Variation in the mu-opioid receptor gene (OPRM1) moderates the influence of maternal sensitivity on child attachment.

The endogenous opioid system is thought to play an important role in mother-infant attachment. In infant rhesus macaques, variation in the µ-opioid receptor gene (OPRM1) is related to differences in attachment behavior that emerges following repeated separation from the mother; specifically, infants carrying at least one copy of the minor G allele of the OPRM1 C77G polymorphism show heightened and more persistent separation distress, as well as a pattern of increased contact-seeking behavior directed towards the mother during reunions (at the expense of affiliation with other group members). Research in adult humans has also linked the minor G allele of the analogous OPRM1 A118G polymorphism with greater interpersonal sensitivity. Adopting an interactionist approach, we examined whether OPRM1 A118G genotype and maternal (in)sensitivity are associated with child attachment style, predicting that children carrying the G allele may be more likely to develop an ambivalent attachment pattern in response to less sensitive maternal care. The sample consisted of 191 mothers participating with their children (n = 223) in the Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project, a community-based, birth cohort study of Canadian mothers and their children assessed longitudinally across the child's development. Maternal sensitivity was coded from at-home mother-child interactions videotaped when the child was 18 months of age. Child attachment was assessed at 36 months using the Strange Situation paradigm. As predicted, G allele carriers, but not AA homozygotes, showed increasing odds of being classified as ambivalently attached with decreasing levels of maternal sensitivity. Paralleling earlier non-human animal research, this work provides support for the theory that endogenous opioids contribute to the expression of attachment behaviors in humans.

Oxytocin receptors in the nucleus accumbens shell are involved in the consolidation of maternal memory in postpartum rats.

Female rats with maternal experience display a shorter onset of maternal responsiveness compared to those with no prior experience. This phenomenon called 'maternal memory' is critically dependent on the nucleus accumbens (NA) shell. We hypothesized that activation of OT receptors in the NA shell facilitates maternal memory. In Experiment 1, postpartum female rats given 1 hour of maternal experience were infused following the experience with either a high or low dose of an OT antagonist into the NA shell and tested for maternal behavior after a 10-day pup isolation period. Females receiving a high dose of the antagonist showed a significantly longer latency to exhibit full maternal behavior after the pup isolation period compared to females that received vehicle or a high dose of antagonist in a control region. In Experiment 2, postpartum female rats were infused with either a high or low dose of OT into the NA shell after a 15-minute maternal experience and tested for maternal behavior after a 10-day pup isolation period. There were no significant differences between the females infused with OT and females treated with a vehicle infused into the NA shell or with OT infused into the control region. One possible reason for a lack of facilitation is a floor effect, since females in the control groups displayed a rapid maternal response after the pup isolation period. These findings suggest that OT receptors, likely in combination with other neurotransmitters, in the NA shell play a role in the consolidation of maternal memory.

The effects of early isolation on sexual behavior and c-fos expression in naïve male Long-Evans rats.

Previous findings have demonstrated that the maternal environment is important for the development of male sexual behavior. The present study examined the effects of complete early life isolation and replacement 'stroking' stimulation on male sexual behavior and neural activation as seen by Fos immunoreactivity (Fos-IR). Animals were either artificially reared (AR) with minimal (AR-MIN) or maximal (AR-MAX) body simulation, or maternally reared (MR). In adulthood, animals were either given an exposure to an estrous female (EXP) or left undisturbed (NoEXP). No significant effects of early development were found in sexual behavior; however differences in activation in response to this exposure were observed. AR-MIN animals showed lower Fos-IR in the medial preoptic area and the ventromedial hypothalamus compared to MR animals. AR-MAX animals were not significantly different from either condition. These findings demonstrate that although there are no differences in the quality of the first copulatory exposure between AR and MR animals, the brain's response to this exposure differs in sites within the brain that subserve sexual behavior.

Parenting begets parenting: A neurobiological perspective on early adversity and the transmission of parenting styles across generations.

