Reduced brain corticotropin‐releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats

The brain corticotropin‐releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety‐related behaviour or non‐selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF‐R) antagonist D‐Phe to manipulate CRF‐R1/2 non‐specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation‐specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D‐Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D‐Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF‐R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour.     

Prenatal stress increases HPA axis activity and impairs maternal care in lactating female offspring: implications for postpartum mood disorder

Early life stress is believed to constitute a risk factor for the development of mood disorders later in life. In the present study, we hypothesized that prenatal stress (PS) exerts long-lasting effects in female rat offspring, resulting in impaired adaptations to stress during lactation and, as such, may be a contributory factor to postpartum mood disorders. PS increased anxiety in adult virgin females compared with controls. During lactation, PS dams nursed significantly less and spent less time with pups compared with controls, whereas dams did not differ in pup retrieval or maternal aggression. HPA axis reactivity was elevated in response to a mild stressor in PS dams compared to their controls, but not in virgins, with the delta corticosterone response returning to the higher level seen in virgins. Moreover, corticotropin-releasing hormone (CRH) mRNA expression within the parvocellular region of the paraventricular nucleus (PVN) was increased in both virgins and dams exposed to PS compared with the relative controls, while the attenuation in expression in lactating controls was abolished following PS. In addition, arginine vasopressin (AVP) mRNA was increased in the parvocellular, but not magnocellular part of the PVN, in both PS-exposed virgins and lactating dams compared with their relative controls; although expression was also higher in controls during lactation compared with virgins. Thus, the present study demonstrates that exposure to PS results in long-lasting behavioural and neuroendocrine alterations in the female offspring, which are manifested during the lactation period. Furthermore, it implicates PS as a potential risk factor for the development of postpartum mood disorders, and that alterations in the HPA axis reactivity, at least partially, are involved.     

Prenatal stress: opposite effects on anxiety and hypothalamic expression of vasopressin and corticotropin-releasing hormone in rats selectively bred for high and low anxiety

We studied the mechanisms of genetic-early environmental interactions to modulate adult stress-coping and tested the hypothesis that prenatal stress (PS) can differentially alter the consequences of a genetic predisposition to either hyper- or hypo-anxiety. Exposure of male Wistar rats, bred for high (HAB) or low (LAB) anxiety-related behaviour, to PS between pregnancy days 4 and 18 resulted in opposite effects on anxiety in adulthood, i.e. HAB rats became less and LAB rats became more anxious compared with their unstressed controls (plus-maze and holeboard). The high anxiety of HAB controls was accompanied by elevated expression of vasopressin and corticotropin-releasing hormone (CRH) mRNA within the hypothalamic paraventricular nucleus compared with LAB rats. PS reduced CRH mRNA expression in HAB rats but increased vasopressin mRNA expression in LAB rats, which may explain the opposite effects of PS on adult emotionality. Differential effects of PS were also found with respect to hypothalamo-pituitary-adrenal axis reactivity; the hypothalamo-pituitary-adrenal hyper-response in virgin female HAB controls became attenuated after PS, without affecting plasma corticosterone concentrations in LAB rats. Differences in maternal plasma corticosterone measured between pregnancy days 6 and 14 of HAB and LAB dams or differential effects of PS on maternal behaviour can be excluded. In conclusion, exposure of rats with genetically determined high or low emotionality to PS mitigates the extremes in behavioural and neuroendocrine stress-coping, thus allowing adequate and similar behavioural responses to potentially dangerous stimuli in adulthood. Differential effects of PS on the activity of the brain vasopressin and CRH systems might represent possible underlying molecular mechanisms.     

Multiparity reveals the blunting effect of breastfeeding on physiological reactivity to psychological stress

