations in HPA axis regulation at a suprapituitary level. Thus, PMD caused long-term changes in the emotional behavior of adult rats of both sexes, although to a differing degree in males and females, whereas it appeared to cause predominantly alterations in the HPA axis response in males, depending on the characteristics of the stressor used.

Section snippets

Animals

Virgin female rats (Wistar, 260–290 g body weight (b.wt.), Charles River, Sulzfeld, Germany) were mated overnight with sexually experienced males, and pregnancy was confirmed by the presence of sperm in the vaginal smears on the next morning (pregnancy day 1). The pregnant rats (n = 6) were housed singly in standard rat cages (40 × 60 cm, 20 cm in height) and maintained under standard laboratory conditions (12:12 h light:dark cycle, lights on at 0700 h, 22°C, 60% humidity, food and water ad

Basal Endocrine Status (Experimental Day 1)

Mean basal levels of plasma ACTH were not significantly altered by postnatal stress either in male or female rats [two-way ANOVA; treatment, F(1, 33) = 2.17, p = 0.15; sex, F(1, 33) = 1.53, p = 0.23; interaction, F(1, 33) = 0.26, p = 0.61; Fig. 1]. Similarly, basal concentrations of plasma corticosterone did not differ significantly in male or female rats after PMD [two-way ANOVA; treatment, F(1, 33) = 1.90, p = 0.67; sex, F(1, 33) = 4.95, p = 0.034; interaction, F(1, 33) = 0.29, p = 0.60;

Discussion

In the present study we demonstrated that repeated maternal deprivation (PMD) for 180 min daily between Days 3 and 12 of life, considered a chronic intermittent postnatal stress (5), produced long-term changes in emotional behavior and in HPA axis responsiveness in rats. In addition, we detected gender-specific effects of PMD on the emotional behavior and HPA axis responsiveness of the rats that appeared to be dependent on the stressor used. As adults, both male and female PMD-treated rats

Acknowledgements

The authors appreciate the excellent technical assistance by P. Lörscher, J. Ganster, and R. Simchen. We also thank G. Kohl and G. Miedl for their professional handling of the radioimmunoassays, and Drs. R. Landgraf, T. Day, and P. Plotsky for their critical reading of the manuscript; and Dr. A. Yassouridis for advice for the performance of the statistical analysis. This work was supported by the Deutsche Forschungsgemeinschaft (DFG). I.D.N. is in receipt of a Heisenberg stipend from the DFG.

References (64)

E.L. Abel
A further analysis of physiological changes in rats in the forced swim test
Physiol. Behav.
(1994)
A. Armario et al.
Forced swimming test in ratsEffect of desipramine administration and the period of exposure to the test on struggling behaviour, swimming, immobility and defecation rate
Eur. J. Physiol.
(1988)
S.R. Bodnoff et al.
Postnatal handling reduces novelty-induced fear and increases [³H]flunitrazepam binding in rat brain
Eur. J. Pharmacol.
(1987)
S. Cabib et al.
Effects of postnatal stress on dopamine mesolimbic system responses to aversive experiences in adult life
Brain Res.
(1993)
E.R. DeKloet et al.
Stress, glucocorticoids and development
A.J. Dunn et al.
Physiological and behavioral responses to corticotropin-releasing factor administrationIs CRF a mediator of anxiety or stress responses?
Brain Res. Rev.
(1990)
C.L. Ehlers et al.
Effects of gender and social isolation on electroenecephalogram and neuroendocrine parameters in rats
Biol. Psychol.
(1993)
S.C. Heinrichs et al.
Corticotropin-releasing factor antagonist reduces emotionality in socially defeated rats via direct neurotropic action
Brain Res.
(1992)
M.B. Hennessy et al.
Adrenocortical activity during conditions of brief social separation in preweaning rats
Behav. Neural Biol.
(1990)
S.J. Kelly et al.
Indices of stress in ratsEffects of sex, perinatal alcohol and artificial rearing
Physiol. Behav.
(1991)

S. Kent et al.

Effects of excitatory amino acids on the hypothalamic–pituitary–adrenal axis of the neonatal rat

Dev. Brain Res.

(1996)

G. Liebsch et al.

Chronic infusion of a CRH₁ receptor antisense oligodeoxynucleotide into the central nucleus of the amygdala reduced anxiety-related behavior in socially defeated rats

Regul. Pept.

(1995)

G.C. Liggins

Adrenocortical-related maturational events in the fetus

Am. J. Obstet. Gynecol.

(1976)

A.B. Lucion et al.