The developing brains of young children are highly sensitive to input from their social environment. Nurturing social experience during this time promotes the acquisition of social and cognitive skills and emotional competencies. However, many young children are confronted with obstacles to healthy development, including poverty, inappropriate care, and violence, and their enhanced sensitivity to the social environment means that they are highly susceptible to these adverse childhood experiences. One source of social adversity in early life can stem from parenting that is harsh, inconsistent, non-sensitive or hostile. Parenting is considered to be the cornerstone of early socio-emotional development and an adverse parenting style is associated with adjustment problems and a higher risk of developing mood and behavioral disorders. Importantly, there is a growing literature showing that an important predictor of parenting behavior is how parents, especially mothers, were parented themselves. In this review, we examine how adversity in early-life affects mothering behavior in later-life and how these effects may be perpetuated inter-generationally. Relying on studies in humans and animal models, we consider evidence for the intergenerational transmission of mothering styles. We then describe the psychological underpinnings of mothering, including responsiveness to young, executive function and affect, as well as the physiological mediators of mothering behavior, including hormones, brain regions and neurotransmitters, and we consider how development in these relevant domains may be affected by adversity experienced in early life. Finally, we explore how genes and early experience interact to predict mothering behavior, including the involvement of epigenetic mechanisms. Understanding how adverse parenting begets adverse parenting in the next generation is critical for designing interventions aimed at preventing this intergenerational cycle of early adversity.

Thinking and doing: the effects of dopamine and oxytocin genes and executive function on mothering behaviours.

Animal and human studies suggest that initial expression of maternal behaviour depends on oxytocin and dopamine systems. However, the mechanism by which these systems affect parenting behaviours and the timing of these effects are not well understood. This article explores the role of mothers' executive function in mediating the relation between oxytocin and dopamine gene variants and maternal responsiveness at 48 months post-partum. Participants (n = 157) were mothers recruited in the Maternal Adversity, Vulnerability and Neurodevelopment Study, which assesses longitudinally two cohorts of mothers and children in Canada. We examined single nucleotide polymorphisms (SNPs) related to the dopamine and oxytocin systems (DRD1 rs686, DRD1 rs265976, OXTR rs237885 and OXTR rs2254298), assessed mothers' decision-making at 48 months using the Cambridge Neurological Automated Testing Battery (CANTAB) and evaluated maternal responsiveness from videotaped interactions during the Etch-A-Sketch co-operation task. Mediation analyses showed that OXTR rs2254298 A-carriers had an indirect effect on positive parenting which was mediated by mothers' performance on decision-making task (estimate = 0.115, P < 0.005), while OXTR rs2254298 A-carriers had both direct and indirect effects on physically controlling parenting, also mediated through enhanced performance on decision-making (estimate = -0.059, P < 0.005). Dopamine SNPs were not associated with any measure of executive function or parenting (all P > 0.05). While oxytocin has previously been associated with only the early onset of maternal behaviour, we show that an OXTR polymorphism is involved in maternal behaviour at 48 months post-partum through mothers' executive function. This research highlights the importance of the oxytocin system to maternal parenting beyond infancy.

Chemical and behavioral stimulation from females accelerates recrudescence in male Syrian hamsters exposed to short days.

Interaction with female hamsters maintained under long photoperiods (LP) accelerates behavioral recrudescence in short photoperiod (SP) males. In this experiment, the authors investigated the effects of various types of female sociosexual cues on different measures of reproductive recrudescence in the male. Five groups of SP males were exposed to different female cues for 3 weeks (Weeks 12 to 15). At Week 16, males were allowed to interact with estrus females; behavioral, physiological, and fecundity measures were monitored. The results show that all measures responded in a pseudo-dose-dependent manner to the different female cues presented. SP males not exposed to any female cues and those exposed to distal visual, auditory, and volatile pheromonal cues from estrus females did not copulate, deposit sperm, or impregnate estrus females presented to them at Week 16. SP males allowed direct access to the bedding of estrus females showed marked improvements on these same reproductive measures by Week 16. However, SP males that interacted with LP females between Weeks 12 and 15 showed the greatest level of reproductive function at Week 16. These results show that the type of female sociosexual stimulation is important in accelerating reproductive recrudescence; whereas interaction with LP females may be important in accelerating behavioral recrudescence, both interaction with and exposure to the bedding of LP females may be important in accelerating physiological and reproductive success measures.