Rat studies show that hypothalamic-pituitary-adrenal (HPA) responsiveness to physical and emotional stressors is attenuated during lactation, although situations evoking pup endangerment can supersede this phenomenon. In the human population, blunted cortisol responses are seen in primiparous breastfeeding compared to bottlefeeding mothers following physical stress, but not after psychosocial stress. It is currently unknown whether stressor salience (child-related versus nonrelated stressor) has a differential effect on cortisol reactivity as a function of infant feeding choice and whether HPA responses to stress could be modified by parity. We investigated the impact of infant feeding type and maternal parity on salivary cortisol and alpha-amylase response to stress in 5-20-week postpartum mothers using exposure to the Trier Social Stress Test (TSST) and to an emotional film evoking threats to a child. Analyses show that alpha-amylase responses were similar in all groups and for both types of stress, suggesting that sympathetic reactivity was independent of infant feeding type and parity. By contrast, cortisol response was affected by these variables. In primiparous mothers, cortisol reactivity to psychological stressors did not vary as a function of infant feeding type while, among multiparous mothers, breastfeeding was associated with reduced responsiveness to the TSST and child-related stressor. We speculate that changes in neural mechanisms occurring as a result of pregnancy and lactation and that modulate the HPA axis in women might be exacerbated with multiple repeats of the pregnancy/lactation period. This would serve to 'desensitise' stress circuits and reduce the overall stress-induced cortisol secretion after multiple births.     

Increased hypothalamic expression of prolactin in lactation: involvement in behavioural and neuroendocrine stress responses

Prolactin (PRL) has recently been shown to exert an anxiolytic effect in male and virgin female rats, as well as an inhibitory tone on hypothalamic-pituitary-adrenal (HPA) axis activity. Reduced emotional and neuroendocrine stress responses have been described in lactation, a time of high blood PRL levels. Here we tested brain PRL-receptor (PRL-R)-mediated effects on anxiety, maternal behaviour, HPA axis and oxytocin stress responses in lactating rats. Chronic intracerebroventricular (i.c.v.) infusion of antisense oligonucleotides against the long form of the PRL-R (AS; osmotic minipump, 0.5 microg/0.5 microL/h) in order to downregulate brain PRL-R expression increased the anxiety-related behaviour on the elevated plus maze (P < 0.01) compared with mixed bases- and vehicle-treated rats. Also, PRL-R AS treatment impaired maternal behaviour (P < 0.05), whereas physiological parameters of lactation (weight gain of the litter, number of milk ejection reflexes during a 20-min suckling period) were not affected. PRL-R AS treatment further evoked an increase (P < 0.05) in the stress-induced adrenocorticotropin release, demonstrating an inhibitory role of PRL on HPA axis responses in lactation. Inhibition of stress responses of the oxytocin system by brain PRL was evidenced by higher stress-induced (P < 0.05) plasma oxytocin concentration in PRL-R AS-treated lactating rats and, in contrast, decreased stress-induced oxytocin release (P < 0.01) in chronic i.c.v. ovine PRL-treated (1 microg/0.5 microL/h) virgin rats. Finally, an increased expression of the hypothalamic PRL gene was seen by RT-PCR in pregnancy and lactation, suggesting an activated state of the brain PRL system during the peripartum period. In summary, activation of the brain PRL system in the peripartum period significantly contributes to emotional and neuroendocrine adaptations, including downregulation of the responsiveness of the HPA axis and oxytocin systems to stressors seen at this time.     

Vasopressin released within the central amygdala promotes maternal aggression

Vasopressin regulates important aspects of social behaviour. Although vasopressin is more prominent in the expression of male social behaviours, we recently demonstrated its role in the fine‐tuned maintenance of maternal care in lactating rats. Here, we investigate the involvement of brain vasopressin in the regulation of maternal aggression in lactating Wistar rats selectively bred for either high (HAB) or low (LAB) anxiety‐related behaviour. The genetically determined elevation in vasopressin mRNA expression was confirmed within the hypothalamic paraventricular nucleus of virgin and lactating HAB rats and was additionally found in limbic brain areas. Lactating HAB dams are more maternally aggressive as part of their generally higher level of maternal care compared with LAB rats. Using intracerebral microdialysis, we describe increased vasopressin release within the central amygdala, but not the paraventricular nucleus, during maternal aggression only in HAB dams. Moreover, the release of vasopressin within the central amygdala was positively correlated with the display of offensive behaviour. Blockade of local vasopressin actions by bilateral administration of a selective vasopressin V1a receptor antagonist into the central amygdala reduced maternal aggression in HAB dams, whereas synthetic vasopressin increased the low level of aggression in LAB rats. Vasopressin receptor binding within the central amygdala or the paraventricular nucleus was similar in HAB and LAB females. In conclusion, vasopressin is an important neuropeptide regulating maternal aggressive behaviour, thus further extending its involvement in female social behaviour. Differences in intracerebral vasopressin release within the central amygdala rather than local vasopressin receptor binding contribute to the level of maternal aggression.     

