Multiparity Dampened the Neurobehavioral Consequences of Mother-Pup Separation Stress in Dams.

Reproductive experience in mammals produces significant neuroendocrine and behavioral changes that are necessary to ensure the survival of the mother and the young. Exposure to stress during postpartum may affect the proper development of maternal behaviors. The present study examined whether previous reproductive experience affects neurobehavioral responses in females exposed to mother-infant separation stress during the postpartum period (4.5 h/day for 3 weeks). Anxiety-like behavior and spatial learning were evaluated in nulliparous (NP), primiparous (PRI) and multiparous (MULT). In maternal animals (PRI and MULT), maternal behavior was also assessed. Cell survival and proliferation in the dentate gyrus, as well as BDNF expression in the hippocampus, were evaluated by immunohistochemistry as possible candidates for mediating brain plasticity in response to reproductive experience and stress. Anxiety-like behavior as measured on the open field test showed an increase in NP and PRI-stressed, while neither stressed nor unstressed MULT expressed this behavior. Maternal unstressed animals both PRI and MULT exhibited enhanced memory task performance in the Barnes maze. Multiparity increased cell proliferation and cell survival in female rats and these changes occurred independently of pup exposure. The expression of BDNF was higher in the CA1 area in MULT rats. Although multiparity protects the mother against some of the effects of maternal separation stress, promoting behaviors directed to the pups during the early postpartum, preventing anxiety-like behaviors and mitigating memory deterioration after weaning, the data showed that disrupting natural dam-pup interaction produced neurobiological consequences on the mother even with multiple reproductive experience.

Maternal separation induces long-term changes in mineralocorticoid receptor in rats subjected to chronic stress and treated with tianeptine.

PURPOSE: The aim of this study was to analyze whether early maternal separation would result in long-term, persistent alterations in stress response in adulthood, altering mineralocorticoid receptor immunoreactivity (MR-ir) in the dorsal hippocampal areas [CA1, CA2, CA3 and dentate gyrus (DG)], paraventricular nucleus of the hypothalamus and medial and central nucleus of the amygdala, key structures involved in stress response regulation. We also analyzed whether chronic treatment with the antidepressant tianeptine reverses these possible changes. MATERIAL AND METHODS: Male Wistar rats were subjected to daily maternal separation for 4.5 h during 3 weeks or left undisturbed. As adults, they were exposed to chronic stress during 24 days or left undisturbed, and they were also daily treated with tianeptine (10 mg/kg i.p.) or isotonic solution. RESULTS: In the CA2 and DG areas of the dorsal hippocampus, there was an increase in MR-ir in non-maternally separated and chronic stressed groups. Tianeptine raised MR-ir in the CA3. In the DG, control and maternally separated + chronic stress groups treated with tianeptine showed more MR-ir than their respective vehicle groups. In the paraventricular nucleus, tianeptine decreased MR-ir in non-separated groups, but not in maternally separated rats. CONCLUSIONS: Our results support findings that early-life events induce long-term changes in stress response regulation, persistent into adulthood, which are manifested during challenges in later life, and that treatment with tianeptine, which tends to attenuate the hypothalamus-pituitary-adrenal axis dysregulation, depends on the individual experience of each rat.

Early maternal separation: neurobehavioral consequences in mother rats.

Repeated separation of dams from their pups during the postpartum period may evoke emotional stress in the dam. In the present study we investigated whether prolonged maternal separation is stressful for rat dams by studying different behavioral and central responses known to be affected by stress. After delivery, female Wistar rats were subjected to either animal facility rearing (AFR) conditions or daily 4.5 h of mother-litter separation from postpartum day (PPD) 1-21. Maternal care (pup retrieval) was evaluated at PPD 3. After weaning on PPD 21, anxiety (elevated plus maze) and depression-like behaviors (forced swimming test) were assessed in the dams. Memory abilities (one-trial step down inhibitory avoidance) were tested either 1 h (short-term memory) or 24 h (long-term memory) after training session. Finally, c-Fos expression was examined in the central nucleus of the amygdala. The results revealed that pup retrieval efficiency at PPD 3 was significantly impaired by maternal separation. AFR dams retrieved their pups sooner and engaged in more pup-directed activities (nest building and carrying pups). Separation from pups increased the number of entries in open arms of the plus maze and decreased latency times in the inhibitory avoidance test for both short and long-term memory in the dams. There were no differences in depression-related behavior as assessed using the forced swimming test. Furthermore, maternal separation yielded high c-Fos expression in the central nucleus of the amygdala. Together, these data indicate that repeated maternal separation in the early postpartum period reduces maternal care and impairs the retention memory, providing further evidence for the detrimental neurobehavioral effects of maternal separation in dams.

Neurobiological effects of neonatal maternal separation and post-weaning environmental enrichment.