Photoperiodic and pineal effects on food intake, food retrieval, and body weight in female Syrian hamsters.

Food intake, food retrieval, and body weight changes were measured in female Syrian hamsters maintained under long and short photoperiods, and in animals sustaining pinealectomy or sham surgery. Animals maintained under short photoperiods gained more weight, ingested more food, and brought more food from more distant compartments into their nest compartments than did animals maintained under long photoperiods. Pinealectomy prevented the short-day elevations in body weight and food retrieval during the period of gonadal recrudescence, but it did not produce significant changes during the period of gonadal regression; in contrast, pinealectomy prevented the short-day increases in food intake only during initial weeks of the period of gonadal regression: The effects of photoperiod or pinealectomy were not evident for any of the dependent measures during pregnancy. The role of the pineal gland in mediating short-day effects is discussed.

Maternal childhood adversity and child temperament: an association moderated by child 5-HTTLPR genotype.

We examined transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5-HTTLPR, in the serotonin-transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother-child dyads, recruited into a longitudinal birth cohort study. We examined the interactive effects of maternal childhood experience using an integrated measure derived from Childhood Trauma Questionnaire (CTQ) and Parental Bonding Index (PBI). Triallelic genotyping of 5-HTTLPR was performed. A measure of 'negative emotionality/behavioural dysregulation' was derived from the Early Childhood Behaviour Questionnaire at 18 and 36 months. Negative emotionality/behavioural dysregulation was highly stable between 18 and 36 months and predicted psychosocial problems at 60 months. After controlling multiple demographics as well as both previous and concurrent maternal depression there was a significant interaction effect of maternal childhood adversity and offspring 5-HTTLPR genotype on child negative emotionality/behavioural dysregulation (ß = 1.03, t(11,115) = 2.71, P < .01). The results suggest a transgenerational effect of maternal developmental history on emotional function in the offspring, describing a pathway that likely contributes to the familial transmission of vulnerability for psychopathology.

Neurobiology of mother-infant interactions: experience and central nervous system plasticity across development and generations.

The optimal coordination between the new mammalian mother and her young involves a sequence of behaviors on the part of each that ensures that the young will be adequately cared for and show healthy physical, emotional, and social development. This coordination is accomplished by each member of the relationship having the appropriate sensitivities and responses to cues that characterize the other. Among many mammalian species, new mothers are attracted to their infants' odors and some recognize them based on their odors; they also respond to their infants' vocalizations, thermal properties, and touch qualities. Together these cues ensure that the mother will nurse and protect the offspring and provide them with the appropriate physical and stimulus environment in which to develop. The young, in turn, orient to the mother and show a suckling pattern that reflects a sensitivity to the mothers odor, touch, and temperature characteristics. This article explores the sensory, endocrine, and neural mechanisms that underlie this early mother-young relationship, from the perspective of, first, the mother and, then, the young, noting the parallels between them. It emphasizes the importance of learning and plasticity in the formation and maintenance of the mother-young relationship and mediation of these experience effects by the brain and its neurochemistry. Finally, it discusses ways in which the infants' early experiences with their mothers (or the absence of these experiences) may come to influence how they respond to their own infants when they grow up, providing a psychobiological mechanism for the inter-generational transmission of parenting styles and responsiveness.

Neuropsychology of maternal behavior in the rat: c-fos expression during mother-litter interactions.

