NMDA- and 6-OHDA-induced Lesions in the Nucleus Accumbens Differently Affect Maternal and Infanticidal Behavior in Pup-naïve Female and Male Mice.

Virgin and pups-naïve female and male adult mice display two opposite responses when they are exposed to pups for the first time. While females generally take care of the pups, males attack them. Since the nucleus accumbens (NA), and its dopaminergic modulation, is critical in integrating information and processing reward and aversion, we investigated if NMDA- and 6-OHDA-induced lesions, damaging mostly NA output and dopaminergic inputs respectively, affected female maternal behavior (MB) or male infanticidal behavior (IB) in mice. Our results revealed minor or no effects of both smaller and larger NMDA-induced lesions in MB and IB. On the other hand, while 6-OHDA-induced lesions in females reduced the incidence of full MB (12.5% 6-OHDA vs. 85.7% SHAM) increasing the latency to retrieve the pups, those lesions did not affect IB in males. There were no differences in locomotor and exploratory activity between the lesioned- and SHAM- females. Despite those lesions did not induce any major effect on IB, NMDA-lesioned males spent less time in the central area of an open field, while dopaminergic-lesioned males showed reduced number of rearing and peripheral crosses. The current study shows that an intact NA is not necessary for the expression of MB and IB. However, dopaminergic inputs to NA play different role in MB and IB. While damaging dopaminergic terminals into the NA did not affect IB, it clearly delayed the more flexible and rewarding expression of parental behavior.

Description and comparison of brain distribution of oxytocin receptors in Rhabdomys pumillio and Rhabdomys dilectus.

Oxytocin receptor (OXTR) distribution in the brain has been associated with different reproductive and social strategies of species. Rhabdomys pumilio (R. pumilio) and Rhabdomys dilectus (R. dilectus) are two sister rodent species that live in large/medium (but flexible) or small (mostly solitary) social groups respectively. In this study, we describe and compare the distribution of OXTR in these two species. OXTR binding in the brain of R. pumilio (8 females and 5 males) and R. dilectus (8 females and 5 males) adults was determined using autoradiography. Our results revealed significant differences in the nucleus accumbens, diagonal band, medial preoptic area, lateral habenula, superior colliculus, periaqueductal area and anterior paraventricular nucleus (higher in R. dilectus), and the dorsal lateral septum and anterior bed nucleus of the stria terminalis (higher in R. pumilio). OXTR density in other brain regions, such as the amygdala nuclei and hippocampus, did not differ between the two species. Sex differences were found in the medial preoptic area and ventral region of the lateral septum in R. pumilio (OXTR density higher in males) and in the anterior paraventricular thalamic nucleus, ventromedial nucleus of the hypothalamus and basolateral amygdala of R. dilectus (OXTR density higher in females). A sex difference in the density of OXTR was also found in the posterior region of the bed nucleus of the stria terminalis, where it was higher in males than in females of both species. This study shows species-specific brain distribution of OXTR in R. pumilio and R. dilectus that are unique, but with similarities with other polygynous or promiscuous rodent species that live in variable size groups, such as R. norvergicus, C. sociabilis, S. teguina and M. musculus.

Prefrontal cortex is associated with the rapid onset of parental behavior in inexperienced adult mice (C57BL/6).

There is significant variability in the immediate behavioral response displayed by inexperienced adult mice when exposed to pups for the first time. The aim of this study was to determine which brain regions were engaged (higher c-Fos-immunoreactivity, c-Fos-ir) when virgin females, that were exposed to pups for 15 or 60 min, displayed full parental behavior (FPB), partial parental behavior (PPB), or non-parental behavior (NPB), or virgin males displayed PPB or infanticidal behavior (IB). The number of c-Fos-ir neurons in the prelimbic cortex (PL) was higher in parental females than in the NPB group (after a 15-min exposure), and the group not exposed to pups (NE). C-Fos expression in the nucleus accumbens (NA) was increased in most groups of females exposed to pups compared to NE. Higher c-Fos-ir was also found in the shell subregion of the NA in infanticidal males, compared to males NE. The cortical (CoA) and medial (MA) amygdala also showed higher c-Fos-ir in parental females compared to NE animals. However, PPB and IB male groups also exhibited higher c-Fos-ir in the CoA and MA compared to the NE group. The expression of c-Fos in the different subregions of medial preoptic area and the ventromedial nucleus of the hypothalamus was not specifically associated with either parental or infanticidal behavior. No brain activation in males was specifically associated with infanticidal behavior. Our results suggest that 15 min of exposure to pups is enough to detect brain regions associated with parental behavior (PL) or pups processing (NA, MA, CoA) in mice. The PL might participate in the immediate onset of parental behavior in virgin females, coordinating and planning its rapid execution.