Adaptive responses of the maternal hypothalamic-pituitary-adrenal axis during pregnancy and lactation

Over the past 40 years, it has been recognised that the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring. The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years. Both basal, including the circadian rhythm, and stress-induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered. Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the corticotropin-releasing factor (CRF) neurones in the parvocellular paraventricular nucleus (pPVN). An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid-pregnancy and persists until the end of lactation. Central to this suppression of stress responsiveness is reduced activation of the pPVN CRF neurones. This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these CRF neurones (for physical stressors) and of altered processing by limbic structures (for emotional stressors). The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an up-regulated endogenous opioid mechanism, which is induced by neuroactive steroid produced from progesterone. By contrast, in lactation suckling the young provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses. Reduced noradrenergic input activity is involved in reduced stress responses in lactation, although central prolactin action also appears important. Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.     

Hyper-Reactive Hypothalamo-Pituitary-Adrenocortical Axis in Rats Bred for High Anxiety-Related Behaviour

Psychiatric patients suffering from anxiety disorders or endogenous depression exhibit increased activity in their hypothalamo-pituitary-adrenocortical (HPA) axis. Recently, two Wistar rat lines, bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze, were described as a unique psychopathological animal model (1). The present study focused on the HPA axis reactivity of HAB and LAB animals to an emotional stressor. Thus, adult male HAB and LAB animals, fitted with jugular vein catheters 5 days prior to the experiment, were exposed to an open arm of the elevated plus-maze for 5 min. Whereas basal levels of ACTH and corticosterone were similar in both lines, HAB rats showed higher plasma concentrations at 5 and 15 min following stressor exposure (both hormones and both time points: P<0.01 vs LAB). Furthermore, increased basal (P<0.05 vs LAB) and stimulated (P<0.01 vs LAB) prolactin concentrations in HAB rats were found. In contrast to ACTH, corticosterone and prolactin, plasma oxytocin and vasopressin levels did not differ between HAB and LAB animals; oxytocin, but not vasopressin, responding to open arm exposure with a significant increase in both lines (P<0.05). In conclusion, particularly due to the association between inborn anxiety and HPA axis hyper-reactivity, the HAB rat represents a promising animal model for further investigation of the relationship between emotional disturbance and neuroendocrine activity.     

Combined pre- and postnatal environmental enrichment programs the HPA axis differentially in male and female rats

Experimental environmental enrichment (EE) is usually applied in adulthood or immediately after weaning, with robust effects on physiology and behaviour. To investigate the effects of EE earlier in life, female rats were maintained under moderate enrichment during pregnancy and, together with their pups, during lactation until weaning. A separate group of dams housed under standard conditions during pregnancy and lactation served as controls. Dams housed under EE exhibited fewer nursing episodes and were off the nest more often, but the frequency of pup licking was not affected on postnatal days 3-5. EE effects on hypothalamus-pituitary-adrenal (HPA) axis responses to an acute stressor were determined in adult male and female offspring with and without previous exposure to the chronic stressor of constant light. In female offspring, chronic stress significantly increased basal corticosterone (CORT) levels, but not if rats had been exposed to early EE. Furthermore, while control females exposed to chronic stress showed a greatly reduced adrenocorticotropin (ACTH) response to an acute stressor, EE females did not display this desensitization. There was no significant effect of EE on basal ACTH and CORT levels in adult male offspring, nor did it alter their response to acute stress. Maternal licking frequency was moderately but significantly correlated with net corticosterone increases in response to acute stress, the direction of the correlation crucially depending on the offspring's sex and stress conditions. This study shows that EE during pregnancy and lactation has long-lasting effects on reactivity to acute and chronic stress in offspring and that these effects are dependent on the offspring's sex but not greatly on early postpartum maternal behaviour.     

