Functional Ontogeny of Hypothalamic Agrp Neurons in Neonatal Mouse Behaviors.

Hypothalamic Agrp neurons regulate food ingestion in adult mice. Whether these neurons are functional before animals start to ingest food is unknown. Here, we studied the functional ontogeny of Agrp neurons during breastfeeding using postnatal day 10 mice. In contrast to adult mice, we show that isolation from the nursing nest, not milk deprivation or ingestion, activated Agrp neurons. Non-nutritive suckling and warm temperatures blunted this effect. Using in vivo fiber photometry, neonatal Agrp neurons showed a rapid increase in activity upon isolation from the nest, an effect rapidly diminished following reunion with littermates. Neonates unable to release GABA from Agrp neurons expressed blunted emission of isolation-induced ultrasonic vocalizations. Chemogenetic overactivation of these neurons further increased emission of these ultrasonic vocalizations, but not milk ingestion. We uncovered important functional properties of hypothalamic Agrp neurons during mouse development, suggesting these neurons facilitate offspring-to-caregiver bonding.

Antagonistic circuits mediating infanticide and maternal care in female mice.

In many species, including mice, female animals show markedly different pup-directed behaviours based on their reproductive state1,2. Naive wild female mice often kill pups, while lactating female mice are dedicated to pup caring3,4. The neural mechanisms that mediate infanticide and its switch to maternal behaviours during motherhood remain unclear. Here, on the basis of the hypothesis that maternal and infanticidal behaviours are supported by distinct and competing neural circuits5,6, we use the medial preoptic area (MPOA), a key site for maternal behaviours7-11, as a starting point and identify three MPOA-connected brain regions that drive differential negative pup-directed behaviours. Functional manipulation and in vivo recording reveal that oestrogen receptor α (ESR1)-expressing cells in the principal nucleus of the bed nucleus of stria terminalis (BNSTprESR1) are necessary, sufficient and naturally activated during infanticide in female mice. MPOAESR1 and BNSTprESR1 neurons form reciprocal inhibition to control the balance between positive and negative infant-directed behaviours. During motherhood, MPOAESR1 and BNSTprESR1 cells change their excitability in opposite directions, supporting a marked switch of female behaviours towards the young.

Neural circuitry for maternal oxytocin release induced by infant cries.

Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing1-6. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers7, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.

Puppy whines mediate maternal behavior in domestic dogs.

In mammals, offspring vocalizations typically encode information about identity and body condition, allowing parents to limit alloparenting and adjust care. But how do these vocalizations mediate parental behavior in species faced with the problem of rearing not one, but multiple offspring, such as domestic dogs? Comprehensive acoustic analyses of 4,400 whines recorded from 220 Beagle puppies in 40 litters revealed litter and individual (within litter) differences in call acoustic structure. By then playing resynthesized whines to mothers, we showed that they provided more care to their litters, and were more likely to carry the emitting loudspeaker to the nest, in response to whine variants derived from their own puppies than from strangers. Importantly, care provisioning was attenuated by experimentally moving the fundamental frequency (fo, perceived as pitch) of their own puppies' whines outside their litter-specific range. Within most litters, we found a negative relationship between puppies' whine fo and body weight. Consistent with this, playbacks showed that maternal care was stronger in response to high-pitched whine variants simulating relatively small offspring within their own litter's range compared to lower-pitched variants simulating larger offspring. We thus show that maternal care in a litter-rearing species relies on a dual assessment of offspring identity and condition, largely based on level-specific inter- and intra-litter variation in offspring call fo. This dual encoding system highlights how, even in a long-domesticated species, vocalizations reflect selective pressures to meet species-specific needs. Comparative work should now investigate whether similar communication systems have convergently evolved in other litter-rearing species.

Maternal care leads to the evolution of long, slow lives.

