Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces "detrimental" effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a "substitute" mother. The maternal care of biological and "substitute" mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the "substitute" mother did not exhibit overt maltreatment. A mixture of "detrimental" and "beneficial" effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may "buffer" the effects of ELS in a context-dependent manner.

Hormonal influences on neuroimmune responses in the CNS of females.

Particular reproductive stages such as lactation impose demands on the female. To cope with these demands, her physiology goes through numerous adaptations, for example, attenuation of immune and stress responses. Hormonal fluctuation during lactation exerts a strong influence, inducing neuroplasticity in the hypothalamus and extrahypothalamic regions, and diminishing the stress and inflammatory responses. Thus, hormones confer decreased vulnerability to the female brain. This mini-review focuses on the adaptations of the immune and stress response during maternity, and on the neuroprotective actions of progesterone and prolactin and their effects on inflammation. The importance of pregnancy and lactation as experimental models to study immune responses and disease is also highlighted.

Nitric oxide has a role in attenuating the neuroendocrine response to anaphylactoid stress during lactation.

Stress increases nitric oxide (NO) production in the paraventricular nucleus of the hypothalamus (PVH). Lactation diminishes the response to stress and increases basal NO production markers in the PVH of the dam. This study investigated whether lactation modified the anaphylactic reaction to egg white (EW) injection, and if nitric oxide regulates the neuroendocrine response to this stressor. The activational response of PVH to EW was assessed by c-Fos immunohistochemistry, and NO production was determined by histological staining of NADPH-diaphorase and neuronal nitric oxide synthase (nNOS) and by measuring the concentration of total nitrates and nitrites (NOx) in the hypothalamus of lactating and diestrus rats. EW injection significantly increased the number of Fos-positive neurons in the parvocellular subdivision of the PVH in diestrus, but not in lactating rats. Similarly, EW injection increased the number of NADPH-diaphorase- and nNOS-positive cells in the PVH of diestrus rats, but it did not alter the already increased basal number of NO-positive cells in lactating rats. Furthermore, the total concentration of NOx in the hypothalamus, the circulating level of corticosterone and interleukin-6 increased significantly after EW in diestrus, but not in lactating rats, compared to their corresponding controls. Intracerebral administration of L-NAME, a general NOS inhibitor, reversed the attenuation of the activational response to EW in the PVH of lactating rats. The present results show that lactation diminishes the anaphylactoid reaction to EW compared to that in diestrus rats. This attenuation was absent after L-NAME treatment, suggesting that sustained NO production in the PVH during lactation may limit the neuroendocrine response to stress.

Suckling-induced oxytocin increase in the spinal cord of the rat.

Oxytocin (OT) is essential for parturition and milk ejection, and OT-containing fibers are present in several regions of the brain and in the spinal cord. During lactation, activation of spinal cord neurons by suckling stimulation involves deep laminae III-X including sympathetic preganglionic neurons of the intermedio-medial cell column. In the present study, experiments were designed to determine if the suckling provided by the litter increased OT levels in the spinal cord of dams, as determined by competitive immunoassay. In addition, we investigated if OT fibers reach neurons of the spinal cord that are known to respond to suckling. The OT content was higher in the hypothalamus than in the spinal cord in animals from all experimental groups. After 6 h of pup separation, OT levels decreased and suckling for 5 min induced a significant increase of OT levels in the spinal cord. Double immunostaining for Fos and OT showed OT-positive fibers adjacent to neurons that had Fos-positive nuclei, located mostly in laminae III, IV, and X. The present data support the notion that OT is released within the spinal cord in response to suckling, suggesting a role for this peptide in modulating the afferent and/or efferent responses generated by suckling.

Changes in c-Fos and NOS expression in the PVH of lactating rats in response to excitotoxicity and stress.

This study investigated how lactation modified the expression patterns of Fos and nitric oxide synthase in the hypothalamic paraventricular nucleus (PVH) induced by excitotoxicity and stress. Kainic acid or egg white treatment weakly activated Fos expression in the PVH of lactating in comparison to diestrus or ovariectomized (OVX) rats. Labels for NADPH-diaphorase and nNOS revealed a different distribution pattern in the PVH depending on the physiological condition and challenge. The present results confirm that lactation attenuates the PVH activational response to stress and excitotoxicity, and both stimuli induced nitric oxide expression in the PVH of diestrus, lactating, and OVX rats.