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Studies have shown that neonate rodents exhibit high ability to learn a preference for novel odors associated with thermo-tactile stimuli that mimics maternal care. Artificial odors paired with vigorous strokes in rat pups younger than 10 postnatal days (P), but not older, rapidly induce an orientation-approximation behavior toward the conditioned odor in a two-choice preference test. The olfactory bulb (OB) and the anterior olfactory cortex (aPC), both modulated by norepinephrine (NE), have been identified as part of a neural circuit supporting this transitory olfactory learning. One possible explanation at the neuronal level for why the odor-stroke pairing induces consistent orientation-approximation behavior in P10, is the coincident activation of prior existent neurons in the aPC mediating this behavior. Specifically, odor-stroke conditioning in P10 pups, promoting orientation-approximation behavior in the former but not in the latter. In order to test this hypothesis, we performed in vitro patch-clamp recordings of the aPC pyramidal neurons from rat pups from two age groups (P5–P8 and P14–P17) and built computational models for the OB-aPC neural circuit based on this physiological data. We conditioned the P5–P8 OB-aPC artificial circuit to an odor associated with NE activation (representing the process of maternal odor learning during mother–infant interactions inside the nest) and then evaluated the response of the OB-aPC circuit to the presentation of the conditioned odor. The results show that the number of responsive aPC neurons to the presentation of the conditioned odor in the P14–P17 OB-aPC circuit was lower than in the P5–P8 circuit, suggesting that at P14–P17, the reduced number of responsive neurons to the conditioned (maternal) odor might not be coincident with the responsive neurons for a second conditioned odor.

During the first ten postnatal days (P), infant rodents can learn olfactory preferences for novel odors if they are paired with thermo-tactile stimuli that mimic components of maternal care. After P10, the thermo-tactile pairing becomes ineffective for conditioning. The current explanation for this change in associative learning is the alteration in the norepinephrine (NE) inputs from the locus coeruleus (LC) to the olfactory bulb (OB) and the anterior piriform cortex (aPC). By combining patch-clamp electrophysiology and computational simulations, we showed in a recent work that a transitory high responsiveness of the OB-aPC circuit to the maternal odor is an alternative mechanism that could also explain early olfactory preference learning and its cessation after P10. That result relied solely on the maturational properties of the aPC pyramidal cells. However, the GABAergic system undergoes important changes during the same period. To address the importance of the maturation of the GABAergic system for early olfactory learning, we incorporated data from the GABA inputs, obtained from in vitro patch-clamp experiment in the aPC of rat pups aged P5–P7 reported here, to the model proposed in our previous publication. In the younger than P10 OB-aPC circuit with GABA synaptic input, the number of responsive aPC pyramidal cells to the conditioned maternal odor was amplified in 30% compared to the circuit without GABAergic input. When compared with the circuit with other younger than P10 OB-aPC circuit with adult GABAergic input profile, this amplification was 88%. Together, our results suggest that during the olfactory preference learning in younger than P10, the GABAergic synaptic input presumably acts by depolarizing the aPC pyramidal neurons in such a way that it leads to the amplification of the pyramidal neurons response to the conditioned maternal odor. Furthermore, our results suggest that during this developmental period, the aPC pyramidal cells themselves seem to resolve the apparent lack of GABAergic synaptic inhibition by a strong firing adaptation in response to increased depolarizing inputs.

Platyrrhini (New World monkeys, NWm) are a group of primates characterized by behavioral and reproductive traits that are otherwise uncommon among primates, including social monogamy, direct paternal care, and twin births. As a consequence, the study of Platyrrhine primates is an invaluable tool for the discovery of the genetic repertoire underlying these taxon-specific traits. Recently, high conservation of vasopressin (AVP) sequence, in contrast with high variability of oxytocin (OXT), has been described in NWm. AVP and OXT functions are possible due to interaction with their receptors: AVPR1a, AVPR1b, AVPR2, and OXTR; and the variability in this system is associated with the traits mentioned above. Understanding the variability in the receptors is thus fundamental to understand the function and evolution of the system as a whole. Here we describe the variability of AVPR1b coding region in 20 NWm species, which is well-known to influence behavioral traits such as aggression, anxiety, and stress control in placental mammals. Our results indicate that 4% of AVPR1b sites may be under positive selection and a significant number of sites under relaxed selective constraint. Considering the known role of AVPR1b, we suggest that some of the changes described here for the Platyrrhini may be a part of the genetic repertoire connected with the complex network of neuroendocrine mechanisms of AVP-OXT system in the modulation of the HPA axis. Thus, these changes may have promoted the emergence of social behaviors such as direct paternal care in socially monogamous species that are also characterized by small body size and twin births.

Social relations are built and maintained from the interaction among individuals. The oxytocin (OT), vasopressin (VP), estrogen, dopamine, and their receptors are involved in the modulation of sexual behavior in females. This study aimed to analyze the impact of OT gene knockout (OTKO) on sexual behavior and the gene expression of oxytocin (OTR), estrogen alpha (ERα), estrogen beta (ERβ), vasopressin (V1aR), and dopamine (D2R) receptors in the olfactory bulb (OB), prefrontal cortex (PFC), hippocampus (HPC), and hypothalamus (HPT), as well as in the synthesis of VP in the HPT of female mice. Wild-type (WT) littermates were used for comparisons. The CDNAs were synthesized by polymerase chain reaction and the gene expression was calculated with the 2-ΔΔCt formula. Our results showed that the absence of OT caused an increase in the frequency and duration of non-receptive postures and a decrease in receptive postures in the OTKO. OTKO females showed a significant decrease in the gene expression of OTR in the HPC, V1aR in the HPT, and ERα and ERβ in the PFC. There was no significant difference in the gene expression of D2R of OTKO. However, OTKO showed an increased gene expression of V1aR in the HPC. There is no significant difference in VP mRNA synthesis in the HPT between OTKO and WT. Our findings demonstrate that the absence of OT leads to significant changes in the expression of the studied genes (OTR, ERα, ERβ, V1aR), and these changes may contribute to the decreased sexual behavior observed in OTKO females.

Disturbances in early mother-infant relationships are strongly associated with changes in the development of a number of physiological and behavioral systems in the neonate that can create a complex change in patterns of vulnerability throughout life. Institutionalized children, despite receiving adequate care, display important behavioral changes in adult life, and such changes are strongly associated with a lack of selective and consistent attachment to the maternal figure in early life. It is not yet clear how human adoption processes alter the mother-infant relationship early in life. Here, to mimic the situation of human adoption and explore the impact on the formation of attachment between the infant and a caregiver, we use a repeated cross-fostering (RCF) model in rodents in two postnatal periods, postnatal days (PND) 1 to 3 (early RCF) and 9 to 11 (late RCF). Early exposure but not late exposure to RCF reduces the pups' preference for the odor of the mother figure. Moreover, early exposure and slightly later exposure to RCF reduce maternal care and motivation in collecting the pups and bringing them to the nest. The RCF protocol creates an unstable environment for mother-pup interaction, but it seems to affect learned attachment to the mother only when it occurs during the corresponding sensitive period of development.