Animals, and mammals in particular, vary widely in their "pace of life," with some species living long lives and reproducing infrequently (slow life histories) and others living short lives and reproducing often (fast life histories). These species also vary in the importance of maternal care in offspring fitness: In some species, offspring are fully independent of their mothers following a brief period of nutritional input, while others display a long period of continued dependence on mothers well after nutritional dependence. Here, we hypothesize that these two axes of variation are causally related to each other, such that extended dependence of offspring on maternal presence leads to the evolution of longer lives at the expense of reproduction. We use a combination of deterministic modeling and stochastic agent-based modeling to explore how empirically observed links between maternal survival and offspring fitness are likely to shape the evolution of mortality and fertility. Each of our modeling approaches leads to the same conclusion: When maternal survival has a strong impact on the survival of offspring and grandoffspring, populations evolve longer lives with less frequent reproduction. Our results suggest that the slow life histories of humans and other primates as well as other long-lived, highly social animals such as hyenas, whales, and elephants are partially the result of the strong maternal care that these animals display. We have designed our models to be readily parameterized with demographic data that are routinely collected by long-term researchers, which will facilitate more thorough testing of our hypothesis.

Innate and plastic mechanisms for maternal behaviour in auditory cortex.

Infant cries evoke powerful responses in parents1-4. Whether parental animals are intrinsically sensitive to neonatal vocalizations, or instead learn about vocal cues for parenting responses is unclear. In mice, pup-naive virgin females do not recognize the meaning of pup distress calls, but retrieve isolated pups to the nest after having been co-housed with a mother and litter5-9. Distress calls are variable, and require co-caring virgin mice to generalize across calls for reliable retrieval10,11. Here we show that the onset of maternal behaviour in mice results from interactions between intrinsic mechanisms and experience-dependent plasticity in the auditory cortex. In maternal females, calls with inter-syllable intervals (ISIs) from 75 to 375 milliseconds elicited pup retrieval, and cortical responses were generalized across these ISIs. By contrast, naive virgins were neuronally and behaviourally sensitized to the most common ('prototypical') ISIs. Inhibitory and excitatory neural responses were initially mismatched in the cortex of naive mice, with untuned inhibition and overly narrow excitation. During co-housing experiments, excitatory responses broadened to represent a wider range of ISIs, whereas inhibitory tuning sharpened to form a perceptual boundary. We presented synthetic calls during co-housing and observed that neurobehavioural responses adjusted to match these statistics, a process that required cortical activity and the hypothalamic oxytocin system. Neuroplastic mechanisms therefore build on an intrinsic sensitivity in the mouse auditory cortex, and enable rapid plasticity for reliable parenting behaviour.

Father's care uniquely influences male neurodevelopment.

Mammalian infants depend on parental care for survival, with numerous consequences for their behavioral development. We investigated the epigenetic and neurodevelopmental mechanisms mediating the impact of early biparental care on development of alloparenting behavior, or caring for offspring that are not one's own. We find that receiving high parental care early in life leads to slower epigenetic aging of both sexes and widespread male-specific differential expression of genes related to synaptic transmission and autism in the nucleus accumbens. Examination of parental care composition indicates that high-care fathers promote a male-specific increase in excitatory synapses and increases in pup retrieval behavior as juveniles. Interestingly, females raised by high-care fathers have the opposite behavioral response and display fewer pup retrievals. These results support the concept that neurodevelopmental trajectories are programmed by different features of early-life parental care and reveal that male neurodevelopmental processes are uniquely sensitive to care by fathers.

Sexual Dimorphism of Parental Care: From Genes to Behavior.

Parental care is found in species across the animal kingdom, from small insects to large mammals, with a conserved purpose of increasing offspring survival. Yet enormous variability exists between different species and between the sexes in the pattern and level of parental investment. Here, we review the literature on the neurobiological mechanisms underlying maternal and paternal care, especially in rodents, and discuss the relationship between sex differences in behavior and sexual dimorphism in the brain. We argue that although several brain regions and circuits regulating parental care are shared by both sexes, some of the fundamental components comprising the maternal brain are innate and sex specific. Moreover, we suggest that a more comprehensive understanding of the underlying mechanisms can be achieved by expanding the methodological toolbox, applying ethologically relevant approaches such as nontraditional wild-derived animal models and complex seminatural experimental set-ups.

Prolactin-mediated restraint of maternal aggression in lactation.