Influence of early postnatal gonadal hormones on anxiety in adult male rats

Physiol. Behav.

(1996)

K. Matthews et al.

Repeated maternal separation of preweanling rats attenuates behavioral responses to primary and conditioned incentives in adulthood

Physiol. Behav.

(1996)

M.J. Meaney et al.

The effects of early postnatal handling on hippocampal glucocorticoid receptor concentrationsTemporal parameters

Dev. Brain Res.

(1985)

M.J. Meaney et al.

The effects of neonatal handling on the development of the adrenocortical response to stressImplications for neuropathology and cognitive deficits in later life

Psychoneuroendocrinology

(1991)

L.R. Noonan et al.

Neonatal stress transiently alters the development of hippocampal oxytocin receptors

Dev. Brain Res.

(1994)

D. O’Donnell et al.

Postnatal handling alters glucocorticoid, but not mineralocorticoid messenger RNA expression in the hippocampus of adult rats

Mol. Brain Res.

(1994)

T. Ogawa et al.

Periodic maternal deprivation alters stress response in adult offspringPotentiates the negative feedback regulation of restraint stress-induced adrenocortical response and reduces the frequencies of open field-induced behaviors

Pharmacol. Biochem. Behav.

(1994)

S. Pellow et al.

Validation of open:closed arms entries in an elevated plus-maze as a measure of anxiety in the rat

J. Neurosci. Methods

(1985)

J.M. Petitto et al.

Relationship of object loss during development to hypothalamo–pituitary–adrenal axis function during major affective illness later in life

Psychol. Res.

(1992)

P.M. Plotsky et al.

Early postnatal experience alters hypothalamic corticotropin-releasing factor (CRF) mRNA, median eminence CRF content and stress induced release in adult rats

Brain Res.

(1993)

P. Rosenfeld et al.

Maternal regulation of the adrenocortical response in preweanling rats

Physiol. Behav.

(1991)

P. Rosenfeld et al.

Effects of repeated maternal separations on the adrenocortical response to stress of preweanling rats

Physiol. Behav.

(1992)

R.M. Sapolsky et al.

Maturation of the adrenocortical stress responseNeuroendocrine control mechanisms and the stress hyporesponsive period

Brain Res. Rev.

(1986)

D. Servant et al.

Early life events and panic disorderCourse of illness and comorbidity

Prog. Neuropsychopharmacol. Biol. Psychiatry

(1994)

D. Suchecki et al.

Maternal regulation of the hypothalamic pituitary–adrenal axis in the infant ratThe roles of feeding and stroking

Dev. Brain Res.

(1993)

D. Suchecki et al.

Activation and inhibition of the hypothalamic–pituitary–adrenal axis of the neonatal ratEffects of maternal deprivation

Psychoneuroendocrinology

(1995)

D.M. Vázquez et al.

Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat

Brain Res.

(1996)

M. Weinstock

Does prenatal stress impair coping and regulation of hypothalamic–pituitary–adrenal axis?

Neurosci. Biobehav. Rev.

(1997)

C. Caldji et al.

Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat

Proc. Natl. Acad. Sci. USA

(1998)

Cited by (405)