Effective coordination of the biological stress response is integral for the behavioural well-being of an organism. Stress reactivity is coordinated by an interplay of the neuroendocrine system and the sympathetic nervous system. The hypothalamic-pituitary-adrenal (HPA) axis plays a key role in orchestrating the bodily responses to stress, and the activity of the axis can be modified by a wide range of experiential events. This review focuses on several factors that influence subsequent HPA axis reactivity. Some of these factors include early-life adversity, exposure to chronic stress, immune activation and traumatic brain injury. The central premise is that each of these experiences serves as a general vulnerability factor that accelerates future HPA axis reactivity in ways that make individuals more sensitive to stress challenges, therefore feeding forward into the exacerbation of ongoing (or greater susceptibility toward) future stress-related disease states, especially as they pertain to negative affect and overall brain health.

The morphological and functional development of inhibitory circuit in the anterior piriform cortex (aPC) during the first three postnatal weeks may be crucial for the development of odor preference learning in infant rodents. As first step toward testing this hypothesis, we examined the normal development of GABAergic synaptic transmission in the aPC of rat pups during the postnatal days (P) 5-8 and 14-17. Whole cell patch-clamp recordings of layer 2/3 (L2/3) aPC pyramidal cells revealed a significant increase in spontaneous (sIPSC) and miniature (mIPSC) inhibitory postsynaptic current frequencies and a decrease in mIPSC rise and decay-time constant at P14-P17. Moreover, as the development of neocortical inhibitory circuit can be driven by sensory experience, we recorded sIPSC and mIPSC onto L2/3 aPC pyramidal cells from unilateral naris-occluded animals. Early partial olfactory deprivation caused by naris occlusion do not affected the course of age-dependent increase IPSC frequency onto L2/3 aPC pyramidal cell. However, this age-dependent increase of sIPSC and mIPSC frequencies were lower on aPC pyramidal cells ipsilateral to the occlusion side. In addition, the age-dependent increase in sIPSC frequency and amplitude were more pronounced on aPC pyramidal cells contralateral to the occlusion. While mIPSC kinetics were not affected by age or olfactory deprivation, at P5-P8, the sIPSC decay-time constant on aPC pyramidal cells of both hemispheres of naris-occluded animals were significantly higher when compared to sham. These results demonstrated that the GABAergic synaptic transmission on the aPC changed during postnatal development by increasing inhibitory inputs on L2/3 pyramidal cells, with increment in frequency of both sIPSC and mIPSC and faster kinetics of mIPSC. Our data suggested that the maturation of GABAergic synaptic transmission was little affected by early partial olfactory deprivation. These results could contribute to unravel the mechanisms underlying the development of odor processing and olfactory preference learning.

Neonatal handling is an experimental procedure used to analyze the effects of environmental interventions during early postpartum days (PPD). Long-lasting effects of repeated stress exposure in the neonatal period on the maternal side are poorly studied in this model. The aim of this study was to verify if handling the pups induces enduring effects on damśstress responses, increasing their risk for depression. Dams were divided into two groups (NH-Non-handled and H-Handled) based on the handling procedure (pups were handled for 1 min/per day from PPD1-PPD10) and then subdivided into four groups (NH, NH + S, H, and H + S) based on the exposure or not to restraint stress after weaning (1 hr/per day for 7 days, PPD22-PPD28). We analyzed damśbehavior in the forced swimming test (FST PPD29-PPD30), plasma basal corticosterone and BDNF levels, as well as adrenal weight (PPD31). The results show that handling alters the stress response of dams to acute and chronic stress, as evidenced by dams of the H group having increased immobility in the first day of FST (p < .001), similar to NH + S (p < .01). Dams of the H and H + S groups show decreased levels of corticosterone when compared to NH and NH + S groups (p < .05), but the H + S group shows an increased adrenal weight, suggesting an increased sensibility of the maternal organism to the chronic stress applied after weaning (p < .05). We show that handling may induce a long-lasting effect on maternal stress response; these changes in the damśemotional reactivity increase their susceptibility for the development of psychiatric disorders such as depression. © 2016 Wiley Periodicals, Inc. Dev Psychobiol 58: 614-622, 2016.

The present study aimed to analyze the effects of sleep restriction (SR) during pregnancy in rats. The following three groups were studied: home cage (HC pregnant females remained in their home cage), Sham (females were placed in tanks similar to the SR group but with sawdust) and SR (females were submitted to the multiple platform method for 20h per day from gestational days (GD) 14 to 20). Plasma corticosterone after 6days of SR was not different among the groups. However, the relative adrenal weight was higher in the SR group compared with the HC group, which suggests possible stress impact. SR during pregnancy reduces the body weight of the female but no changes in liver glycogen, cholesterol and triglycerides, and muscle glycogen were detected. On GD 20, the fetuses of the females submitted to SR exhibited increased brain derived neurotrophic factor (BDNF) in the hippocampus, which indicates that sleep restriction of mothers during the final week of gestation may affect neuronal growth factors in a fetal brain structure, in which active neurogenesis occurs during the deprivation period. However, no changes in the total reactive oxygen species (ROS) in the cortex, hippocampus, or cerebellum of the fetuses were detected. SR females showed no major change in the maternal behavior, and the pups' preference for the mother's odor on postpartum day (PPD) 7 was not altered. On GD 20, the SR females exhibited increased plasma prolactin (PRL) and oxytocin (OT) compared with the HC and Sham groups. The negative outcomes of sleep restriction during delivery could be related, in part, to this hormonal imbalance. Sleep restriction during pregnancy induces different changes compared with the changes described in males and affects both the mother and offspring.

The neurohormone oxytocin is a key player in the modulation of reproductive and social behavioral traits, such as parental care. Recently, a correlation between different forms of oxytocin and behavioral phenotypes has been described in the New World Monkeys (NWMs). Here, we demonstrate that, compared with the Leu8OXT found in most placental mammals, the Cebidae Pro8OXT and Saguinus Val3Pro8OXT taxon-specific variants act as equi-efficacious agonists for the Gq-dependent pathway but are weaker agonists for the β-arrestin engagement and subsequent endocytosis toward the oxytocin receptor (OXTR). Upon interaction with the AVPR1a, Pro8OXT and the common Leu8OXT yielded similar signaling profiles, being equally efficacious on Gq and β-arrestin, while Val3Pro8OXT showed reduced relative efficacy toward β-arrestin. Intranasal treatment with either of the variants increased maternal behavior and also promoted unusual paternal care in rats, as measured by pup-retrieval tests. We therefore suggest that Val3Pro8OXT and Pro8OXT are functional variants, which might have been evolutionarily co-opted as an essential part of the adaptive genetic repertoire that allowed the emergence of taxon-specific complex social behaviors, such as intense parental care in the Cebidae and the genus Saguinus.

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.