Aggressive behavior is rarely observed in virgin female mice but is specifically triggered in lactation where it facilitates protection of offspring. Recent studies demonstrated that the hypothalamic ventromedial nucleus (VMN) plays an important role in facilitating aggressive behavior in both sexes. Here, we demonstrate a role for the pituitary hormone, prolactin, acting through the prolactin receptor in the VMN to control the intensity of aggressive behavior exclusively during lactation. Prolactin receptor deletion from glutamatergic neurons or specifically from the VMN resulted in hyperaggressive lactating females, with a marked shift from intruder-directed investigative behavior to very high levels of aggressive behavior. Prolactin-sensitive neurons in the VMN project to a wide range of other hypothalamic and extrahypothalamic regions, including the medial preoptic area, paraventricular nucleus, and bed nucleus of the stria terminalis, all regions known to be part of a complex neuronal network controlling maternal behavior. Within this network, prolactin acts in the VMN to specifically restrain male-directed aggressive behavior in lactating females. This action in the VMN may complement the role of prolactin in other brain regions, by shifting the balance of maternal behaviors from defense-related activities to more pup-directed behaviors necessary for nurturing offspring.

Attachment Reminders Trigger Widespread Synchrony across Multiple Brains.

Infant stimuli elicit widespread neural and behavioral response in human adults, and such massive allocation of resources attests to the evolutionary significance of the primary attachment. Here, we examined whether attachment reminders also trigger cross-brain concordance and generate greater neural uniformity, as indicated by intersubject correlation. Human mothers were imaged twice in oxytocin/placebo administration design, and stimuli included four ecological videos of a standard unfamiliar mother and infant: two infant/mother alone (Alone) and two mother-infant dyadic contexts (Social). Theory-driven analysis measured cross-brain synchrony in preregistered nodes of the parental caregiving network (PCN), which integrates subcortical structures underpinning mammalian mothering with cortical areas implicated in simulation, mentalization, and emotion regulation, and data-driven analysis assessed brain-wide concordance using whole-brain parcellation. Results demonstrated widespread cross-brain synchrony in both the PCN and across the neuroaxis, from primary sensory/somatosensory areas, through insular-cingulate regions, to temporal and prefrontal cortices. The Social context yielded significantly more cross-brain concordance, with PCNs striatum, parahippocampal gyrus, superior temporal sulcus, ACC, and PFC displaying cross-brain synchrony only to mother-infant social cues. Moment-by-moment fluctuations in mother-infant social synchrony, ranging from episodes of low synchrony to tightly coordinated positive bouts, were tracked online by cross-brain concordance in the preregistered ACC. Findings indicate that social attachment stimuli, representing evolutionary-salient universal cues that require no verbal narrative, trigger substantial interbrain concordance and suggest that the mother-infant bond, an icon standing at the heart of human civilization, may function to glue brains into a unified experience and bind humans into social groups.SIGNIFICANCE STATEMENT Infant stimuli elicit widespread neural response in human adults, attesting to their evolutionary significance, but do they also trigger cross-brain concordance and induce neural uniformity among perceivers? We measured cross-brain synchrony to ecological mother-infant videos. We used theory-driven analysis, measuring cross-brain concordance in the parenting network, and data-driven analysis, assessing brain-wide concordance using whole-brain parcellation. Attachment cues triggered widespread cross-brain concordance in both the parenting network and across the neuroaxis. Moment-by-moment fluctuations in behavioral synchrony were tracked online by cross-brain variability in ACC. Attachment reminders bind humans' brains into a unitary experience and stimuli characterized by social synchrony enhance neural similarity among participants, describing one mechanism by which attachment bonds provide the neural template for the consolidation of social groups.

Nurture outpaces nature: fostering with an attentive mother alters social dominance in a mouse model of stress sensitivity.