Role of oxytocin in parental behaviour.

Both animal and human studies have provided conclusive evidence that oxytocin (OXT) acts in the brain (eg, medial preoptic area, ventral tegmental area, nucleus accumbens) to promote parental behaviour under different reproductive and physiological conditions. OXT appears to accelerate and strengthen the neural process that makes newborns attractive or rewarding. Furthermore, OXT reduces stress/anxiety and might improve mood and well being, resulting in indirect benefits for parents. However, OXT also plays a role in the development of species reproductive and social strategies, making some species or individuals more prone to display caring activities in nonreproductive contexts. There are important differences in the development of the OXT system and its regulation by gonadal hormones that can make individuals or species very different. Those intra- and interspecific differences in the OXT system have been associated with differences in parental behaviour. For example, differences in OXT levels in body fluids and genetic variants for the OXT and OXT receptor genes have been associated with variability in parental mood and behaviour in humans. Thus, OXT has received much attention as a potential therapeutic agent for affective, emotional and behavioural problems. Despite many preliminary studies indicating promising findings, several unknown aspects of the OXT system remain to be addressed before we can achieve a complete understanding of its function in the brain. The enormous interest that this area of study has attracted in the last decade will likely continually contribute to advancing our understanding of the role of OXT in parental behaviour and other behavioural and physiological functions.

Oxytocin receptors in the nucleus accumbens facilitate "spontaneous" maternal behavior in adult female prairie voles.

Oxytocin and the nucleus accumbens have been extensively implicated in the regulation of maternal behavior, and the processing of pup-related stimuli relevant for this behavior. Oxytocin receptor density in the nucleus accumbens is highly variable in virgin female prairie voles, as is their behavioral response to pups, ranging from neglecting and infanticidal to full maternal behavior. We hypothesized that oxytocin receptor in the nucleus accumbens facilitates the expression of "spontaneous" maternal behavior in prairie voles. Forty sexually-naive adult females were exposed to pups for the first time and tested for maternal behavior. Oxytocin receptor binding in the nucleus accumbens and other brain regions was later determined using autoradiography. Females that showed maternal behavior (lick and groom the pups and hover over them for at least 30 s, n=24) had higher oxytocin receptor density in the nucleus accumbens (shell subregion) (P<0.05) than females that did not show maternal behavior or attacked the pups (n=16). No differences were found in other brain regions (medial preoptic area, septum, prelimbic cortex). In a second experiment, we tested whether infusions of the oxytocin receptor antagonist (d(CH2)5(1),Tyr(Me)2,Orn8)-AVT into the nucleus accumbens would block "spontaneous" maternal behavior. As a control region, oxytocin receptor antagonist was also infused into the caudate putamen. Ten females were infused bilaterally into the nucleus accumbens or caudate putamen with either 2 ng/0.5 microl of oxytocin receptor antagonist or CSF (vehicle). While five of 10 nucleus accumbens CSF-infused animals showed maternal behavior, none of the nucleus accumbens oxytocin receptor antagonist-infused subjects did (0/10; chi2, P<0.01). Nucleus accumbens oxytocin receptor antagonist-infused females recovered the next day and were not different from controls. Animals infused with CSF or oxytocin receptor antagonist into the caudate putamen did not differ (four/10, four/10). This is the first study to show that the nucleus accumbens is involved in the regulation of "spontaneous" maternal behavior and that oxytocin receptor in this brain region facilitates maternal responses.

Species and individual differences in juvenile female alloparental care are associated with oxytocin receptor density in the striatum and the lateral septum.