The 5-HT1A receptor subtype has been postulated to modulate aggressive behavior particularly when it is excessive. F15599 is a high affinity and selective 5-HT1A receptor agonist that exhibits biased agonism for postsynaptic receptors that are preferentially coupled to Gαi3 protein subunits, with more potent action in the cortex, and with potential for selectively reducing aggression. The aims of the current study were to investigate the anti-aggressive effects of the novel 5-HT1A receptor agonist, F15599, microinjected into the ventral orbital prefrontal cortex (VO PFC) and into the infralimbic cortex (ILC) of CF-1 male mice that had been previously socially provoked and to confirm the specific action at this receptor by blocking its effects using the 5-HT1A receptor antagonist, WAY100,635. Microinjection of the lower doses of F15599 (0.03 and 0.1 μg) into the VO PFC, but not into the ILC, significantly reduced the frequency of attack bites and sideways threats, without affecting other elements of the behavioral repertoire related to aggression such as pursuing and sniffing the intruder and tail rattle. There were also no changes observed in the duration of walking and rearing. Pretreatment with WAY100,635 prevented the anti-aggressive effects of F15599 when microinjected into VO PFC. The present results demonstrated that F15599 is effective in reducing the most intense behavioral elements of aggressive behavior in male mice, when microinjected into the VO PFC, but not into the ILC, without affecting nonaggressive behavior, and confirmed the critical role of this cortical region and specifically the 5-HT1A heteroreceptors in the modulation of escalated aggressive behavior.

Recently, several studies have shown different conclusions regarding the effect of oxytocin (OT) on the social behaviors of male mice. Most of these studies used exogenous OT, but currently, investigations of the neural bases of social behavior are increasingly employing gene inactivation. This study aimed to analyze the role of OT in the modulation of social behaviors (i.e., sexual and social interaction behaviors) in male mice with selective deletions of the OT gene (OTKO) and the influence of this deletion in basal vasopressin (AVP) plasma concentrations. Our results showed that in the social interaction test, OTKO mice exhibited lower levels of social behaviors and higher levels of non-social behaviors compared to the wild type (WT) group. Additionally, the OTKO group showed a decrease in the number of agonistic behaviors delivered, and consequently, their dominance score was lower than that of the WT group. In the ethological analysis, the OTKO group had a lower aggressive performance and increased social investigation than the WT group. No significant differences were observed in the sexual behavior between groups. Finally, we found lower AVP plasma concentrations in the OTKO compared with the WT group. In conclusion, our data suggest that OT modulates social investigation behavior and the aggressiveness of male mice. The decrease in AVP concentrations in the OTKO group allows us to infer that AVP is physiologically relevant to these behavioral modulations. However, sexual behaviors do not seem to be affected by the lack of OT or by a decrease in the AVP concentration.

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.

The Locus Coeruleus (LC) is a noradrenergic nucleus involved in several neuroendocrine and behavioral functions. During the neonatal period, the LC is critical for olfactory learning. Full development occurs during the early postnatal period. Environmental interventions after birth may affect neurogenesis. In rats, the neonatal handling procedure has been used as a model to analyze the effects of environmental intervention early in life. It has been related to several long-lasting behavioral and neuroendocrine changes. The present study analyzed the effects of handling on the number of neurons, cellular proliferation, and apoptosis in the LC of 11-day-old female rats. Wistar rat pups were submitted to brief maternal separation followed by handling (1 min per day from postnatal day [PND] 1 to 10). On PND 11, the LC was analyzed using immunohistochemistry for NeuN and BrdU, TUNEL staining, and electron microscopy. The intervention reduced the number of neurons in the LC but showed no significant change in the number of apoptotic cells, as measured by the TUNEL technique. However, the number of proliferating cells was significantly lower in the handled rat pups as compared with the nonhandled ones. This study demonstrates that the infant LC is sensitive to changes in maternal behavior. A seemingly mild environmental intervention during the neonatal period may reprogram the development of the LC, altering cell proliferation. (PsycINFO Database Record

Our aim was to investigate serum brain-derived neurotrophic factor (BDNF) levels in postpartum women, according to the presence of postpartum affective disorder (PPAD) and suicidality. A cross-sectional study was carried out with women between 45 and 90 days after delivery. PPAD (depression, manic and mixed episode) and suicide risk were assessed using the Mini International Neuropsychiatric Interview. BDNF was assessed using a commercial ELISA kit. Linear regression was used for multivariate analyses. A hundred ninety women participated in the study, 15.3 % had PPAD, 7.4 % showed PPAD with suicide risk. BDNF levels were lower in subjects with three or more Stressful Life Events (P = 0.01). The serum BDNF levels of women with PPAD presenting suicide risk were significantly lower than those of women without suicide risk (1.50 ± 1.38 and 2.33 ± 1.28 ng/ml, P = 0.02). Clinicians should enquire postpartum women about their history of stressful life events, PPAD, and suicidality. This study shows the potential role of BDNF in the neurobiology of the association of PPAD and suicidality.

There is an association between hypertension and reproductive dysfunction. Angiotensin II (Ang II) is involved in the pathogenesis of hypertension and the regulation of reproduction. The present study aimed to determine whether the angiotensinergic system mediates the effects of hypertension on reproductive function in male rats subjected to a two-kidney, one-clip (2K1C) model. Sexual behavior parameters, gametogenesis and plasma concentrations of Ang II, testosterone, prolactin and corticosterone were evaluated in male rats 28 days after 2K1C or sham surgery and losartan (Los) treatment (a type 1 angiotensin II (AT1) receptor antagonist) or vehicle (V) treatment. The animals were divided into Sham + V, 2K1C + V, Sham + Los and 2K1C + Los groups. The 2K1C + V group showed a hypertensive response, inhibition of sexual behavior, spermatogenesis dysfunction, and increases in plasma Ang II and prolactin. Conversely, plasma testosterone decreased, and plasma corticosterone remained constant. Losartan treatment normalized blood pressure and prevented the changes in plasma testosterone and prolactin, sexual behavior and spermatogenesis in the 2K1C + Los group. In addition, losartan treatment caused an additional increase in circulating Ang ll in both groups (Sham + Los and 2K1C + Los). Together, these results suggest that Ang ll, acting through the AT1 receptor, modulates behavioral and endocrine parameters of reproductive function during renovascular hypertension. In addition, the effects of circulating Ang II on plasma testosterone and prolactin seem to contribute to the spermatogenic and sexual dysfunctions in hypertensive rats.

Neonatal handling is an experimental procedure used to understand how early-life adversity can negatively affect neurobehavioral development and place animals on a pathway to pathology. Decreased preference for the maternal odor during infancy is one of many behavioral deficits induced by neonatal handling. Here, we hypothesize that deficits in maternal odor preference may interfere with partner preference in the adult. To test this hypothesis, we assessed infant maternal odor preference and adult partner preference in different reproductive stages in both male and female rats that received neonatal handling. Our results indicate that only neonatally handled females present deficits in maternal odor preference during infancy, but both male and females present deficits in adult partner preference. However, sexual experience was effective in rescuing partner preference deficits in males. These results indicate that, considering infant and adult social interactions, females are more susceptible to the effects of neonatal handling than males.