Maternal care is critical for epigenetic programming during postnatal brain development. Stress is recognized as a critical factor that may affect maternal behavior, yet owing to high heterogeneity in stress response, its impact varies among individuals. We aimed here to understand the connection between inborn stress vulnerability, maternal care, and early epigenetic programming using mouse populations that exhibit opposite poles of the behavioral spectrum (social dominance [Dom] and submissiveness [Sub]) and differential response to stress. In contrast to stress-resilient Dom dams, stress-vulnerable Sub dams exhibit significantly lower maternal attachment, serum oxytocin, and colonic Lactobacillus reuteri populations. Sub offspring showed a reduced hippocampal expression of key methylation genes at postnatal day (PND) 7 and a lack of developmentally-dependent increase in 5-methylcytosine (5-mC) at PND 21. In addition, Sub pups exhibit significant hypermethylation of gene promoters connected with glutamatergic synapses and behavioral responses. We were able to reverse the submissive endophenotype through cross-fostering Sub pups with Dom dams (Sub/D). Thus, Sub/D pups exhibited elevated hippocampal expression of DNMT3A at PND 7 and increased 5-mC levels at PND 21. Furthermore, adult Sub/D offspring exhibited increased sociability, social dominance, and hippocampal glutamate and monoamine levels resembling the neurochemical profile of Dom mice. We postulate that maternal inborn stress vulnerability governs epigenetic patterning sculpted by maternal care and intestinal microbiome diversity during early developmental stages and shapes the array of gene expression patterns that may dictate neuronal architecture with a long-lasting impact on stress sensitivity and the social behavior of offspring.

Prolactin is associated with proximity to incubating partner rather than parental care in black-headed gulls.

The peptide hormone prolactin plays an important role in the expression of parental care behaviours across bird and mammal taxa. While a great deal is known about how plasma prolactin concentrations vary across the reproductive cycle, the few studies that investigate how prolactin relates to individual-level variation in parental care have reported mixed results. We argue that, since parental care is also affected by social interactions and environmental constraints, prolactin may better reflect behaviours that are indirectly related to parenting than the absolute level of care that is eventually expressed. In this study, we tested for associations between plasma prolactin and the expression of both parental care and proximity to the partner in incubating black-headed gulls, Chroicocephalus ridibundus. Baseline prolactin levels increased with calendar date but were unrelated to incubation behaviours. However, parents who showed a weaker decrease in prolactin to an acute stressor spent more time in close proximity to their incubating partner while not on the nest themselves, suggesting that individual variation in stress-induced prolactin changes reflect differences in parents' tendency to be closely associated with their partner and the joint nesting attempt. Baseline and stress-induced levels of the stress hormone corticosterone were unrelated to both prolactin levels and parental behaviours, suggesting that this hormone is not a strong moderator of parental care in black-headed gulls. One potential explanation for the link between prolactin dynamics and partner proximity is that prolactin reflects parental motivation to provide parental care or retain contact with the breeding partner, but further work is needed to directly test this hypothesis.

Functional circuit architecture underlying parental behaviour.

Parenting is essential for the survival and wellbeing of mammalian offspring. However, we lack a circuit-level understanding of how distinct components of this behaviour are coordinated. Here we investigate how galanin-expressing neurons in the medial preoptic area (MPOAGal) of the hypothalamus coordinate motor, motivational, hormonal and social aspects of parenting in mice. These neurons integrate inputs from a large number of brain areas and the activation of these inputs depends on the animal's sex and reproductive state. Subsets of MPOAGal neurons form discrete pools that are defined by their projection sites. While the MPOAGal population is active during all episodes of parental behaviour, individual pools are tuned to characteristic aspects of parenting. Optogenetic manipulation of MPOAGal projections mirrors this specificity, affecting discrete parenting components. This functional organization, reminiscent of the control of motor sequences by pools of spinal cord neurons, provides a new model for how discrete elements of a social behaviour are generated at the circuit level.

Evolutionary change in the construction of the nursery environment when parents are prevented from caring for their young directly.