The neuropeptide oxytocin has been implicated in the regulation of affiliative behavior and maternal responsiveness in several mammalian species. Rodent species vary considerably in the expression of juvenile alloparental behavior. For example, alloparental behavior is spontaneous in juvenile female prairie voles (approximately 20 days of age), takes 1-3 days of pup exposure to develop in juvenile rats, and is nearly absent in juvenile mice and meadow voles. Here, we tested the hypothesis that species differences in pup responsiveness in juvenile rodents are associated with oxytocin receptor (OTR) density in specific brain regions. We found that OTR density in the nucleus accumbens (NA) is highest in juvenile prairie voles, intermediate in juvenile rats, and lowest in juvenile mice and meadow voles. In the caudate putamen (CP), OTR binding was highest in prairie voles, intermediate in rats and meadow voles, and lowest in mice. In contrast, the lateral septum (LS) shows an opposite pattern, with OTR binding being high in mice and meadow voles and low in prairie voles and rats. Thus, alloparental responsiveness in juvenile rodents is positively correlated with OTR density in the NA and CP and negatively correlated with OTR density in the LS. We then investigated whether a similar receptor-behavior relationship exists among juvenile female prairie voles by correlating individual variation in alloparental behavior with variation in OTR density. The time spent adopting crouching postures, the most distinctive component of alloparental behavior in juveniles, was positively correlated with OTR density in the NA (r = 0.47) and CP (r = 0.45) and negatively correlated with OTR density in the lateral septum (r = -0.53). Thus, variation in OTR density in the NA, CP, and LS may underlie both species and individual differences in alloparental care in rodents.

Juvenile rats show reduced c-fos activity in neural sites associated with aversion to pups and inhibition of maternal behavior.

Juvenile rats (18-23 days old) interact avidly with pups as novel stimuli and show maternal behavior after only 1-3 days of pup exposure; adults initially avoid pups and require 3-9 days of pup exposure. Upon exposure to pups as novel stimuli, adults had more c-Fos-immunoreactive neurons in the hypothalamus and amygdala--regions associated with aversion to pups--than adults exposed to familiar pup stimuli (maternal) or not exposed to pups (p < .05). In juvenile rats exposed to pups as novel stimuli, only the medial amygdala had a small significant increase of c-Fos neurons. In juveniles, this blunted engagement of c-Fos neurons may reflect the diminished activation of inhibitory neurons, facilitating the interaction of juveniles with pups as novel stimuli and onset of maternal behavior.

The content of dopamine, serotonin, and their metabolites in the neural circuit that mediates maternal behavior in juvenile and adult rats.

Continuous exposure of non-parturient rats to pups can induce maternal behavior similar in most aspects to that found in the postpartum rat. Surprisingly, young juvenile rats (20-24 days of age) only require 1-3 days of exposure to pups, while adults require 4-8 days before maternal behavior emerges. Dopamine (DA) and possibly serotonin (5-HT) may mediate the expression of adult maternal behavior. We hypothesize that postnatal changes in DA and 5-HT within the neural circuit that supports maternal behavior including the medial preoptic area (MPOA), medial and cortical amygdala (MCA), and nucleus accumbens (NAC), may underlie these differences in responsiveness across juveniles and adults. We measured DA, 5-HT, and their metabolites in postmortem samples of these regions in maternal and non-maternal juvenile and adult females. The only difference found across behavioral groups was that the MPOA of adults induced into maternal behavior by pup exposure had more DA than did that of isolated adult females or maternal juveniles. However, when adults versus juveniles were compared, the content of DA and 3,4-dihydroxyphenylacetic (DOPAC) was higher in the adult than in the juvenile NAC and MCA; the content of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in these structures did not vary across the age groups. In contrast, higher levels of 5-HT and 5-HIAA were found in the MPOA in juveniles compared to adults. We propose that these region-specific age differences in DA and 5HT may underlie differences in juvenile-adult responses to pups.

Maternal behavior in rats with kainic acid-induced lesions of the hypothalamic paraventricular nucleus.

The rat maternal behavior consists of different pup-caring activities, such as retrieving, licking, and crouching. Mothers also build a nest, consume more food, are more aggressive, and show less fear behavior than in other stages of the reproductive cycle. It has been reported that oxytocin (OT) and the milk-ejection pathway could be involved in modulating maternal behavior. The paraventricular nucleus (PVN) of the hypothalamus forms part of the milk-ejection pathway and is also the major source of OT release in the brain. Kainic acid (KA) lesions (0.5 microg/0.5 microl) in the PVN performed on day 2 after parturition, affected retrieving behavior in the mother rat and produced a decrease in pups' weight gain. Because KA destroys only cell bodies, the changes that we observed could be due to the local destruction of neurons, rather than that of the fibers of passage. No alteration was observed in other components of the pup-caring activities, food intake, aggressive behavior, and fear in the lesioned mothers.