This series of studies used the pattern of nuclear Fos-like immunoreactivity (Fos-lir) to map the functional pathways in the brain that mediate the onset and retention of maternal behavior. In the first two experiments, parturient rat dams were exposed to either pups or to other stimuli on Day 1 postpartum. Dams interacting with pups were either intact or sustained ventral somatosensory, olfactory, or combined desensitizations. Results showed that 1) all intact pup-interacting dams showed elevated levels of Fos-lir in the medial preoptic area (MPOA) and the medial and cortical amygdala as compared to control groups, and 2) olfactory and ventral somatosensory desensitization, either alone or in combination, did not decrease Fos-lir in the MPOA. However, olfactory desensitizations did decrease Fos-lir in the medial amygdala and the combined desensitizations significantly reduced Fos-lir in both the basolateral and central amygdala. In the third study, dams were either exposed to pups or to other stimuli and were subsequently reexposed to pups or to pup cues. Regardless of prior maternal experience, females who were able to interact with pups upon reexposure showed increased Fos-lir in the MPOA, the basolateral and central nuclei of the amygdala, and the nucleus accumbens when compared to females which did not interact with pups. Taken together, these studies suggest that the neuroanatomy of maternal behavior is a complex one, involving multiple systems that interconnect with the MPOA and that mediate the many behavioral processes activated when an animal responds maternally.

Factors influencing maternal responsiveness in humans: usefulness of an animal model.

In this article we review some of the hormonal, sensory and experiential factors that regulate the onset and early maintenance of maternal responsiveness in rat and human mothers. We discuss data suggesting that, in humans, pregnancy is associated with changes in feelings and attitudes that may bear on adjustment to motherhood postpartum. Preliminary studies indicate that these changes are probably not hormonally mediated but are associated with a variety of psychosocial factors. Once women give birth, there is some suggestion that they undergo a period of elevated "responsiveness" which may be influenced by puerperal hormones and during which experiences with the newborn take on a special salience. Following the early postpartum period, a variety of factors influence maternal responsiveness, including the mother's affective state, her social relationships, and experiences caring for young. We discuss the relative contributions of psychological and physiological influences to maternal responsiveness at different stages of the maternity cycle.

Effects of diet on feeding and body weight regulation during pregnancy and lactation in the golden hamster (Mesocricetus auratus).

The hypothesis was tested that the weight loss shown by lactating hamsters constitutes a "regulated" weight loss. The results support the hypothesis: Prefattened overweight hamsters lost more weight from the time of mating to the end of lactation than did unmanipulated controls. However, the weight loss during lactation was reduced by giving hamsters access to a high-fat diet, a result indicating that a portion of the lactational weight loss may also be regulated by the diet provided. When lactating hamsters were given access to a fractionated diet consisting of pure fat, pure carbohydrate, or 45% protein, they increased their proportional intake of both protein and fat but not of carbohydrate. These studies show that hamsters differ from rats in their pattern of energy regulation during pregnancy, lactation, and the postsuckling period. Reasons for these species differences are discussed.

Plasticity in the maternal circuit: effects of maternal experience on Fos-Lir in hypothalamic, limbic, and cortical structures in the postpartum rat.

To determine what brain sites are activated during the acquisition and retention of a maternal experience in postpartum rats, 3 studies examined the number of cells showing Fos-like immunoreactivity (Fos-lir) in brains following reexposure to pups and pup-associated cues in maternally experienced and inexperienced rats. Day 1 postpartum rats were given a 2- or 4-hr interactive experience with pups and then reexposed to pups in a perforated box, or to a neutral stimulus (perforated box only) 4 or 10 days later. At the end of the test phase, brains were prepared for immunohistochemical detection of Fos-lir. The brain sites showing the most consistent difference between experienced and inexperienced rats were the medical preoptic area, the basolateral amygdala, the parietal cortex, and the prefrontal cortex.

Plasticity in the maternal circuit: effects of experience and partum condition on brain astrocyte number in female rats.

Female rats that have received a maternal experience undergo enhanced c-fos expression in a number of brain sites when reexposed to pups. The present 2 studies examined changes in the expression of another brain protein, glial fibrillary acidic protein (GFAP), which is a major unit of the astrocytic cytoskeleton. In both experiments, primiparous and multiparous female rats were given varying amounts of postpartum contact with pups and overdosed after varying intervals, with no pups. Brains were prepared for GFAP immunohistochemical analysis. In both studies, Day 5 postpartum multiparous subjects given additional postpartum contact with pups, when compared with pup-exposed primiparous subjects, were found to have significantly higher numbers of GFAP positive cells in the medial preoptic area of the hypothalamus, an area critical for the expression of maternal behavior, but not in control sites. In Experiment 2, an opposite effect of parity was found in the medial amygdala and habenula.

