NMDA lesions in the prefrontal cortex delay the onset of maternal, but not infanticidal behavior in pup-naïve adult mice (C57BL/6).

While most pup-naïve adult female mice can display, or be induced (by repeated exposure to pups) to display parental behavior rapidly, adult males are infanticidal or nonparental. The medial prefrontal cortex (mPFC) participates in attentional selection, decision-making, behavioral flexibility, and planning that may be critical in the rapid display of parental or infanticidal behavior. We investigated if NMDA-induced lesions in the mPFC (targeting prelimbic cortex) inhibited maternal or infanticidal behavior in pup-naïve adult female and male mice (C57BL/6), respectively. All Control females displayed full maternal behavior at the first encounter with pups. Lesioned female groups were partially maternal (50%) or nonmaternal (50%). Five repeated exposures of 60-min to pups were needed to induce full maternal behavior in female NMDA-lesioned groups. Control and lesioned males did not show significant differences. Control males displayed nonparental (17%) or infanticidal (83%) behavior, while all lesioned males were infanticidal. There was no difference in general locomotor and exploratory activity (i.e., peripheral crosses, rearings, immobility time) in female or male groups. Nevertheless, females and males of lesioned groups showed a reduction in the number of central crosses and time in the central area of an open field respectively, suggesting an increase in anxiety. Our results show that the mPFC is engaged in the rapid onset of maternal behavior in females, contributing with the motivation and planning of its rapid execution, or reducing the anxiety to the first encounter with pups. In contrast, infanticidal behavior, likely a more impulsive behavior, might require less planning from the mPFC. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Variation in the density of oxytocin receptors in the brain as mechanism of adaptation to specific social and reproductive strategies.

Most species have predominant forms of social and reproductive behavior driven by many years of selection pressures and evolution. For example, rodent species can live in small or large groups, behave more tolerant or aggressively toward conspecifics (including newborns), and form or not bonds with other members of the group (including sexual partners). Any of those behavioral adaptations could result in good fitness for the species, but could also require compromises such as sharing resources, greater parental investment, increased risk of predation, etc. We propose that the oxytocin (OXT) system, among others neuroendocrine peptides, is at the basis of a neural mechanism that adapts and predisposes species to a particular social and reproductive form of living. In this review we will show evidence that the variability in the density of receptors for OXT (OXTR) in the nucleus accumbens (NAc) and the lateral septum (LS) predisposes species to adopt at least 4 different social and reproductive strategies in rodents. Large or medium size groups with lower conspecific spacing (preferred separation distance maintained by adult conspecifics), and high levels of promiscuity are characterized by low levels of OXTR in the NAc and LS (e.g. Ratus norvegicus, Ctenomys sociabilis, Scotinomys teguina, Cavia porcellus); small size groups with higher conspecific spacing and low levels of promiscuity are characterized by high OXTR in the NAc and the LS (e.g. Peromyscus californicus); large or medium groups with lower conspecific spacing and low levels of promiscuity characterized by high levels of OXTR in the NAc but low levels in the LS (e.g. Microtus ochrogaster, Heterocephalus glaber, Microtus kikuchii); and small or medium size groups with higher conspecific spacing and high levels of promiscuity characterized by low levels of OXTR in the NAc and high OXTR in the LS (e.g. Mus musculus, Ctenomys haigi, Peromyscus maniculatus, Microtus pennsylvanicus, Microtus montanus). Careful analysis of the distribution of OXTR, and other peptides receptors, in the brain can contribute to understand its function but also to predict reproductive and social strategies of species.

Are age and sex differences in brain oxytocin receptors related to maternal and infanticidal behavior in naïve mice?

This article is part of a Special Issue "Parental Care". There is significant variability in the behavioral responses displayed by naïve young and adult mice when first exposed to pups. This variability has been associated with differences in the expression of oxytocin receptors (OXTRs) in the brain in several species. Experiment I investigated the behavioral responses of juvenile, adolescent, and adult CB57BL/6 males and females when first exposed to pups. We found an age increase in maternal females (11% of juveniles, 20% of adolescents, and 50% of young adults), and infanticidal males (0% of juveniles, 30% of adolescents, 44.5% of young adults, and 100% of older adults). Experiment II investigated OXTR density in the brain of juvenile and adult mice. Our results revealed an age decline in the density of OXTR in several brain regions, including the lateral septum, cingulated and posterior paraventricular thalamic nucleus in both males and females. Adult females had higher OXTR density in the ventromedial nucleus/postero-ventral hypothalamus (VMH) and the accessory olfactory bulb (AOB), but lower density in the ventral region of the lateral septum (LSv) than juveniles. Males had lower OXTR density in the anterior olfactory area (AOA) compared to juveniles. No age or sex differences were found in the medial preoptic area, and amygdaloid nuclei, among other brain regions. This study suggests that 1) maturation of parental and infanticidal behavioral responses is not reached until adulthood; 2) the pattern of development of OXTR in the mouse brain is unique, region specific, and differs from that observed in other rodents; 3) either up or down regulation of OXTR in a few brain regions (VMH/AOB/LSv/AOA) might contribute to age or sex differences in parental or infanticidal behavior.