The natural variation in maternal care is an interesting model to analyze the physiological mechanisms that lead to differences in the mother-infant interaction. Several studies have shown differences in the expression of brain receptors such as the dopamine, estrogen and oxytocin receptors in areas classically involved in the onset and/or maintenance of maternal behavior: the medial preoptic area, the nucleus accumbens, the amygdala, the lateral septum, and the bed nucleus of the stria terminalis. The present study examined the responses of HL and LL rats in several behavioral tests and analyzes the transcription of the oxytocin receptor (OXTR) in the olfactory bulb (OB), the prefrontal cortex (FPC), the hippocampus (HP) and the striatum (ST) in different patterns of licking behavior. Our results showed that, in the second week postpartum, HL and LL mothers did not show behavioral differences in the elevated plus maze (EPM), the forced swimming test (FST) or the open field test. In the maternal aggressive behavior test, HL females showed a higher frequency of biting compared to LL females, but no significant differences in other aggressive behaviors were detected. LL mothers had higher levels of transcriptional OXTR in the OB and in the HP when compared to HL mothers. No differences in other areas were detected when compared LL and HL. These findings suggest that variations in maternal behavior may be associated with biting behavior of mothers and that OXTR participates in modulation of maternal behavior in rats, while other emotional behaviors are less related to such behavior.

Prenatal stress (PS) and early postnatal environment may alter maternal care. Infant rats learn to identify their mother through the association between maternal care and familiar odors. Female Wistar rats were exposed to restraint stress for 30min, 4 sessions per day, in the last 7days of pregnancy. At birth, pups were cross-fostered and assigned to the following groups: prenatal non-stressed mothers raising non-stressed pups (NS:NS), prenatal stressed mothers raising non-stressed pups (S:NS), prenatal non-stressed mothers raising stressed pups (NS:S), prenatal stressed mothers raising stressed pups (S:S). Maternal behaviors were assessed during 6 postpartum days. On postnatal day (PND) 7, the behavior of male and female pups was analyzed in the odor preference test; and noradrenaline (NA) activity in olfactory bulb (OB) was measured. The results showed that restraint stress increased plasma levels of corticosterone on gestational day 15. After parturition, PS reduced maternal care, decreasing licking the pups and increasing frequency outside the nest. Female pups from the NS:S, S:NS, S:S groups and male pups from the S:S group showed no nest odor preference. Thus, at day 7, female pups that were submitted to perinatal interventions showed more impairment in the nest odor preference test than male pups. No changes were detected in the NA activity in the OB. In conclusion, repeated restraint stress during the last week of gestation reduces maternal care and reduces preference for a familiar odor in rat pups in a sex-specific manner.

Objective: The purpose of the present study was to evaluate the association between the 5-HTTLPR and 5-HTTVNTR polymorphisms in the serotonin transporter gene (SLC6A4) in Brazilian women with diagnosed postpartum depression (PPD) and the presence of depressive symptoms. Method: The cohort consisted of 128 white women who were charac-terized based on skin color and morphological characteristics. The Beck Depression Inventory was used to diagnose PPD and to score the depressive symptoms. The 5-HTTLPR and 5-HTTVNTR polymorphisms were analyzed by PCR-based methods. Results: No association was observed between the PPD diagnosis and either the 5-HTTLPR (p = 0.48) or the 5-HTTVNTR (p = 0.77) polymorphism. When the polymorphisms were analyzed together with haplotype data, the analyses demonstrated that women carriers of the L-12/L-12 diplotype have lower Beck Depression Inventory scores than women carrying other diplotypes (p = 0.04). Discussion: Few studies have investigated the association of SLC6A4 polymorphisms with PPD, and the role of 5-HTTLPR and 5-HTTVNTR polymorphisms in PPD susceptibility has not been established to date. Therefore, our findings link the haplotypes of these two variants with depression symptoms, thereby contributing to our understanding of PPD susceptibility.

There is increasing evidence that early life events can influence neurodevelopment and later susceptibility to disease. Chronic variable stress (CVS) has been used as a model of depression. The objective of this study was to evaluate the interaction between early experience and vulnerability to chronic variable stress in adulthood, analyzing emotional, metabolic and neurochemical aspects related to depression. Pups were (1) handled (10 min/day) or (2) left undisturbed from day 1 to 10 after birth. When the animals reached adulthood, the groups were subdivided and the rats were submitted or not to CVS, which consisted of daily exposure to different stressors for 40 days, followed by a period of behavioral tasks, biochemical (plasma corticosterone and insulin sensitivity) and neurochemical (Na⁺,K⁺-ATPase activity in hippocampus, amygdala and parietal cortex) measurements. Neonatally-handled rats demonstrated shorter immobility times in the forced swimming test, independently of the stress condition. There was no difference concerning basal corticosterone or insulin sensitivity between the groups. Na⁺,K⁺-ATPase activity was decreased in hippocampus and increased in the amygdala of neonatally-handled rats. CVS decreased the enzyme activity in the three structures, mainly in the non-handled group. These findings suggest that early handling increases the ability to cope with chronic variable stress in adulthood, with animals showing less susceptibility to neurochemical features associated with depression, confirming the relevance of the precocious environment to vulnerability to psychiatric conditions in adulthood.

Alterations in attachment behavior might play a role in the dysfunction in social behavior displayed by autistic infants. Here we show that neonatal gastrin-releasing peptide receptor (GRPR) blockade induces a reduction in maternal odor preference, a task involving attachment behavior, in infant rats. These findings provide the first evidence that the GRPR regulates odor preference, supporting the view that the GRPR is involved in attachment and social behaviors.

objective of this study was to assess the role of environmental/nest components and maternal behavior after several neonatal interventions on subsequent behavioral responses. Male Wistar rats were subjected to different neonatal interventions and were later evaluated for innate fear-like behavior in adulthood. The experimental groups included nonhandled (i.e., animals were not touched), handled (i.e., animals were separated from their mother, removed from the nest, and handled for 10 min/day), brief maternal separation (i.e., the mother was removed from the homecage for 10 min/day, and the pups remained in their cages without being touched), and tactile stimulation (i.e., the mother was removed from the homecage, and pups were stimulated with a brush for 10 min/day within the nest). The mother's behavior was recorded during the neonatal period, and the male pups were later tested in the open field as adults. The results revealed that only mothers whose pups were handled had an increase in the duration of licking behavior compared with the other groups. In the open field test, we observed decreased behavioral innate fear-like responses in male adults in the handled and brief separation groups compared with the others groups. Our results confirm that interventions during the neonatal period cause stable behavioral changes (decreased innate fear) in adulthood and that absent or excessive tactile stimulation appears to be an important factor. Both repeated disruption of the mother-infant relationship and withdrawal from the environment/nest are factors that exert profound effects on the development of the animals. Keywords: brief separation, neonatal handling, tactile stimulation, innate fear, rats.

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.