Activation of Fos-like immunoreactivity in the medial preoptic area and limbic structures by maternal and social interactions in rats.

The researchers examined the number of cells showing Fos-like immunoreactivity (Fos-lir) in the brains of hormonally primed parturient rat dams immediately following their first behavioral interactions with pups. Groups were exposed to newborn pups (pup), adult conspecifics (social), or a new food (food), or they were left alone in cages (control/isolate) for a 1-hr period. Rats were then killed, and their brains were prepared for immunohistochemical detection of Fos-lir. Rats in the pup group had higher numbers of cells showing. Fos-lir within the medial preoptic area (MPOA) nuclei than did the social, control/isolate, and, marginally, food groups and higher levels of Fos-lir in a number of amygdaloid nuclei (medial and cortical) and in cingulate and somatosensory cortices than did control/isolate or food groups. Fos-lir in amygdala did not differ between pup and social groups. There were also group differences in Fos-labeling in the olfactory bulbs, with the pup group showing the highest densities. These results show elevated expression of Fos-lir in brain structures that were activated during the expression of maternal behavior, including the olfactory structures, amygdala, and MPOA.

The effects of olfactory and somatosensory desensitization on Fos-like immunoreactivity in the brains of pup-exposed postpartum rats.

Fos-like immunoreactivity (fos-lir) was examined in sites within the "maternal circuit" in postpartum female rats that received various sensory desensitizations and were exposed to pups for 1 or 2 hr. Neither olfactory bulbectomy nor thelectomy (nipple removal) significantly reduced the fos-lir in the anterior medial preoptic area (MPOA), although reductions following bulbectomy in medial amygdala did occur. Peripherally induced hyposmia by ZnSo4 reduced fos-lir in the olfactory structures (olfactory bulbs, piriform cortex, and olfactory tubercle), in medial and cortical nuclei of the amygdala, but not in anterior MPOA. Application of the topical anesthetic Emla to the ventrum only reduced fos-lir in the somatosensory cortex. Combined olfactory and ventral desensitizations produced marginal reductions in posterior MPOA. It is suggested that the MPOA is primarily involved as part of the effector system in the expression of the behavior. In contrast, the amygdala is involved in processing sensory cues received from pups during dam-litter interactions.

Neuroanatomical basis of maternal memory in postpartum rats: selective role for the nucleus accumbens.

The experience of interacting with pups causes long-term changes in mothers' brains that mediate long-term changes in maternal behavior. As little as 1 hr of pup experience postpartum results in enhanced maternal responses to pups 10 days later. This experiment investigated the effects of lesions in multiple neural sites that have been implicated either in the actual expression of maternal behavior or in learning and memory within other behavioral contexts on the initiation and the long-term experience-based retention of maternal behavior. Electrolytic lesions were performed either before or after a 1-hr or 24-hr maternal experience. Rats sustaining lesions of the nucleus accumbens (NACC), whether administered before parturition and experience or immediately after a brief experience, failed to show a maternal experience effect. NACC lesions sustained 24 hr after a maternal experience did not disrupt long-term retention of the maternal behavior.

Mother rats bar-press for pups: effects of lesions of the mpoa and limbic sites on maternal behavior and operant responding for pup-reinforcement.

