Early-life environmental events can induce profound long-lasting changes in several behavioral and neuroendocrine systems. The neonatal handling procedure, which involves repeated brief maternal separations followed by experimental manipulations, reduces stress responses and sexual behavior in adult rats. The purpose of this study was to analyze the effects of neonatal handling on social behaviors of male and female rats in adulthood, as manifest by the results of social memory and social interaction tests. The number of oxytocin (OT) and vasopressin (VP) neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of hypothalamus were also analyzed. The results did not demonstrate impairment of social memory. Notwithstanding, handling did reduce social investigative interaction and increase aggressive behavior in males, but did not do so in females. Furthermore, in both males and females, handling was linked with reduced number of OT-neurons in the parvocellular region of the PVN, while no differences were detected in the magnocellular PVN or the SON. On the other hand, handled males exhibited increased number of VP-neurons in the magnocellular zone of the PVN. We may conclude that the repeated brief maternal separations can reduce affiliative social behavior in adult male rats. Moreover, the disruption of the mother-infant relationship caused by the handling procedure induced long-lasting morphological changes in critical neuroendocrine areas that are involved in social bonding in mammals.

The present study aimed to analyze the effects of neonatal stimulation on species-specific behaviors (defensive reactions to a predator and social interactions) in adult male and female rats. Handling and an unpredictable sequence of aversive stimuli were applied to male and female pups from the 1st to the 10th day after delivery; behavioral inhibition, aggression, and sexual behavior were evaluated in adulthood. Results showed that either neonatal handling or aversive stimulation decreased behavioral inhibition in a novel and potentially harmful situation (open field with a predator) in both male and female rats and increased maternal aggressive behavior. Sexual behavior in both males and females decreased, which could affect reproductive capability. The results could cast doubts on the generalization of beneficial effects of neonatal stimulation on the behavior of adult rats.

The purpose of the present study was to analyze the role of somatodendritic autoreceptors and postsynaptic 5-HT1A receptors in the modulation of maternal aggressive behavior. The 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) was microinjected (0.2, 0.5 and 2.0 microg/0.2 microl) in different brain areas of female Wistar rats: median raphe nucleus (MnR); medial septal area (MS); anterior corticomedial amygdaloid nucleus (ACoM); and dorsal periaqueductal gray (DPAG). The behaviors of lactating female rats with pups against a conspecific male intruder were recorded on day 7 post-partum. Results showed that in the median raphe nuclei, in the dorsal periaqueductal gray and in the corticomedial amygdaloid nucleus 8-OH-DPAT decreased maternal aggression; while in the medial septum, the intermediate dose (0.5 microg/0.2 microl) of the 5-HT1A receptor agonist increased the aggressive behavior of the lactating female rat. It is concluded that the main role of the 5-HT1A somatodendritic autoreceptors and the post-synaptic receptors of the brain areas studied is to decrease maternal aggression, however, at a specific dosage, 8-OH-DPAT acting on postsynaptic receptors of the medial septal area can increase aggressiveness.

As one of the first rodent models designed to investigate the effects of early-life experiences, the neonatal handling paradigm has helped us better understand how subtle changes in the infant environment can powerfully drive neurodevelopment of the immature brain in typical or atypical trajectories. Here, we review data from more than 50 years demonstrating the compelling effects of neonatal handling on behavior, physiology, and neural function across the lifespan. Moreover, we present data that challenge the classical view of neonatal handling as an animal model that results only in positive/beneficial outcomes. Indeed, the overall goal of this review is to offer the suggestion that the effects of early-life experiences—including neonatal handling—are nuanced rather than unidirectional. Both beneficial and negative outcomes may occur, depending on the parameters of testing, sex of the subject, and neurobehavioral system analyzed.

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The present study investigated the long-lasting effects of prenatal repeated restraint stress on social behavior and anxiety, as well as its repercussions on oxytocin (OT) and vasopressin (VP)-positive neurons of the paraventricular (PVN) and supraoptic (SON) nuclei from stressed pups in adulthood. Female Wistar rats were exposed to restraint stress in the last 7 days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatally non-stressed offspring raised by prenatally non-stressed mothers (NS:NS), prenatally non-stressed offspring raised by prenatally stressed mothers (S:NS), prenatally stressed offspring raised by prenatally non-stressed mothers (NS:S), prenatally stressed offspring raised by prenatally stressed mothers (S:S). As adults, male prenatally stressed offspring raised both by stressed mothers (S:S group) and non-stressed ones (NS:S group) showed impaired social memory and interaction. In addition, when both adverse conditions coexisted (S:S group), increased anxiety-like behavior and aggressiveness was observed in association with a decrease in the number of OT-positive magnocellular neurons, VP-positive magnocellular and parvocellular neurons of the PVN. The NS:S group exhibited a reduction in the amount of VP-positive magnocellular neurons compared to the S:NS. Thus, the social behavior deficits observed in the S:S and NS:S groups may be only partially associated with these alterations to the peptidergic systems. No changes were shown in the OT and VP cellular composition of the SON nucleus. Nevertheless, it is clear that a special attention should be given to the gestational period, since stressful events during this time may be related to the emergence of behavioral impairments in adulthood.

Oxytocin is a nonapeptide involved in a wide range of physiologic and behavioral functions. Until recently, it was believed that an unmodified oxytocin sequence was present in all placental mammals. This study analyzed oxytocin (OXT) in 29 primate species and the oxytocin receptor (OXTR) in 21 of these species. We report here three novel OXT forms in the New World monkeys, as well as a more extensive distribution of a previously described variant (Leu8Pro). In structural terms, these OXTs share the same three low-energy conformations in solution during molecular dynamic simulations, with subtle differences in their side chains. A consistent signal of positive selection was detected in the Cebidae family, and OXT position 8 showed a statistically significant (P = 0.013) correlation with litter size. Several OXTR changes were identified, some of them promoting gain or loss of putative phosphorylation sites, with possible consequences for receptor internalization and desensitization. OXTR amino acid sites are under positive selection, and intramolecular and intermolecular coevolutionary processes with OXT were also detected. We suggest that some New World monkey OXT-OXTR forms can be correlated to male parental care through the increase of cross-reactivity with its correlated vasopressin system.OXT | OXTR | primates | coevolution | behavior

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