In rats, mating at postpartum estrus and delayed dispersal of the young would result in the overlapping of two different-age litters. As a consequence, newborn pups' early experience will include not only that acquired during the interaction with the mother and age-matched littermates, but also with older siblings. As early-life experience modulates rodents' brain function, behavior and reproduction, we aimed to assess how changes in the early environment provoked by the overlapping of litters would affect emotionality, stress response and reproductive functions of male and female pups during adulthood. Results showed that both male and female overlapped reared pups exhibited a reduced behavioral inhibition in the open field test during adulthood. In addition, overlapped reared adult females, but not males, showed a blunted corticosterone response to an acute stressor during diestrus and a reduction in sexual behavior. In summary, natural changes in early experience provoked by the overlapping of litters, long-term modulate affective and reproductive behaviors, and the endocrine stress response in a sex dimorphic manner. © 2008 Wiley Periodicals, Inc. Dev Psychobiol 51: 259–267, 2009

The activity of the hypothalamic-pituitary-adrenal axis is modulated by the norepinephrinergic system and, in females, also by the ovarian hormones. We investigated the role of ovarian steroids and the locus coeruleus (LC) on stress-induced corticosterone secretion in female rats. Ovariectomized rats without hormonal replacement (OVX) or treated with estradiol (OVE) or estradiol plus progesterone (OVEP) were subjected to jugular cannulation. Immediately after that, each hormonal treatment group was subjected to LC lesion or sham surgery or no brain surgery. After 24 h, blood samples of all 9 groups were collected before and after ether inhalation. Other four groups (OVX control, sham and lesioned, and OVE) were perfused for glucocorticoid receptor (GR) immunocytochemistry in hippocampal CA1 neurons and paraventricular nucleus (PVN). Estradiol replacement decreased while LC lesions increased stress-induced corticosterone secretion. The effect of LC lesion was potentiated with the removal of ovarian steroids. Since GR expression of lesioned animals decreased in the hippocampus, but not in PVN, we suggest that the effect of LC lesion on corticosterone secretion could be due to a reduction in the efficiency of the negative feedback system in the CA1 neurons. However, this mechanism is not involved in the estradiol modulation on corticosteroid secretion, as no change in GR expression was observed in estradiol-treated animals.

Social instigation is used in rodents to induce high levels of aggression, a pattern of behavior with certain parallels to that of violent individuals. This procedure consists of a brief exposure to a provocative stimulus male, before direct confrontation with an intruder. Studies using 5-HT1A and 5-HT1B receptor agonists show an effective reduction in aggressive behavior. An important site of action for these drugs is the ventral orbitofrontal cortex (VO PFC), an area of the brain which is particularly relevant in the inhibitory control of aggressive and impulsive behavior.The objectives of the study are to assess the anti-aggressive effects of 5-HT1A and 5-HT1B agonist receptors [8-hydroxy-2-(di-n-propylamino) tetralin hydrobromide (8-OH-DPAT) and CP-93,129] in the VO PFC of socially provoked male mice. To confirm the specificity of the receptor, 5-HT1A and 5-HT1B antagonist receptors (WAY-100,635 and SB-224,289) were microinjected into the same area, in order to reverse the agonist effects.8-OH-DPAT (0.56 and 1.0 microg) reduced the frequency of attack bites. The lowest dose of CP-93,129 (0.1 microg) also decreased the number of attack bites and lateral threats. 5-HT1A and 5-HT1B receptor agonists differed in their effects on non-aggressive activities, the former decreasing rearing and grooming, and the latter, increasing these acts. Specific participation of the 1A and 1B receptors was verified by reversal of anti-aggressive effects using selective antagonists WAY-100,635 (10.0 microg) and SB-224,289 (1.0 microg).The decrease in aggressiveness observed with microinjections of 5-HT1A and 5-HT1B receptor agonists into the VO PFC of socially provoked mice, supports the hypothesis that activation of these receptors modulates high levels of aggression in a behaviorally specific manner.

Female rats have a fertile postpartum estrus, which can result in a simultaneous gestation and lactation and later in the overlapping of two different-age litters. These different physiological and contextual situations may affect the maternal behavior of lactating rats and provoke long-lasting changes in the affective behavior of the litter. Therefore, we aimed to assess the effect of pregnancy and of litter overlapping on the maternal behavior of lactating rats and to describe the maternal- and anxiety-like behaviors of the juveniles that remained in contact with their younger siblings. Results showed that pregnant lactating rats spent more time outside the nest and less time nursing than non-pregnant mothers. On the other side, mothers with overlapping litters licked less the newborn pups than mothers with single litters. These deficits in maternal licking received by neonates were overridden by the juveniles' licking behavior to their younger siblings. Adult male and diestrous female rats reared with younger siblings showed a reduced anxiety-like behavior as compared to age-weaning matched animals without this experience. Thus, natural changes in the reproductive conditions and in the early experience, affect the maternal behavior and long-term modulate affective behavior of the individuals.

Physical or emotional stress can affect the female reproductive physiology and angiotensin II (Ang II) is a hormone that participates in the stress response and also in the control of reproductive hormones. The present study aimed at evaluating the effects of acute stress in the morning and afternoon of proestrus on sexual behavior and ovulation and the participation of Ang II in the stress-induced effects. Female rats with regular estrous cycles were used. Several different stress protocols were tested in the morning and in the afternoon of proestrus: restraint stress 10 min; restraint stress 1 h and ether stress, respectively. The participation of Ang II was evaluated by injecting Ang II receptor antagonists (losartan and PD123319) 15 min before stress. The lordosis quotient was recorded and the number of oocytes was counted. Plasma levels of luteinizing hormone, progesterone, prolactin and corticosterone were measured. All types of stress in the morning of proestrus induced a reduction in the number of oocytes. Restraint stress (1 h) in the afternoon of proestrus induced a significant reduction in the lordosis quotient. Peripheral and central losartan, but not PD123319, injections partly reverted the effects of stress on ovulation in the morning of proestrus. Acute stress in the morning of proestrus also reduced luteinizing hormone, progesterone and prolactin surges later on the same day. In conclusion, acute stress on the day of proestrus can affect female reproductive physiology. Moreover, the angiotensinergic system, through AT(1) receptors, participates in the effects of acute stress in the morning of proestrus.

Serotonin (5-HT1B) receptors play an essential role in the inhibition of aggressive behavior in rodents. CP-94,253, a 5-HT1B receptor agonist, can reduce aggression in male mice when administered directly into the ventro-orbitofrontal (VO) prefrontal cortex (PFC). The objective of the current study was to assess the effects of two selective 5-HT1B receptor agonists (CP-94,253 and CP-93,129), microinjected into the VO PFC, on maternal aggressive behavior after social instigation in rats. CP-94,253 (0.56 microg/0.2 microL, N = 8, and 1.0 microg/0.2 microL, N = 8) or CP-93,129 (1.0 microg/0.2 microL, N = 9) was microinjected into the VO PFC of Wistar rats on the 9th day postpartum and 15 min thereafter the aggressive behavior by the resident female against a male intruder was recorded for 10 min. The frequency and duration of aggressive and non-aggressive behaviors were analyzed using ANOVA and post hoc tests. CP-93,129 significantly decreased maternal aggression. The frequency of lateral attacks, bites and pinnings was reduced compared to control, while the non-aggressive behaviors and maternal care were largely unaffected by this treatment. CP-94,253 had no significant effects on aggressive or non-aggressive behaviors when microinjected into the same area of female rats. CP-93,129, a specific 5-HT1B receptor agonist, administered into the VO PFC reduced maternal aggressive behavior, while the CP-94,253 agonist did not significantly affect this behavior after social instigation in female rats. We conclude that only the 5-HT1B receptor agonist CP-93,129 administered into the VO PFC decreased aggression in female rats postpartum after social instigation.