This series of studies explored the operant response rates for pup-reinforcement of female Sprague Dawley rats that were either postpartum or cycling and sustained lesions of the medial preoptic area (mpoa), the lateral amygdala, the nucleus accumbens, or sham lesions. The last experiment tested the effects on operant responding of preventing direct access to pups in mpoa and sham-lesioned postpartum mothers. All animals were trained prior to mating on an FR-1 bar-press schedule to criterion (50 presses in 30 min) for a food (Froot Loops) reward in an operant chamber. At the end of pregnancy animals that were to be tested postpartum were provided in their home cages with six newborn foster pups; mother-litter interactions were observed on the last 3 days of pregnancy and throughout the postpartum period. On each of these same days after a period of separation from pups, females were tested in the operant box for delivery of rat pups. With each bar-press response, a rat pup rather than a Fruit Loop was delivered down a gentle shoot into the hopper. Non-postpartum, but maternal, multiparous animals who were showing estrous cycles were tested using the same procedures. The first and second studies showed that animals (both postpartum and as cycling multiparous animals) with mpoa lesions exhibited a significant reduction in bar-press rate for pup reinforcement in the operant box. In postpartum animals, amygdala lesions also produced a bar-press deficit, whereas nucleus accumbens lesions did not. All lesioned groups showed deficits in maternal responding in the home cage and deficits in retrieval in the operant box. These results indicate that systems associated with the mpoa mediate both the stereotypical maternal behaviors and pup-reinforcement. In contrast, the expression of home cage maternal behavior is dependent on the integrity of both the amygdala and nucleus accumbens, whereas operant responding need not be. These results indicate a dissociation of mechanisms mediating expression of the species-typical maternal behavior and pup-reinforcement.

Mother rats bar-press for pups: effects of lesions of the mpoa and limbic sites on maternal behavior and operant responding for pup-reinforcement.

This series of studies explored the operant response rates for pup-reinforcement of female Sprague Dawley rats that were either postpartum or cycling and sustained lesions of the medial preoptic area (mpoa), the lateral amygdala, the nucleus accumbens, or sham lesions. The last experiment tested the effects on operant responding of preventing direct access to pups in mpoa and sham-lesioned postpartum mothers. All animals were trained prior to mating on an FR-1 bar-press schedule to criterion (50 presses in 30 min) for a food (Froot Loops) reward in an operant chamber. At the end of pregnancy animals that were to be tested postpartum were provided in their home cages with six newborn foster pups; mother-litter interactions were observed on the last 3 days of pregnancy and throughout the postpartum period. On each of these same days after a period of separation from pups, females were tested in the operant box for delivery of rat pups. With each bar-press response, a rat pup rather than a Fruit Loop was delivered down a gentle shoot into the hopper. Non-postpartum, but maternal, multiparous animals who were showing estrous cycles were tested using the same procedures. The first and second studies showed that animals (both postpartum and as cycling multiparous animals) with mpoa lesions exhibited a significant reduction in bar-press rate for pup reinforcement in the operant box. In postpartum animals, amygdala lesions also produced a bar-press deficit, whereas nucleus accumbens lesions did not. All lesioned groups showed deficits in maternal responding in the home cage and deficits in retrieval in the operant box. These results indicate that systems associated with the mpoa mediate both the stereotypical maternal behaviors and pup-reinforcement. In contrast, the expression of home cage maternal behavior is dependent on the integrity of both the amygdala and nucleus accumbens, whereas operant responding need not be. These results indicate a dissociation of mechanisms mediating expression of the species-typical maternal behavior and pup-reinforcement.

Disruption of maternal behaviour in virgin and postparturient rats following sagittal plane knife cuts in the preoptic area-hypothalamus.

Parasagittal knife cuts along the medial preoptic area-medial anterior hypothalamus were placed at either the medial (near lateral or NL cuts) or lateral (far lateral or FL cuts) border o the medial forebrain bundle in separate groups of virgin (Experiment 1) and postparturient (Experiment 2) rats. FL cuts were placed so as to spare preoptic-hypothalamic efferent connections with the medial forebrain bundle. NL and FL knife cuts were equally effective in preventing the induction of maternal behaviour produced by repeated exposure of virgin rats to foster pups. Both types of cuts also reduced nest building in virgins. In postparturient rats, NL and FL cuts both abolished pup retrievaL and reduced nursing behaviour. However, only NL cuts disrupted lactation and nest building. NL cuts also produced chronic hyperthermia. The deficits in maternal behaviour and nest building may be independent of this hyperthermia, as shaving the fur in animals with NL cuts reduced body temperatures to control levels but did not restore these behaviours. These findings indicate that while preoptic/hypothalamic connections through the medial forebrain bundle are important for nest building and possibly lactation, other lateral connections must also be important for pup retrieval and nursing behaviour. The identity of these connections remains to be determined.