Development and expression of maternal behavior in naïve female C57BL/6 mice.

Naïve female mice are usually described as spontaneously maternal. We investigated how many exposures to pups (15 min vs. 1 hr) were needed to induce full maternal behavior (FMB) in 20-22, 30-35, 60-65-days-old naïve female mice (C57BL/6), and how cohabitation with the parturient mother and newborn siblings facilitated juvenile maternal behavior (MB). Only 20% of the adults displayed FMB immediately after the first exposure to pups. Incomplete MB was present in 11%, 20%, and 30% of juveniles, adolescents and adults, respectively. Three-sixty minute exposures to pups induced FMB in all adult subjects. All naïve juveniles that were not exposed to their siblings and maternal fluids failed to show maternal behavior. In contrast, more than half of the juveniles present at their homecage during delivery of a second litter showed incomplete MB (34.5%) or FMB (21.5%) when tested individually housed in a novel cage. This study suggests that most adult female mice are not spontaneously maternal but gradually sensitized. Besides, naïve juveniles could be inhibited or not motivated to show MB, but display adult-like behavior toward pups if previously exposed to newborn siblings and maternal fluids.

Comparative analysis of oxytocin receptor density in the nucleus accumbens: an adaptation for female and male alloparental care?

Parental behavior is commonly displayed by progenitors. However, other individuals, genetically related (e.g. siblings, aunts, uncles) or not with the newborns, also display parental behavior (commonly called alloparental, or adoptive behavior). I hypothesize that species that live in family or social groups where other non-reproductive members (males and females) take care of infants, have brain adaptations to promote or facilitate that behavioral response. The present work revises the evidence supporting the hypothesis that high density of oxytocin receptors (OXTR) in the nucleus accumbens (NA) is one of those adaptations. All species known to have high NA OXTR show not only female, but also male alloparental care. Therefore, I predict that high NA OXTR could be present in all species in which juvenile and adult male alloparental behavior have been observed. Strategies to test this and other alternative working hypothesis and its predictions are presented.

Flexibility and adaptation of the neural substrate that supports maternal behavior in mammals.

Maternal behavior is species-specific and expressed under different physiological conditions, and contexts. It is the result of neural processes that support different forms (e.g. postpartum, cycling sensitized and spontaneous maternal behavior) and modalities of mother-offspring interaction (e.g. maternal interaction with altricial/precocious young; selective/non-selective bond). To understand how the brain adapts to and regulates maternal behavior in different species, and physiological and social conditions we propose new neural models to explain different forms of maternal expression (e.g. sensitized and spontaneous maternal behavior) and the behavioral changes that occur across the postpartum period. We emphasize the changing role of the medial preoptic area in the neural circuitry that supports maternal behavior and the cortical regulation and adjustment of ongoing behavioral performance. Finally, we discuss how our accumulated knowledge about the psychobiology of mothering in animal models supports the validity of animal studies to guide our understanding of human mothering and to improve human welfare and health.

New theoretical and experimental approaches on maternal motivation in mammals.

Maternal behavior is expressed in different modalities, physiological conditions, and contexts. It is the result of a highly motivated brain, that allows the female to flexibily adapt her caring activities to different situations and social demands. To understand how mothers coordinate maternal and other motivated behaviors we discuss the limitations of current theoretical approaches to study maternal motivation (e.g. distinction between appetitive and consummatory behaviors), and propose a different approach (i.e. motorically active vs. passive motivations) and a distinction between maternal motivated state and maternal motivated behaviors. We review the evidence supporting dopamine mediation of maternal motivation and describe how different phases of the dopaminergic response - basal, tonic, and phasic release in the nucleus accumbens - relate to increased salience, invigorating behavior, and behavioral switching. The existing and new experimental paradigms to investigate maternal motivation, and its coexpression and coordination with other social or non-social motivations are also analyzed. An example of how specificity of motivational systems (e.g. maternal and sexual behavior at postpartum estrus) could be processed at the neural level is also provided. This revision offers new theoretical and experimental approaches to address the fundamental question of how mothers flexibly adapt and coordinate the different components of maternal behavior with other motivated behaviors, also critical for the survival of the species.