Maternal care differs in mice bred for high vs. low trait anxiety: Impact of brain vasopressin and cross-fostering

Brain arginine vasopressin (AVP) not only regulates male social behavior and emotionality, but also promotes maternal behavior, as has been shown in rats. In our CD1 mice breed for high (HAB) or low (LAB) anxiety-related behavior, LAB mice have markedly less AVP mRNA expression in the hypothalamic paraventricular nucleus compared with HAB mice. Together these findings suggest that HAB and LAB mice represent a good model to assess the role of AVP in mouse maternal behavior. Therefore, we studied maternal care of HAB and LAB mouse dams and investigated the impact of maternal care on the offspring's anxiety in a cross-fostering paradigm. In comparison with HAB dams, LABs displayed less maternal care. Daily acute intracerebroventricular infusions of AVP in early lactation increased maternal care of LAB dams and acted anxiogenically. Cross-fostering on postnatal day 5 did not alter separation-induced high and low ultrasonic vocalization calling frequency, a measure of inborn anxiety, in HAB and LAB offspring, respectively. However, adult cross-fostered HAB mice displayed a trend towards decreased anxiety on the elevated plus-maze, which was still significantly higher compared with LAB mice. The low levels of depressive-like behavior, stress-reactivity, and hypothalamic AVP mRNA expression in adult LAB offspring were found to be independent of cross-fostering. In conclusion, the HAB/LAB differences in maternal care and anxiety are robust and strongly depend on differences in the AVP system. The seemingly rigid genetic predisposition to hyperanxiety can only be moderately attenuated by the received nurturing.     

Prenatal stress reduces postnatal neurogenesis in rats selectively bred for high, but not low, anxiety: possible key role of placental 11β-hydroxysteroid dehydrogenase type 2

Prenatal stress (PS) produces persistent abnormalities in anxiety-related behaviors, stress responsivity, susceptibility to psychopathology and hippocampal changes in adult offspring. The hippocampus shows a remarkable degree of structural plasticity, notably in response to stress and glucocorticoids. We hypothesized that PS would differentially affect hippocampal neurogenesis in rats selectively bred for genetic differences in anxiety-related behaviors and stress responsivity. Pregnant dams of high anxiety-related behavior (HAB) and low anxiety-related behavior (LAB) strains were stressed between days 5 and 20 of pregnancy. The survival of newly generated hippocampal cells was found to be significantly lower in 43-day-old HAB than in LAB male offspring of unstressed pregnancies. PS further reduced newly generated cell numbers only in HAB rats, and this was paralleled by a reduction in doublecortin-positive cell numbers, indicative of reduced neurogenesis. As maternal plasma corticosterone levels during PS were similar in both strains, we examined placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which catalyses rapid inactivation of maternal corticosterone to inert 11-dehydrocorticosterone and thus serves as a physiological 'barrier' to maternal glucocorticoids. PS significantly increased placental 11β-HSD2 activity in LAB, but not HAB, rats. We conclude that PS differentially affects the number of surviving newly generated cells and neurogenesis in HAB and LAB rats. The high sensitivity of hippocampal neurogenesis to PS in HAB rats is paralleled by a failure to increase placental 11β-HSD2 activity after stress rather than by different maternal corticosterone responses. Hence, stress-induced placental 11β-HSD2 expression may be critical in protecting the fetal brain from maternal stress-induced effects on adult neurogenesis.     

Social stress induces hypothalamo-pituitary-adrenal axis responses in lactating rats bred for high trait anxiety

Hypothalamo-pituitary-adrenal axis responses to various stressors are typically attenuated during lactation, including in rats selectively bred for high or low anxiety. As high-anxiety dams are more aggressive towards intruders than low-anxiety dams during maternal defence, we investigated their hypothalamo-pituitary-adrenal axis responses to this social stress. Maternal defence induced elevated stress responses in high-anxiety dams only; nerve-growth-factor-induced gene B mRNA expression in the parvocellular paraventricular nucleus and adrenocorticotropin hormone secretory responses were substantially enhanced after maternal defence. In contrast, secretory responses to a non-social stress (elevated platform) were not different between high- and low-anxiety dams. Thus, responsiveness of the stress axis in lactation is dependent upon the innate level of anxiety of the dam and, as a consequence, her reactiveness to social threat.     