The expression of angiotensin II (Ang II) receptors in the brain is modulated by estradiol and progesterone. Considering that Ang II plays a critical role in controlling prolactin secretion and that neurons in the arcuate nucleus (ARC) are the main regulator of this function, the present study aimed to evaluate ARC Ang II receptor binding in 2 experimental models with different estradiol and progesterone plasma levels. Animals were divided into 4 groups: ovariectomy (OVX) plus oil vehicle, OVX plus estradiol and progesterone replacement, lactating rats on day 7 postpartum, and lactating rats on day 20. Animals were killed by decapitation, and the brains were removed. Ang II receptors were quantified by autoradiography in ARC. Trunk blood samples were collected, and plasma estradiol and progesterone were measured by radioimmunoassay. Treatment of OVX rats with estradiol and progesterone increased Ang II receptor binding when compared to OVX vehicle-treated animals. Plasma estradiol (r = +0.77) and progesterone (r = +0.87) were highly correlated with Ang II receptors in ovariectomized animals. Lactating rats (day 20) showed a significant decrease in Ang II receptor binding and plasma progesterone when compared to lactating rats (day 7), however, no difference was seen in plasma estradiol. Plasma levels of progesterone (r = +0.81), but not estradiol (r = +0.32), were highly correlated with Ang II receptors in lactating rats. In conclusion, present results show that ARC Ang II receptors decreases on day 20 of lactation compared to day 7 and are highly correlated with plasma progesterone, indicating a pivotal role for progesterone in this regulation.

This study aimed at identifying the effects of neonatal handling (H) and maternal separation (MS) on two paradigms of fear, learned and innate, and on the tyrosine hydroxylase (TH) immunoreactive cells in adult life. Wistar rats were daily handled with a brief maternal separation, maternal separated for 3 h or left undisturbed during the first 10 days of life. Behavioural responses in the open-field (innate fear) and conditioned fear (learned fear) were evaluated. Moreover, a semi-quantitative analysis of TH immunoreactivity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) was performed using optical densitometry and confirmed by planar measurements of neuronal density. Early handling decreased behaviour responses of innate and learned fear in adult life, while maternal separation had no significant long-lasting effect on these responses compared to the non-handled group. The behavioural effects of early handling could not be explained by changes in the density of midbrain dopaminergic cells, which were not affected by handling or maternal separation.

Neonatal handling alters the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonads axis (HPG) in adult animals, and angiotensin II (Ang II) modulates the functions in these axes. We tested whether neonatal handling could change the density of Ang II receptors in some central areas in female rats. Results showed decreased density of the Ang II receptors in the medial preoptic area (MPOA) and hypothalamic paraventricular nucleus (PVN) of the neonatal handled group.

Neonatal handling reduces fear in male and cycling female rats, but increases maternal aggressive behavior against intruders to the nest area. Present study aimed to analyze the effects of neonatal handling on the maternal aggressive behavior and the activity in the open field with a predator of lactating rats on the 8th and the 18th postpartum days (periods of high and low aggressiveness). As pups, animals were divided into two groups: nonhandled (no neonatal manipulation) and handled (handling for 1 min during the first 10 days after delivery). As adults, females of both groups were impregnated and tested against a male intruder for aggressive behavior and in the open field with a cat inside a wire-meshed cage. Results showed that on the 8th day frequency of aggressive behaviors of handled females was higher than that of the nonhandled ones, but on the 18th day, no significant difference was detected. Surprisingly, in the open field test, handled females showed decreased locomotion and increased freezing on the 8th day compared to the nonhandled ones. The opposite relationship between increased aggressiveness with reduced fear is observed in the nonhandled control females in early and late lactation periods. However, neonatal handling abolishes this relationship. Apparently, the increased aggressiveness in neonatal handled lactating females does not depend on a decrease in fear. Our findings support the hypothesis that long lasting effects of early life stimulation is a dynamic function depending on the behavioral system and the period of life analyzed. Moreover, they caution the relationship between aggressive behavior and fear.

Vários estudos recentes têm demonstrado a repercussão da privação materna no desenvolvimento neurobiológico e psicológico da criança. A depressão pós-parto, quando persistente, pode favorecer a ocorrência de situações de negligência e abuso infantil. Este trabalho tem como objetivo revisar estudos publicados a partir de 1988 que demonstrem alterações no desenvolvimento neurológico, endócrino, mental e comportamental de crianças cujas mães tiveram depressão pós-parto. A importância do meio ambiente inicial foi revisada em estudos pré-clínicos com mamíferos não-humanos, demonstrando que, quando há privação ou estresse no início do desenvolvimento, ocorrem alterações persistentes em estruturas encefálicas, em secreções neuro-hormonais e na densidade de receptores específicos. Também serão descritos alguns aportes teóricos sobre a importância da relação mãe-bebê concordantes com os achados experimentais. Many recent studies have shown that maternal deprivation has important effects on the psychological and neurobiological development of the child. Puerperal depression, when persistent, predisposes to child abuse and negligence. This paper aims at reviewing studies published as of 1988 that demonstrated changes in the neurological, endocrine, mental and behavioral development of children born from depressed puerperal women. Environmental influence was also revised, focusing on pre-clinical studies carried out with non-human mammals, which showed that deprivation or stress in early development stages predicts changes in brain structure, neuro-humoral secretions and density of specific receptors. Finally, the study also revises some theoretical aspects of the child-mother relationship importance, which are in accordance with the experimental findings. Varios estudios recientes vienen demostrando la repercusión de la privación materna en el desarrollo neurobiológico y psicológico del niño. La depresión postparto, cuando persistente, puede favorecer la ocurrencia de situaciones de negligencia y abuso infantil. El objetivo de este trabajo es revisar estudios publicados a partir de 1988, que demuestren alteraciones en el desarrollo neurológico, endocrino, mental y comportamental de niños cuyas madres sufrieron con depresión postparto. La importancia del medio ambiente inicial ha sido revisada en estudios preclínicos con mamíferos no-humanos, demostrando que, cuando hay privación o estrés en el comienzo del desarrollo, ocurren alteraciones persistentes en estructuras encefálicas, en secreciones neuro-hormonales y en la densidad de receptadores específicos. También se describirán algunos aportes teóricos acerca de la importancia de la relación madre-niño, en concordancia a los hallazgos experimentales.