Stability and potential inheritance of infanticidal behavior in prairie voles.

Naïve female prairie voles show significant variability in their behavioral response to newborns. We investigated whether that behavioral response (a) was related to the quality of postpartum maternal behavior; (b) was affected by postpartum maternal experience; and (c) could be selectively bred. The behavior of females was recorded in three conditions: as naïve in a nonreproductive context, as single lactating (no male present), and as experienced mother in a nonreproductive context. Finally, females and males with similar behavioral response to newborns were selectively bred for three generation. Males were removed before the offspring was born. Our results revealed that (a) naïve females that attacked pups, spent more time distant from them after parturition than those that were maternal or ignored the pups (p < .05); (b) postpartum maternal experience did not reverse infanticidal behavior; and (c) at the third generation of selective breeding, 90% of the offspring of females that were nonmaternal as virgins, behaved as their mothers. These findings suggest that the infanticidal behavioral response is a stable behavioral trait and might be passed to the offspring.

Variability in "spontaneous" maternal behavior is associated with anxiety-like behavior and affiliation in naïve juvenile and adult female prairie voles (Microtus ochrogaster).

Juvenile female prairie voles (Microtus ochrogaster) are spontaneously maternal, while virgin adult females show significant variability in their response to first pup exposure, ranging from infanticidal to full maternal behavior. In the present study, we investigated whether differences in anxiety-like behavior and affiliation are associated with juvenile-adult and adult individual differences in the response to pups. Forty juvenile (19-20 days) and 42 adult (60-90 days) female prairie voles were exposed to pups for the first time and tested for maternal behavior, anxiety-like behavior (elevated plus maze, open field), and affiliation toward age-matched, same sex conspecifics. Juveniles displayed less anxiety-like behavior, were more affiliative to unfamiliar conspecifics, and interacted with pups more positively than adults. Adults that displayed maternal behavior spent less time immobile, made more crosses through the center of the open field arena, and were more affiliative than adults that attacked the pups. This suggests that lower locomotion or exploration in a novel environment and poor affiliative behavior are negatively associated with maternal responsiveness in female prairie voles.

Enhanced partner preference in a promiscuous species by manipulating the expression of a single gene.

The molecular mechanisms underlying the evolution of complex behaviour are poorly understood. The mammalian genus Microtus provides an excellent model for investigating the evolution of social behaviour. Prairie voles (Microtus ochrogaster) exhibit a monogamous social structure in nature, whereas closely related meadow voles (Microtus pennsylvanicus) are solitary and polygamous. In male prairie voles, both vasopressin and dopamine act in the ventral forebrain to regulate selective affiliation between adult mates, known as pair bond formation, as assessed by partner preference in the laboratory. The vasopressin V1a receptor (V1aR) is expressed at higher levels in the ventral forebrain of monogamous than in promiscuous vole species, whereas dopamine receptor distribution is relatively conserved between species. Here we substantially increase partner preference formation in the socially promiscuous meadow vole by using viral vector V1aR gene transfer into the ventral forebrain. We show that a change in the expression of a single gene in the larger context of pre-existing genetic and neural circuits can profoundly alter social behaviour, providing a potential molecular mechanism for the rapid evolution of complex social behaviour.

MPOA cytotoxic lesions and maternal behavior in the rat: effects of midpubertal lesions on maternal behavior and the role of ovarian hormones in maturation of MPOA control of maternal behavior.

Small neurotoxin lesions in the medial preoptic area (MPOA) block maternal behavior (MB) in adults but large lesions are required to produce the same effect in juvenile rats (23-27 days of age). To study the maturation of MPOA control of MB, in Experiment I, we compared the effects of small versus large neurotoxin MPOA lesions at midpuberty (38 days of age) on MB. Midpubertal females with large MPOA lesions showed severe impairment in MB affecting retrieving, crouching, and nest building, but 85% of females with small MPOA lesions exhibited all components of MB and performed like control females without MPOA lesions. To study the role of ovarian hormones during puberty on the maturation of MPOA mediation of MB (Experiment IIA), females were ovariectomized either before or after puberty and small MPOA cytotoxic lesions were made at 53 days of age. At 60 days of age both groups showed similar deficits in MB which indicated that the maturation of the MPOA mediation of MB is not dependent on pubertal ovarian hormones. In Experiment IIB, we administered estradiol benzoate (sc) and this overcame the deficit in MB after small MPOA lesions in females that had been deprived of estrogen for shorter periods (30 days) but had not been deprived for longer periods (60 days). In addition, ovary-intact females with circulating estrogen and small lesions in the MPOA at 53 days of age did not show deficits in MB.