Maternal behavior is a defining characteristic of mammals, which is regulated by a core, conserved neural circuit. However, mothering behavior is not always a default response to infant conspecifics. For example, initial fearful, fragmented or aggressive responses toward infants in laboratory rats and mice can give way to highly motivated and organized caregiving behaviors following appropriate hormone exposure or repeated experience with infants. Therefore hormonal and/or experiential factors must be involved in determining the extent to which infants access central approach and avoidance neural systems. In this review we describe evidence supporting the idea that infant conspecifics are capable of activating distinct neural pathways to elicit avoidant, aggressive and parental responses from adult rodents. Additionally, we discuss the hypothesis that alterations in transcriptional regulation within the medial preoptic area of the hypothalamus may be a key mechanism of neural plasticity involved in programming the differential sensitivity of these neural pathways.

Adaptation virtually defines survival. For mammals, arguably, no other developmental milestone is exemplified by--nor more reliant on--the sudden and dramatic behavioral alterations observed in the maternal female, which rapidly must undergo change in order to express a large suite of proper and effective maternal behaviors. As pregnancy progresses, as well as during lactation, when pup cues are rich and rampant, the female is literally transformed from an organism that actively avoided offspring-related signals, to one highly motivated by those same cues to build nests, be attracted to pups and to retrieve, group, groom, crouch-over, care for, and protect, the young. Ancillary responses such as reference memory, spatial learning, foraging (including predation), and boldness improve in mothers compared to virgins. Such modifications arise early and are persistent, with neural benefits that last well into senescence. Evolutionarily, such enhancements have likely reduced the maternal burdens associated with sheltering and feeding the vulnerable young; collectively, this strengthens the mother's/parent's reproductive fitness and that of the pups in which all this effort is invested. Of the many behaviors that change as a function of pending or concurrent maternity, therefore, what is the role of modifications to resilience, the ability to withstand the numerous, unpredictable, and threatening environmental events that the mother/parent must daily, indeed, multiply daily, face and thwart in order to bring the offspring from pups to fully functioning adults. We explore these questions, and their connections, here in a multi-disciplinary manner focused on the constellation of change that summates to fundamentally alter the female for the rest of her life. Behavior, brain, neurochemistry and genes are fundamentally changed as the substrate for reproduction unfolds and expresses its inherent plasticity.

The peripartum period is associated with the onset of behaviors that shelter, feed and protect young offspring from harm. The neural pathway that regulates caregiving behaviors has been mapped in female rats and is conserved in mice. However, rats rely on late gestational hormones to shift their perception of infant cues from aversive to attractive, whereas laboratory mice are "spontaneously" maternal, but their level of responding depends on experience. For example, pup-naïve virgin female mice readily care for pups in the home cage, but avoid pups in a novel environment. In contrast, pup-experienced virgin mice care for pups in both contexts. Thus, virgin mice rely on experience to shift their perception of infant cues from aversive to attractive in a novel context. We hypothesize that alterations in immediate early gene activation may underlie the experience-driven shift in which neural pathways (fear/avoidance versus maternal/approach) are activated by pups to modulate context-dependent changes in maternal responding. Here we report that the effects of sodium butyrate, a drug that allows for an amplification of experience-induced histone acetylation and gene expression in virgins, are comparable to the natural onset of caregiving behaviors in postpartum mice and induce postpartum-like patterns of immediate early gene expression across brain regions. These data suggest that pups can activate a fear/defensive circuit in mice and experience-driven improvements in caregiving behavior could be regulated in part through decreased activation of this pathway.

The majority of mammalian species are uniparental, with the mother solely providing care for young conspecifics, although fathering behaviours can emerge under certain circumstances. For example, a great deal of individual variation in response to young pups has been reported in multiple inbred strains of laboratory male mice. Furthermore, sexual experience and subsequent cohabitation with a female conspecific can induce caregiving responses in otherwise indifferent, fearful or aggressive males. Thus, a highly conserved parental neural circuit is likely present in both sexes; however, the extent to which infants are capable of activating this circuit may vary. In support of this idea, fearful or indifferent responses toward pups in female mice are linked to greater immediate early gene (IEG) expression in a fear/defensive circuit involving the anterior hypothalamus compared to that in an approach/attraction circuit involving the ventral tegmental area. However, experience with infants, particularly in combination with histone deacetylase inhibitor (HDACi) treatment, can reverse this pattern of pup-induced activation of fear/defence circuitry and promote approach behaviour. Thus, HDACi treatment may increase the transcription of primed/poised genes that play a role in the activation and selection of a maternal approach circuit in response to pup stimuli. In the present study, we investigated whether HDACi treatment would impact behavioural response selection and associated IEG expression changes in virgin male mice that are capable of ignoring, attacking or caring for pups. The results obtained indicate that systemic HDACi treatment induces spontaneous caregiving behaviour in non-aggressive male mice and alters the pattern of pup-induced IEG expression across a fear/defensive neural circuit.

Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain.

Background

Maternal care during early-life plays a crucial role in the sculpting of the mammalian brain. Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this potent phenotypic change commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood.

Methods

Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression.

Results

A significant decrease in global DNA methylation was observed in offspring hypothalamus following a week of augmented maternal care, corresponding to differential methylation and expression of thousands of genes. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes with three lines of evidence (methylation, expression, and altered miRNA target) were identified as highly relevant to the stress resiliency phenotype.

Conclusions

This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the central epigenomic mechanisms underlying the profound effects of maternal care on the developing brain.