Long-term impacts of prenatal maternal immune activation and postnatal maternal separation on maternal behavior in adult female rats: Relevance to postpartum mental disorders
2024, Behavioural Brain Research
Early life adversities are known to exert long-term negative impacts on psychological and brain functions in adulthood. The present work examined how a prenatal brain insult and a postnatal stressor independently or interactively influence the quality of maternal care of postpartum female rats and their cognitive and emotional functions, as a way to identify the behavioral dysfunctions underlying childhood trauma-induced postpartum mental disorders (as indexed by impaired maternal care). Sprague-Dawley female offspring born from mother rats exposed to polyinosinic:polycytidylic acid (PolyI:C, 4.0–6.0 mg/kg) intended to cause gestational maternal immune activation (MIA) or saline were subjected to a repeated maternal separation stress (RMS, 3 h/day) or no separation for 9 days in the first two weeks of life (a 2 × 2 design). When these offspring became mothers, their attentional filtering ability (as measured in the prepulse inhibition of acoustic startle reflex test), positive hedonic response (as measured in the sucrose preference test), and negative emotional response (as measured in the startle reflex and fear-potentiated startle test) were examined, along with their home-cage maternal behavior. Virgin littermates served as controls in all the behavioral tests except in maternal behavior. Results showed that mother rats who experienced RMS displayed impaired nest building and crouching/nursing activities. RMS also interacted with MIA to alter pup retrieval latency and startle reactivity, such that MIA-RMS dams demonstrated significantly slower pup retrieval latency and higher startle magnitude compared to either RMS-only and MIA-only mothers. MIA also disrupted attentional filtering ability, with significantly lower prepulse inhibition. However, neither prenatal MIA nor postnatal RMS impaired sucrose preference or the acquisition of fear-potentiated startle. These results indicate that prenatal stress and postnatal adversity could impair maternal behavior individually, and interact with each other, causing impairments in attention, emotion and maternal motivation.
Subcutaneous Mycobacterium vaccae ameliorates the effects of early life adversity alone or in combination with chronic stress during adulthood in male and female mice
2023, Neurobiology of Stress
Chronic psychosocial stress is a burden of modern society and poses a clear risk factor for a plethora of somatic and affective disorders, of which most are associated with an activated immune status and chronic low-grade inflammation. Preclinical and clinical studies further suggest that a failure in immunoregulation promotes an over-reaction of the inflammatory stress response and, thus, predisposes an individual to the development of stress-related disorders. Therefore, all genetic (i.e., sex) and environmental (i.e., early life adversity; ELA) factors facilitating an adult's inflammatory stress response are likely to increase their stress vulnerability.
In the present study we investigated whether repeated subcutaneous (s.c.) administrations with a heat-killed preparation of Mycobacterium vaccae (M. vaccae; National Collection of Type Cultures (NCTC) 11659), an abundant soil saprophyte with immunoregulatory properties, are protective against negative behavioral, immunological and physiological consequences of ELA alone or of ELA followed by chronic psychosocial stress during adulthood (CAS) in male and female mice. ELA was induced by the maternal separation (MS) paradigm, CAS was induced by 19 days of chronic subordinate colony housing (CSC) in males and by a 7-week exposure to the social instability paradigm (SIP) in females.
Our data indicate that ELA effects in both sexes, although relatively mild, were to a great extent prevented by subsequent s.c. M. vaccae administrations. Moreover, although the use of different paradigms for males and females impedes a direct comparison, male mice seemed to be more susceptible to CAS than females, with only females benefitting slightly from the stress protective effects of s.c. M. vaccae administrations when given prior to CAS alone. Finally, our data support the hypothesis that female mice are more vulnerable to the additive effects of ELA and CAS than male mice and that s.c. M. vaccae administrations subsequent to ELA but prior to CAS are protective in both sexes.
Taken together and considering the limitation that CAS in males and females was induced by different paradigms, our findings are consistent with the hypotheses that murine stress vulnerability during different phases of life is strongly sex dependent and that developing immunoregulatory approaches, such as repeated s.c. administrations with immunoregulatory microorganisms, have potential for prevention/treatment of stress-related disorders.
Selective breeding of rats for high (HAB) and low (LAB) anxiety-related behaviour: A unique model for comorbid depression and social dysfunctions
2023, Neuroscience and Biobehavioral Reviews
Animal models of selective breeding for extremes in emotionality are a strong experimental approach to model psychopathologies. They became indispensable in order to increase our understanding of neurobiological, genetic, epigenetic, hormonal, and environmental mechanisms contributing to anxiety disorders and their association with depressive symptoms or social deficits. In the present review, we extensively discuss Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze. After 30 years of breeding, we can confirm the prominent differences between HAB and LAB rats in trait anxiety, which are accompanied by consistent differences in depressive-like, social and cognitive behaviours. We can further confirm a single nucleotide polymorphism in the vasopressin promotor of HAB rats causative for neuropeptide overexpression, and show that low (or high) anxiety and fear levels are unlikely due to visual dysfunctions. Thus, HAB and LAB rats continue to exist as a reliable tool to study the multiple facets underlying the pathology of high trait anxiety and its comorbidity with depression-like behaviour and social dysfunctions.
Sex differences in addiction-relevant behavioral outcomes in rodents following early life stress
2023, Addiction Neuroscience
In humans, exposure to early life stress (ELS) is an established risk factor for the development of substance use disorders (SUDs) during later life. Similarly, rodents exposed to ELS involving disrupted mother-infant interactions, such as maternal separation (MS) or adverse caregiving due to scarcity-adversity induced by limited bedding and nesting (LBN) conditions, also exhibit long-term alterations in alcohol and drug consumption. In both humans and rodents, there is a range of addiction-related behaviors that are associated with drug use and even predictive of subsequent SUDs. In rodents, these include increased anxiety-like behavior, impulsivity, and novelty-seeking, altered alcohol and drug intake patterns, as well as disrupted reward-related processes involving consummatory and social behaviors. Importantly, the expression of these behaviors often varies throughout the lifespan. Moreover, preclinical studies suggest that sex differences play a role in how exposure to ELS impacts reward and addiction-related phenotypes as well as underlying brain reward circuitry. Here, addiction-relevant behavioral outcomes and mesolimbic dopamine (DA) dysfunction resulting from ELS in the form of MS and LBN are discussed with a focus on age- and sex-dependent effects. Overall, these findings suggest that ELS may increase susceptibility for later life drug use and SUDs by interfering with the normal maturation of reward-related brain and behavioral function.
Long-lasting and sex-dependent effects of late lactational maternal deprivation on socioemotional behaviors in adult mice
2023, Neuroscience Letters
The lactation period is an important period for individual development and a sensitive period for the behavioral phenotypes and plasticity of individual offspring. Early life experiences (e.g., maternal deprivation (MD) and neglect) have significant long-lasting and dual effects on individual stress reactivities during adulthood. Theoretically, stress inoculation can improve the adaptive capacity of the body, but overstress can lead to dysfunction when adaptive mechanisms fail. To date, the potential effects of late lactational MD on the socioemotional behaviors of mouse offspring during adulthood are still not fully understood. In the present study, mice were subjected to early deprivation by individually separating pups from their dam for 0 min, 15 min, and 3 h per day from PND 13–25. The social dominance test (SDT), social interaction test (SI), open field test (OFT), and forced swim test (FST) were carried out during adulthood. The results showed that the social dominance of male mice in the 15 min/d MD group significantly increased, especially in low-rank mice. In the 3 h/d MD group, the social dominance of female mice was decreased, especially in the lower-rank mice. The anxiolytic and antidepressant-like effects of the 15 min/d MD group were significantly increased in male mice. Our study provides direct evidence that MD during late lactation period results in long-lasting effects on social dominance as well as on anxiety and depression phenotypes in a sex-dependent manner.
Sex matters: The impact of oxytocin on healthy conditions and psychiatric disorders
2023, Comprehensive Psychoneuroendocrinology
Oxytocin (OT) is involved in the regulation of physiological processes and emotional states, with increasing evidence for its beneficial actions being mediated by the autonomic and immune systems. Growing evidence suggests that OT plays a role in the pathophysiology of different psychiatric disorders. Given the limited information in humans the aim of this study was to retrospectively explore plasma OT levels in psychiatric patients, particularly focusing on sex-related differences, as compared with healthy controls. The patients studied here were divided into three groups diagnosed with obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). Plasma OT levels were significantly different between healthy men and women, with the latter showing higher values, while none of the three psychiatric groups showed sex-related differences in the parameters measured here. The intergroup analyses showed that the OT levels were significantly higher in OCD, lower in PTSD and even more reduced in MDD patients than in healthy subjects. These differences were also confirmed when gender was considered, with the exception of PTSD men, in whom OT levels were similar to those of healthy men. The present results indicated that OT levels were higher amongst healthy women than men, while a sex difference was less apparent or reversed in psychiatric patients. Reductions in sex differences in psychopathologies may be related to differential vulnerabilities in processes associated with basic adaptive and social functions.