Throughout the lifespan, the brain has a considerable degree of plasticity and can be strongly influenced by sensory input from the outside environment. Given the importance of the environment in the regulation of the brain structure, behavior and physiology, the aim of the present work was to analyze the effects of different environmental qualities during two critical ontogenic periods (early life and peripuberty) on behavior and hippocampal physiology. Male Wistar rats were separated from their mothers for 4.5h daily during the first 3 weeks of life. They were weaned on day 21 and housed under either standard or enriched conditions. At 60 d of age, all animals were then housed in same-treatment groups, two per cage, until testing began on day 74. Emotional and cognitive responses were tested using the open field, novel object recognition test and step-down inhibitory avoidance learning. In the dorsal hippocampus, glucocorticoid receptor expression and neuronal activity were examined by immunoreactivity. Grooming behavior in the open field was found to be significantly lower in maternally separated animals, but post-weaning environmental enrichment completely reversed this tendency. Inhibitory avoidance but not object recognition memory was impaired in maternally separated animals, suggesting that early maternal separation alters learning and memory in a task-specific manner. Again, environmental enrichment reversed the effects of maternal separation on the inhibitory avoidance task. Even though maternal separation did not significantly affect Fos and glucocorticoid receptor (GR) expression, environmental enrichment increased both Fos expression in the total hippocampal area and also the overall number of GR positive cells per hippocampal area, mainly due to the changes in CA1. These findings suggest that differential rearing is a useful procedure to study behavioral and physiological plasticity in response to early experience and that, although the effects of adverse experience early in life such as maternal separation can persist until adulthood, some of them can be compensated by early favorable environments, possibly through nervous system plasticity.

Tianeptine influence on plasmatic catecholamine levels and anxiety index in rats under variable chronic stress after early maternal separation.

The aim of this work was to determine the effect of chronic treatment with 5 mg/kg of tianeptine in male adult Wistar rats separated from the mother as neonates and submitted to variable chronic stress, plasma catecholamines, and anxiety. The plus maze test was performed in order to calculate the anxiety index and catecholamine levels were determined by high-pressure liquid chromatography. Both stress and maternal separation elevated catecholamine levels without affecting anxiety. In the maternally separated stress group, tianeptine decreased epinephrine. Anxiety was reduced in the maternally separated unstressed tianeptine group. Also, all groups showed a tendency to lower anxiety index.

Maternal separation and lesion of adtn alters anxiety and adrenal activity in male rats.

The present study investigated the effect of early maternal separation on anxiety and hypophyso-adrenal system activity to anterodorsal thalamic nuclei (ADTN) lesion in male rats as adults in order to compare this with previous results with female rats. During the first 3 weeks of life, male rats were isolated 4.5 hr daily and tested as adults. Thirty days after ADTN lesion we found that adrenocorticotropic hormone (ACTH) plasma levels were affected neither by maternal separation nor by ADTN lesion. Plasma corticosterone (CORT) concentration was increased with lesion of the ADTN in maternally separated rats. A significant increase in plasma catecholamine concentration was induced by early maternal separation. In ADTN-lesioned rats, plasma norepinephrine (NE) concentration was significantly lower than in the respective sham-lesioned groups. In terms of anxiety, there were no significant effects of early experience. However, the ADTN lesion tended to decrease anxiety-related behavior.

Early maternal separation and chronic variable stress in adulthood changes the neural activity and the expression of glucocorticoid receptor in limbic structures.

There is increasing evidence that early adverse experience contributes to the development of stress susceptibility, and increases the onset of stress-related psychiatric disorders in stressful environments in adulthood. This study addressed whether or not prolonged maternal separation, a well-established model of early stress, affects adult limbic areas related to the regulation of the hypothalamic-pituitary-adrenal axis in exposure to chronic variable stress in adulthood. Rats were subjected to daily maternal separation for 4.5h during postnatal days 1-21. As adults, the animals were exposed to a variable chronic stress paradigm of 24 days. Persistent changes were assessed in glucocorticoid receptor density and Fos activity in the anterodorsal thalamic nuclei, mammillary nuclei and retrosplenial cortex. Immunohistochemical analysis revealed that adult maternally separated animals had increased levels of c-Fos immunoreactivity in the anterodorsal thalamic nuclei as well as in the mammillary nuclei compared to normal non-maternally separated animals. Chronic variable stress in maternally separated and non-maternally separated animals diminished glucocorticoid receptor density in the anterodorsal thalamic nuclei but not in the rest of the nuclei analyzed. These results indicate that c-Fos immunoreactivity as well as glucocorticoid receptor expression in the anterodorsal thalamic nuclei and mammillary nuclei exhibit long-term alterations in adult rats following repeated maternal separation and subsequent stress exposure. Recognition of these adaptations helps to define the brain regions and neural circuitry associated with persistent alterations induced by early life environment and the development of stress-associated disorders.

Early maternal separation and chronic variable stress as adults differentially affect Fos expression in the anterodorsal thalami nuclei.

The present study examined the participation of the anterodorsal thalamic nuclei (ADTN) in mediating the long-term effects of early maternal separation on the stress/hypothalamic-pituitary-adrenal axis response of adult animals. The study measured Fos and glucocorticoid receptor immunoreactivity (GR-ir) in the ADTN of maternally separated female rats subsequently exposed to variable chronic stress. Maternal separation increased the number of neurons immunoreactive to Fos in the ADTN of chronically stressed adult rats. GR-ir was absent in the ADTN. Linking these results with previous endocrine evidence led the authors to propose a dual role of these nuclei. Maternal separation and chronic stress enhance the neuronal activity of the ADTN, nevertheless it is not regulated, at least directly, via GR.