Parental care can be partitioned into traits that involve direct engagement with offspring and traits that are expressed as an extended phenotype and influence the developmental environment, such as constructing a nursery. Here, we use experimental evolution to test whether parents can evolve modifications in nursery construction when they are experimentally prevented from supplying care directly to offspring. We exposed replicate experimental populations of burying beetles (Nicrophorus vespilloides) to different regimes of posthatching care by allowing larvae to develop in the presence (Full Care) or absence of parents (No Care). After only 13 generations of experimental evolution, we found an adaptive evolutionary increase in the pace at which parents in the No Care populations converted a dead body into a carrion nest for larvae. Cross-fostering experiments further revealed that No Care larvae performed better on a carrion nest prepared by No Care parents than did Full Care larvae. We conclude that parents construct the nursery environment in relation to their effectiveness at supplying care directly, after offspring are born. When direct care is prevented entirely, they evolve to make compensatory adjustments to the nursery in which their young will develop. The rapid evolutionary change observed in our experiments suggests there is considerable standing genetic variation for parental care traits in natural burying beetle populations-for reasons that remain unclear.

The Effect of Massage on Maternal Role Adaptation in Mothers with Premature Infants.

Background: Accepting and adapting the maternal role by mothers with premature infants is complicated. Active participation of mothers in neonate massage may facilitate this process. Primary Study Objective: Determining the effect of massage on maternal role adaptation in mothers of premature infants admitted to the neonatal intensive care unit (NICU). Methods/Design: A non-parallel quasi-experimental study with a sequential sampling method. Setting: This study was done in the NICU of Imam Ali Hospital in Amol City, Iran. Participants: 90 mothers of premature infants hospitalized in the NICU participated in this study. Intervention: The mothers in the intervention group after receiving two training sessions massaged their infant for 15 minutes daily from the third day of hospitalization for 5 consecutive days. Primary Outcome Measures: A maternal role adaptation questionnaire was used. Participants completed the maternal role adaptation questionnaire 3 times: before, on the fifth day, and 14 days after the first day of intervention. The maternal role adaptation questionnaire was used to assess the maternal role adaptation. The participants of the control group also filled out the questionnaire at similar time. Results: The mean scores of maternal adaptation were significantly different between the two control groups (5th day and 14th day) and intervention (day 5: 136.88 ± 10.062 (P = .025); day 14: 151.93 ± 6 (P < .001)). Maternal role adaptation showed an upward trend in the two groups during the 14 days of study, but this trend was significantly higher in the intervention group over time, compared to the control group. Conclusion: Massage of premature infants facilitates the adaptation to maternal role. It is recommended, along with other nursing interventions, to empower mothers with premature neonates admitted to the NICU.

Interactive effects of maternal physiological arousal and regulation on maternal sensitivity: Replication and extension in an independent sample.

This study examined the extent to which mothers' physiological arousal (i.e., skin conductance level [SCL] augmentation) and regulation (i.e., respiratory sinus arrhythmia [RSA] withdrawal) interacted to predict subsequent maternal sensitivity. Mothers' (N = 176) SCL and RSA were measured prenatally during a resting baseline and while watching videos of crying infants. Maternal sensitivity was observed during a free-play task and the still-face paradigm when their infants were 2 months old. The results demonstrated that higher SCL augmentation but not RSA withdrawal predicted more sensitive maternal behaviors as a main effect. Additionally, SCL augmentation and RSA withdrawal interacted, such that well-regulated maternal arousal was associated with greater maternal sensitivity at 2 months. Further, the interaction between SCL and RSA was only significant for the negative dimensions of maternal behavior used to derive the measure of maternal sensitivity (i.e., detachment and negative regard) suggesting that well-regulated arousal is particularly important for inhibiting the tendency to engage in negative maternal behaviors. The results replicate findings from mothers in previous studies and demonstrate that the interactive effects of SCL and RSA in relation to parenting outcomes are not sample specific. Considering joint effects of physiological responding across multiple biological systems may enhance understanding of the antecedents of sensitive maternal behavior.

Hearing Vocalizations during First Social Experience with Pups Increase Bdnf Transcription in Mouse Auditory Cortex.