View all citing articles on Scopus

View full text

ArticlesPeriodic Maternal Deprivation Induces Gender-Dependent Alterations in Behavioral and Neuroendocrine Responses to Emotional Stress in Adult Rats

Abstract

Section snippets

Animals

Basal Endocrine Status (Experimental Day 1)

Discussion

Acknowledgements

Physiol. Behav.

Eur. J. Physiol.

Eur. J. Pharmacol.

Brain Res.

Brain Res. Rev.

Biol. Psychol.

Brain Res.

Behav. Neural Biol.

Physiol. Behav.

Dev. Brain Res.

Regul. Pept.

Am. J. Obstet. Gynecol.

Physiol. Behav.

Physiol. Behav.

Dev. Brain Res.

Psychoneuroendocrinology

Dev. Brain Res.

Mol. Brain Res.

Pharmacol. Biochem. Behav.

J. Neurosci. Methods

Psychol. Res.

Brain Res.

Physiol. Behav.

Physiol. Behav.

Brain Res. Rev.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Dev. Brain Res.

Psychoneuroendocrinology

Brain Res.

Neurosci. Biobehav. Rev.

Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat

Proc. Natl. Acad. Sci. USA

Articles
Periodic Maternal Deprivation Induces Gender-Dependent Alterations in Behavioral and Neuroendocrine Responses to Emotional Stress in Adult Rats