Neurobiological mechanisms of aggression and stress coping: a comparative study in mouse and rat selection lines

Aggression causes major health and social problems and constitutes a central problem in several psychiatric disorders. There is a close relationship between the display of aggression and stress coping strategies. In order to gain more insight into biochemical pathways associated with aggression and stress coping, we assessed behavioral and neurobiological responses in two genetically selected rodent models, namely wild house mice selectively bred for a short (SAL) and long (LAL) attack latency and Wistar rats bred for high (HAB) or low (LAB) anxiety-related behavior. Compared to their line counterparts, the SAL mice and the LAB rats display a high level of intermale aggression associated with a proactive coping style. Both the SAL mice and the LAB rats show a reduced hypothalamic-pituitary-adrenal (HPA) axis response to non-social stressors. However, when exposed to social stressors (resident-intruder, sensory contact), SAL mice show an attenuated HPA response, whereas LAB rats show an elevated HPA response. In both rodent lines, the display of aggression is associated with high neuronal activation in the central amygdala, but reduced neuronal activation in the lateral septum. Furthermore, in the lateral septum, SAL mice have a reduced vasopressinergic fiber network, and LAB rats show a decreased vasopressin release during the display of aggression. Moreover, the two lines show several indications of an increased serotonergic neurotransmission. The relevance of these findings in relation to high aggression and stress coping is discussed. In conclusion, exploring neurobiological systems in animals sharing relevant behavioral characteristics might be a useful approach to identify general mechanisms of action, which in turn can improve our understanding of specific behavioral symptoms in human psychiatric disorders.     

Neuroendocrine control of maternal stress responses and fetal programming by stress in pregnancy

The major changes in highly dynamic neuroendocrine systems that are essential for establishing and maintaining pregnancy are outlined from studies on rodents. These changes optimise the internal environment to provide the life support system for the placenta, embryo and fetus. These include automatic prevention of further pregnancy, blood volume expansion, increased appetite and energy storage. The brain regulates these changes, in response to steroid (estrogens, progesterone) and peptide (lactogens, relaxin) hormone signals. Activation of inhibitory endogenous opioid mechanisms in the brain in late pregnancy restrains premature secretion of oxytocin, and attenuates hypothalamo-pituitary-adrenal (HPA) responses to stress. This opioid mechanism is activated by allopregnanolone, a neuroactive progesterone metabolite. The significance of reduced HPA axis responses in shifting maternal metabolic balance, and in protecting the fetuses from adverse programming of HPA axis stress responsiveness and anxious behaviour in later life is critically discussed. Experimental studies showing sex-dependent fetal programming by maternal stress or glucocorticoid exposure in late pregnancy are reviewed. The possibility of over-writing programming in offspring through neurosteroid administration is discussed. The impact of maternal stress on placental function is considered in the context of reconciling studies that show offspring programming by stress in very early or late pregnancy produce similar phenotypes in the offspring.     

Central V1b Receptor Antagonism in Lactating Rats: Impairment of Maternal Care But Not of Maternal Aggression

Maternal behaviour in rodents is mediated by the central oxytocin and vasopressin systems, amongst others. The role of vasopressin, acting via the V1a receptor (V1aR), on maternal care and maternal aggression has recently been described. However, a potential involvement of the V1b receptor (V1bR) in maternal behaviour has only been demonstrated in knockout mice. The present study aimed to examine the effects of central pharmacological manipulation of the V1bR on maternal behaviour in lactating Wistar rats. On pregnancy day 18, female rats were implanted with a guide cannula targeting the lateral ventricle. After parturition, dams received an acute central infusion of a specific V1bR agonist (d[Leu4,Lys8]VP) or V1bR antagonist (SSR149415) once daily, followed by observations of maternal care [lactation day (LD) 1], maternal motivation in the pup retrieval test (LD 2), anxiety‐related behaviour on the elevated plus‐maze (LD 3) and maternal aggression in the maternal defence test followed by maternal care monitoring (LD 4). Our data demonstrate that, under nonstress conditions, the V1bR antagonist decreased the occurrence of both nursing and mother–pup interaction, whereas the V1bR agonist did not affect either parameter. Under stress conditions (i.e. after the maternal defence test), mother–pup interaction was decreased by infusion of the V1bR antagonist. During the maternal defence test, neither treatment affected aggressive or non‐aggressive behaviour. Finally, neither treatment altered maternal motivation or anxiety. In conclusion, central V1bR antagonism modulates aspects of maternal care but not of maternal aggression or maternal motivation in lactating rats. These findings further extend our knowledge on the vasopressin system as a vital mediator of maternal behaviour.     