Vários estudos recentes têm demonstrado a repercussão da privação materna no desenvolvimento neurobiológico e psicológico da criança. A depressão pós-parto, quando persistente, pode favorecer a ocorrência de situações de negligência e abuso infantil. Este trabalho tem como objetivo revisar estudos publicados a partir de 1988 que demonstrem alterações no desenvolvimento neurológico, endócrino, mental e comportamental de crianças cujas mães tiveram depressão pós-parto. A importância do meio ambiente inicial foi revisada em estudos pré-clínicos com mamíferos não-humanos, demonstrando que, quando há privação ou estresse no início do desenvolvimento, ocorrem alterações persistentes em estruturas encefálicas, em secreções neuro-hormonais e na densidade de receptores específicos. Também serão descritos alguns aportes teóricos sobre a importância da relação mãe-bebê concordantes com os achados experimentais.Varios estudios recientes vienen demostrando la repercusión de la privación materna en el desarrollo neurobiológico y psicológico del niño. La depresión postparto, cuando persistente, puede favorecer la ocurrencia de situaciones de negligencia y abuso infantil. El objetivo de este trabajo es revisar estudios publicados a partir de 1988, que demuestren alteraciones en el desarrollo neurológico, endocrino, mental y comportamental de niños cuyas madres sufrieron con depresión postparto. La importancia del medio ambiente inicial ha sido revisada en estudios preclínicos con mamíferos no-humanos, demostrando que, cuando hay privación o estrés en el comienzo del desarrollo, ocurren alteraciones persistentes en estructuras encefálicas, en secreciones neuro-hormonales y en la densidad de receptadores específicos. También se describirán algunos aportes teóricos acerca de la importancia de la relación madre-niño, en concordancia a los hallazgos experimentales.Many recent studies have shown that maternal deprivation has important effects on the psychological and neurobiological development of the child. Puerperal depression, when persistent, predisposes to child abuse and negligence. This paper aims at reviewing studies published as of 1988 that demonstrated changes in the neurological, endocrine, mental and behavioral development of children born from depressed puerperal women. Environmental influence was also revised, focusing on pre-clinical studies carried out with non-human mammals, which showed that deprivation or stress in early development stages predicts changes in brain structure, neuro-humoral secretions and density of specific receptors. Finally, the study also revises some theoretical aspects of the child-mother relationship importance, which are in accordance with the experimental findings.

The central effect of oxytocin (OT) on the aggressive behavior of lactating rats was studied. Female rats are more aggressive than nonlactating resident females, vigorously attacking conspecific intruder male or females. This behavior is considered important for pup protection against infanticide. The present work aimed to test the effects on maternal aggressive behavior of OT infused into the central amygdaloid nucleus (CeM) or bed nucleus of stria terminalis (BNST). The surgeries for bilateral cannula implantation were performed between the 2nd and 4th postpartum day. Three days after the surgery, saline or OT was infused and 5 min later a male intruder was placed in the home-cage and the behaviors were videotaped for 10 min. The frequency of the aggressive behaviors and the duration of locomotion during the aggressive behavior test were measured. The latency to retrieve the pups was also evaluated. The results showed that OT injected into CeM (10 and 20 ng/nucleus) decreased frequency of biting and frontal attack while in the BNST (10 and 20 ng/nucleus) decreased the frequency of biting. No significant change on retrieval activity was detected. OT in CeM and BNST has an inhibitory effect on the aggressive behavior of lactating female rats.

Neonatal handling induces anovulatory estrous cycles and decreases sexual receptivity in female rats. The synchronous secretion of hormones from the gonads (estradiol (E2) and progesterone (P)), pituitary (luteinizing (LH) and follicle-stimulating (FSH) hormones) and hypothalamus (LH-releasing hormone (LHRH)) are essential for the reproductive functions in female rats. The present study aimed to describe the plasma levels of E2 and P throughout the estrous cycle and LH, FSH and prolactin (PRL) in the afternoon of the proestrus, and the LHRH content in the medial preoptic area (MPOA), median eminence (ME) and medial septal area (MSA) in the proestrus, in the neonatal handled rats. Wistar pup rats were handled for 1 min during the first 10 days after delivery (neonatal handled group) or left undisturbed (nonhandled group). When they reached adulthood, blood samples were collected through a jugular cannula and the MPOA, ME and MSA were microdissected. Plasma levels of the hormones and the content of LHRH were determined by RIA. The number of oocytes counted in the morning of the estrus day in the handled rats was significantly lower than in the nonhandled ones. Neonatal handling reduces E2 levels only on the proestrus day while P levels decreased in metestrus and estrus. Handled females also showed reduced plasma levels of LH, FSH and PRL in the afternoon of the proestrus. The LHRH content in the MPOA was significantly higher than in the nonhandled group. The reduced secretion of E2, LH, FSH and LHRH on the proestrus day may explain the anovulatory estrous cycle in neonatal handled rats. The reduced secretion of PRL in the proestrus may be related to the decreased sexual receptiveness in handled females. In conclusion, early-life environmental stimulation can induce long-lasting effects on the hypothalamus-pituitary-gonad axis.

O objetivo deste estudo foi analisar os efeitos do estresse pre-natal repetido por contencao sobre a preferencia sexual de ratos Wistar na idade adulta, quando somente as maes e/ou filhotes foram submetidos a intervencao. Para esse experimento, ratas da linhagem Wistar foram expostas a 30 minutos de estresse por contencao 4 vezes por dia na ultima semana de gravidez. No primeiro dia de vida pos-parto, os filhotes foram submetidos a adocao cruzada e divididos nos seguintes grupos: filhotes nao- estressados prenatalmente adotados por maes nao-estressadas prenatalmente (C-c), filhotes nao estressados prenatalmente adotados por maes estressadas (Ep-c), filhotes estressados prenatalmente adotados por maes nao-estressadas (C-ep) e filhotes estressados prenatalmente adotados por maes tambem estressadas prenatalmente (Ep-ep). Para avaliacao da preferencia sexual, os filhotes machos adultos dos quatro grupos formados foram expostos simultaneamente a femeas receptivas e nao receptivas (castradas). Os resultados mostraram que o estresse pre-natal realizado na ultima semana de gestacao foi capaz de prejudicar a preferencia sexual somente de machos dos grupos Ep-ep e C-ep. Todavia, nao foram observadas diferencas para os demais grupos. Assim, nosso estudo mostrou que o ambiente pos-natal nao foi capaz de reverter os efeitos produzidos pelo estresse gestacional sobre o comportamento de preferencia sexual de filhotes na idade adulta.

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.