While infant cues are often assumed to innately motivate maternal response, recent research highlights how the neural coding of infant cues is altered through maternal care. Infant vocalizations are important social signals for caregivers, and evidence from mice suggests that experience caring for mouse pups induces inhibitory plasticity in the auditory cortex (AC), though the molecular mediators for such AC plasticity during the initial pup experience are not well delineated. Here, we used the maternal mouse communication model to explore whether transcription in AC of a specific, inhibition-linked, memory-associated gene, brain-derived neurotrophic factor (Bdnf) changes due to the very first pup caring experience hearing vocalizations, while controlling for the systemic influence of the hormone estrogen. Ovariectomized and estradiol or blank-implanted virgin female mice hearing pup calls with pups present had significantly higher AC exon IV Bdnf mRNA compared to females without pups present, suggesting that the social context of vocalizations induces immediate molecular changes at the site of auditory cortical processing. E2 influenced the rate of maternal behavior but did not significantly affect Bdnf mRNA transcription in the AC. To our knowledge, this is the first time Bdnf has been associated with processing social vocalizations in the AC, and our results suggest that it is a potential molecular component responsible for enhancing future recognition of infant cues by contributing to AC plasticity.

Aberrant Maturation of the Uncinate Fasciculus Follows Exposure to Unpredictable Patterns of Maternal Signals.

Across species, unpredictable patterns of maternal behavior are emerging as novel predictors of aberrant cognitive and emotional outcomes later in life. In animal models, exposure to unpredictable patterns of maternal behavior alters brain circuit maturation and cognitive and emotional outcomes. However, whether exposure to such signals in humans alters the development of brain pathways is unknown. In mother-child dyads, we tested the hypothesis that exposure to more unpredictable maternal signals in infancy is associated with aberrant maturation of corticolimbic pathways. We focused on the uncinate fasciculus, the primary fiber bundle connecting the amygdala to the orbitofrontal cortex and a key component of the medial temporal lobe-prefrontal cortex circuit. Infant exposure to unpredictable maternal sensory signals was assessed at 6 and 12 months. Using high angular resolution diffusion imaging, we quantified the integrity of the uncinate fasciculus using generalized fractional anisotropy (GFA). Higher maternal unpredictability during infancy presaged greater uncinate fasciculus GFA in children 9-11 years of age (n = 69, 29 female). In contrast to the uncinate, GFA of a second corticolimbic projection, the hippocampal cingulum, was not associated with maternal unpredictability. Addressing the overall functional significance of the uncinate and cingulum relationships, we found that the resulting imbalance of medial temporal lobe-prefrontal cortex connectivity partially mediated the association between unpredictable maternal sensory signals and impaired episodic memory function. These results suggest that unbalanced maturation of corticolimbic circuits is a mechanism by which early unpredictable sensory signals may impact cognition later in life.SIGNIFICANCE STATEMENT Our prior work across species demonstrated that unpredictable patterns of maternal care are associated with compromised memory function. However, the neurobiological mechanisms by which this occurs in humans remain unknown. Here, we identify an association of exposure to unpredictable patterns of maternal sensory signals with the integrity of corticolimbic circuits involved in emotion and cognition using state-of-the-art diffusion imaging techniques and analyses. We find that exposure to early unpredictability is associated with higher integrity of the uncinate fasciculus with no effect on a second corticolimbic pathway, the cingulum. The resulting imbalance of corticolimbic circuit development is a novel mediator of the association between unpredictable patterns of maternal care and poorer episodic memory.

How early maternal deprivation changes the brain and behavior?

Early life stress can adversely influence brain development and reprogram brain function and consequently behavior in adult life. Adequate maternal care in early childhood is therefore particularly important for the normal brain development, and adverse early life experiences can lead to altered emotional, behavioral, and neuroendocrine stress responses in the adulthood. As a form of neonatal stress, maternal deprivation/separation is often used in behavioral studies to examine the effects of early life stress and for modeling the development of certain psychiatric disorders and brain pathologies in animal models. The temporary loss of maternal care during the critical postpartum periods remodels the offspring's brain and provokes long-term effects on learning and cognition, the development of mental disorders, aggression, and an increased tendency for the drug abuse. Early life stress through maternal deprivation affects neuroendocrine responses to stress in adolescence and adulthood by dysregulating the hypothalamic-pituitary-adrenal axis and permanently disrupts stress resilience. In this review, we focused on how improper maternal care during early postnatal life affects brain development resulting in modified behavior later in life.