Epigenetic programming of the stress response in male and female rats by prenatal restraint stress

Exposure to hostile conditions results in a series of coordinated responses aimed at enhancing the probability of survival. The activation of the hypothalamo-pituitary-adrenocortical (HPA) axis plays a pivotal role in the stress response. While the short-term activation of the HPA axis allows adaptive responses to the challenge, in the long run this can be devastating for the organism. In particular, life events occurring during the perinatal period have strong long-term effects on the behavioral and neuroendocrine response to stressors. In male and female rats exposed to prenatal restraint stress (PRS), these effects include a long-lasting hyperactivation of the HPA response associated with an altered circadian rhythm of corticosterone secretion. Furthermore, male animals exhibit sleep disturbances. In males, these HPA dysfunctions have been reported in infant, young, adult and aged animals, thus suggesting a permanent effect of early stress. Interestingly, after exposure to an intense inescapable footshock, female PRS rats durably exhibit a blunted corticosterone secretion response to stress. In male PRS rats exposed to an alcohol challenge, the HPA axis is similarly hyporesponsive. Rats exposed to PRS also show behavioral disturbances. Both male and female PRS rats show high anxiety levels and depression-like behavior during adulthood, although some studies suggest that female PRS rats present low anxiety levels. With ageing, male and female PRS rats exhibit memory impairments in hippocampus-dependent tasks, while female PRS rats improve their memory performance during adulthood. The gender effect on behavior seems to be related to a reduction in hippocampal plasticity in male PRS rats, and an increase in female PRS rats. Despite the permanent imprinting induced by early stress, the dysfunctions observed after PRS can be reversed by environmental or pharmacological strategies such as environmental enrichment or antidepressive and neurotrophic treatments. Mechanisms underlying the effects of PRS on the offspring remain largely unknown. However, previous studies have demonstrated that maternal glucocorticoids during pregnancy play an important role in the HPA disturbances reported in male offspring. Finally, gestational stress has long-lasting effects on the HPA axis and on behavior in the dams. Alterations in maternal behavior could thus also make a strong contribution to the long-term effects of PRS, through epigenetic mechanisms.     

The long-term behavioural consequences of prenatal stress

Maternal distress during pregnancy increases plasma levels of cortisol and corticotrophin releasing hormone in the mother and foetus. These may contribute to insulin resistance and behaviour disorders in their offspring that include attention and learning deficits, generalized anxiety and depression. The changes in behaviour, with or independent of alterations in the function of the hypothalamic pituitary adrenal (HPA) axis, can be induced by prenatal stress in laboratory rodents and non-human primates. The appearance of such changes depends on the timing of the maternal stress, its intensity and duration, gender of the offspring and is associated with structural changes in the hippocampus, frontal cortex, amygdala and nucleus accumbens. The dysregulation of the HPA axis and behaviour changes can be prevented by maternal adrenalectomy. However, only the increased anxiety and alterations in HPA axis are re-instated by maternal injection of corticosterone. Conclusion: Excess circulating maternal stress hormones alter the programming of foetal neurons, and together with genetic factors, the postnatal environment and quality of maternal attention, determine the behaviour of the offspring.     

Permanent alterations in stress responsivity in female offspring subjected to combined maternal lead exposure and/or stress