For most mammalian species, maternal behavior has an essential role in the development of the offspring. The frequency of licking/grooming (LG) the pups has been used as a parameter to evaluate maternal care, having mothers with high (HL) or low (LL) frequencies of LG. This study aimed to analyze the gene expression of the receptors for dopamine (Drd1a), prolactin (Prlr), serotonin (Htr1a, Htr1b), estrogen (Esr1, Esr2), and of Bdnf in the olfactory bulb (OB), hippocampus (HP), prefrontal cortex (PFC), and striatum (ST) of Wistar rats from three groups: LL (n = 8); HL (n = 8); virgin females in diestrus (D; n = 6). Maternal behavior was studied between the 1st and 7th postpartum days. Brain parts were analyzed by qRT-PCR. LL showed a decrease in the frequency of nursing, and an increase of remaining off the pups. There was an increase in gene expression of Drd1a, Prlr, Htr1a, Htr1b and Esr1 in the OB of HL, compared to LL. In the HP, Drd1a, Prlr and Htr1a were differently expressed when comparing HL, or LL, with D. The main finding is that HL had higher gene expression levels in the OB, which is a crucial structure to promote behavioral differences.

During the postnatal period, the nervous system is modified and shaped by experience, in order to adjust it to the particular environment in which the animal will live. This plasticity, one of the most remarkable characteristics of the nervous system, promotes adaptive changes, but it also makes brain more vulnerable to insults. This chapter will focus on the effects of interventions during the postnatal development in animal models of neonatal handling (usually up to 15 min of handling) and maternal separation (usually at least for 3 h). Sex-specific changes and effects of prepubertal stress such as social isolation later on in life were also considered. These interventions during development induce long-lasting traces in the pups’ nervous system, which will be reflected in changes in neuroendocrine functions, including the hypothalamus–pituitary–adrenal and hypothalamus–pituitary–gonadal axes; anxiety and cognitive performance; and feeding, sexual, and social behavior. These enduring changes may be adaptive or maladaptive, depending on the environment in which the animal will live. The challenge researchers facing now is to determine how to reverse the deleterious effects that may result from early-life stress exposure.

Neonatal handling has long-lasting effects on behavior and stress reactivity. The purpose of the present study was to investigate the effect of neonatal handling on the number of dopaminergic neurons in the hypothalamic nuclei of adult male rats as part of a series of studies that could explain the long-lasting effects of neonatal stimulation. Two groups of Wistar rats were studied: nonhandled (pups were left undisturbed, control) and handled (pups were handled for 1 min once a day during the first 10 days of life). At 75-80 days, the males were anesthetized and the brains were processed for immunohistochemistry. An anti-tyrosine hydroxylase antibody and the avidin-biotin-peroxidase method were used. Tyrosine hydroxylase-immunoreactive (TH-IR) neurons were counted bilaterally in the arcuate, paraventricular and periventricular nuclei of the hypothalamus in 30-microm sections at 120-microm intervals. Neonatal handling did not change the number of TH-IR neurons in the arcuate (1021 +/- 206, N = 6; 1020 +/- 150, N = 6; nonhandled and handled, respectively), paraventricular (584 +/- 85, N = 8; 682 +/- 62, N = 9) or periventricular (743 +/- 118, N = 7; 990 +/- 158, N = 7) nuclei of the hypothalamus. The absence of an effect on the number of dopaminergic cells in the hypothalamus indicates that the reduction in the amount of neurons induced by neonatal handling, as shown by other studies, is not a general phenomenon in the brain.

High levels of aggressive behaviors against intruders in the nest area are displayed by female rats during the first 10 days after delivery, declining thereafter to very low levels, even though lactation continues. Cross-fostering experiments were undertaken to test the hypothesis that pup age may affect aggression in lactating rats. The behavior of females on the 8th day after delivery when raising fostered 8- day-old pups was compared to that of females on the 8th postpartum day raising older pups (18 days old) for the last 5 days, and females on the 18th day after delivery raising fostered 18-day-old pups were compared to females in the same postpartum period nursing younger pups (8 days of age at the time of the maternal aggression test) for 5 days. Pup retrieval activity and plasma prolactin level were also analyzed. Females on the 8th postpartum day nursing 18-day-old pups were less aggressive than females in the same postpartum period, but with 8-day-old pups. Likewise, females on the 18th postpartum day nursing younger pups were more aggressive and presented higher levels of prolactin than females nursing older pups. Thus, pup development can alter the natural decline of maternal aggressive behavior.

Since previous work has shown that stimulation early in life decreases sexual receptiveness as measured by the female lordosis quotient, we suggested that neonatal handling could affect the function of the hypothalamus-pituitary-gonadal axis. The effects of neonatal handling on the estrous cycle and ovulation were analyzed in adult rats. Two groups of animals were studied: intact (no manipulation, N = 10) and handled (N = 11). Pups were either handled daily for 1 min during the first 10 days of life or left undisturbed. At the age of 90 days, a vaginal smear was collected daily at 9:00 a.m. and analyzed for 29 days; at 9:00 a.m. on the day of estrus, animals were anesthetized with thiopental (40 mg/kg, ip), the ovaries were removed and the oviduct was dissected and squashed between 2 glass slides. The number of oocytes of both oviductal ampullae was counted under the microscope. The average numbers for each phase of the cycle (diestrus I, diestrus II, proestrus and estrus) during the period analyzed were compared between the two groups. There were no significant differences between intact and handled females during any of the phases. However, the number of handled females that showed anovulatory cycles (8 out of 11) was significantly higher than in the intact group (none out of 10). Neonatal stimulation may affect not only the hypothalamus-pituitary-adrenal axis, as previously demonstrated, but also the hypothalamus-pituitary-gonadal axis in female rats.

Central oxytocin (OT) appears to be crucial for maternal behavior. OT, through the parvocellular neurons of the hypothalamic paraventricular nucleus (PVN), can exert its physiological and behavioral effects by acting on OT receptors in nonpituitary projections of the PVN. The purpose of the present study was to analyze the role of the PVN and OT on maternal aggressive behavior in two different periods after delivery: on the fifth day (period of high aggressiveness) and on the eighteenth day postpartum (period of low aggressiveness). In the first experiment, ibotenic acid was injected into the PVN in order to lesion the parvocellular neurons. A second experiment was designed to study more specifically the effects of OT using the antisense technique. On the fifth day postpartum, both the PVN lesion by the ibotenic acid and a possible acute reduction of OT synthesis by the antisense administration in that nucleus increased maternal aggressive behavior, while on the eighteenth day postpartum no effect was recorded. We may conclude that central projections of the PVN modulate maternal aggression during a restricted period after delivery, only when lactating females show naturally high levels of aggressive behaviors.

This review discusses the effects of stress and nutrition throughout development and summarises studies investigating how exposure to stress or alterations in nutrition during the pre-conception, prenatal and early postnatal periods can affect the long-term health of an individual. In general, the data presented here suggest that that anything signalling potential adverse conditions later in life, such as high levels of stress or low levels of food availability, will lead to alterations in the offspring, possibly of an epigenetic nature, preparing the offspring for these conditions later in life. However, when similar environmental conditions are not met in adulthood, these alterations may have maladaptive consequences, resulting in obesity and heightened stress sensitivity. The data also suggest that the mechanism underlying these adult phenotypes might be dependent on the type and the timing of exposure.