Elevated lead (Pb) exposures preferentially impact low socioeconomic status (SES) populations, the same groups thought to sustain the highest levels of environmental stress. As co-occurring risk factors, therefore, Pb and stress could interact, a possibility further supported by the fact that both act on mesocorticolimbic dopamine systems of the brain. We recently demonstrated in rats that maternal Pb exposure could permanently increase basal corticosterone levels of offspring consistent with altered hypothalamic pituitary adrenal (HPA) axis function. The current study was thus designed to test the hypothesis that stress responsivity of offspring should likewise be altered, with the outcome differing in response to Pb, stress or Pb+stress. The impact of intermittent variable stress challenges (restraint, novelty, cold) on behavior sensitive to Pb exposure (fixed interval (FI) schedule-controlled responding) and on stress-induced corticosterone changes were evaluated in adult female offspring of dams that had been exposed to Pb (150 ppm) in drinking water from 2 months prior to breeding through lactation with or without maternal restraint stress on days 16 and 17 of gestation. This design yielded four treatment groups: (NS/0, no maternal Pb, no maternal stress; S/0, no maternal Pb, maternal stress; NS/150, maternal Pb, no maternal stress; and S/150, maternal Pb exposure and maternal stress). While maternal Pb alone and stress alone each altered components of stress responsivity, the greatest number of effects was seen in response to Pb + stress. This included alterations in FI performance following both restraint and cold stress and in the corticosterone response to cold stress. Collectively, these studies reveal that maternal Pb exposure alone can permanently alter stress responsivity and that the profile of effects produced by maternal Pb differ from those produced by maternal Pb in conjunction with stress, findings which have both mechanistic and risk assessment significance.     

HPA axis programming by maternal undernutrition in the male rat offspring

Epidemiological and experimental studies have demonstrated that perinatal alterations such as maternal undernutrition are frequently associated with the onset of several chronic adult diseases. Although the physiological mechanisms involved in this "fetal programming" remain largely unknown, it has been shown that early exposure to undernutrition programs hypothalamic-pituitary-adrenal (HPA) axis throughout lifespan. However, the wide spectrum of experimental paradigms used (species, sex, age of the animals, and duration and severity of undernutrition exposure) has given rise to variable results that are difficult to interpret. To circumvent this problem, we used the same experimental protocol of maternal food restriction to study the effects of a severe maternal undernutrition on the HPA axis activity in the male rat offspring throughout the life, namely from fetal stage to adulthood. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation and lactation. In FR50 fetuses, HPA axis function was reduced and associated with a decreased placental 11beta-HSD2 activity and a greater transplacental transfer of glucocorticoids. At weaning, maternal food restriction reduced HPA axis activity in response to an ether inhalation stress. In young adults (4-month-old), only fine HPA axis alterations were observed, whereas in older ones (8-month-old), maternal undernutrition was associated with chronic hyperactivity of this neuroendocrine axis. Interestingly, excessive glucocorticoids production is observed in a growing number of pathologies such as metabolic, cognitive, immune and inflammatory diseases, suggesting that they could, at least in part, result from fetal undernutrition and thus have a neurodevelopmental origin.     

Maternal separation changes maternal care,anxiety‐like behaviour and expression of paraventricular oxytocin and corticotrophin‐releasing factor immunoreactivity in lactating rats

The early postnatal period is a time of tremendous change for the dam and her offspring. During this time, environmental insults such as repeated stress exposure can have detrimental effects. In research that has focused on the effect of postnatal stress exposure on the dams, conflicting changes in maternal care and anxiety‐like behaviour have been reported. Additionally, changes to hypothalamic neuropeptides that are crucially involved in the transition to motherhood and stress regulation, namely oxytocin and corticotrophin‐releasing factor (CRF), have not been examined. Accordingly, the present study aimed to determine (i) whether repeated postpartum stress increases engagement in maternal care behaviours and anxiety‐like behaviour and (ii) whether these behavioural changes correspond with changes to CRF‐ or oxytocin‐immunoreactive (‐IR) cells in the paraventricular nucleus (PVN) of the hypothalamus. A non‐lactating group was also included to control for the effects of lactation on anxiety and the hypothalamic neuroendocrine system. Following the birth of their litters, Long‐Evans dams were separated from their pups from postnatal day (PND) 1 to PND21 for either 15 minutes (maternal separation [MS]15) or 6 hours (MS360). Maternal behaviours were recorded for 30 minutes on select PNDs following the separation. On PND22, dams were exposed to the elevated plus maze, brains were collected, and immunofluorescence analysis of PVN oxytocin‐ and CRF‐IR cells was conducted. Our findings demonstrate that prolonged maternal separation altered typical maternal behaviours and reduced anxiety relative to MS15 dams. At the cellular level, oxytocin‐IR cells in the caudal PVN were reduced in MS360 dams to a level similar to that in non‐lactating controls, and PVN CRF‐IR cells were reduced relative to both MS15 and non‐lactating controls. Taken together, these data reveal the behavioural and neuronal changes that occur in the mother dam following repeated postnatal stress exposure.