The Behavioral Neuroendocrinology of Maternal Behavior: Past Accomplishments and Future Directions

Abstract

Research on the neuroendocrine-endocrine-neural regulation of maternal behavior has made significant progress the past 50 years. In this mini-review progress during this period has been divided into five stages. These stages consist of advances in the identification of endocrine factors that mediate maternal care, the characterization of the neural basis of maternal behavior with reference to endocrine actions, the impact of developmental and experiential states on maternal care, the dynamic neuroplastic maternal brain, and genes and motherhood. A final section concludes with a discussion of future directions in the field of the neurobiology/neuroendocrinology of motherhood.

The relationship between the endocrine/neuroendocrine systems and maternal behavior has been of research interest for nearly a century starting with the investigations reported by Wiesner and Sheard (1933) and those of Oscar Riddle and colleagues (1935; 1942). In order to gain a historical perspective on the advances in the biological regulation of maternal care in mammals it is useful to delineate the stages of investigations that have ensued the past 50 years during the existence of the journal Hormones and Behavior. These stages can be separated into five groupings. The initial stage or period focused on the possible role of hormones in the regulation of maternal behavior. A second phase of research explored what is considered the neural substrate of maternal care that included the involvement of hormones on motherhood. A third stage explored how maternal behavior is expressed over normal development. A fourth phase delves into how the brain changes as a function of maternal experience, i.e. neuroplasticity. The more recent and fifth phase of study draws upon these preceding phases to assess how genes govern the expression of motherhood, including the intergenerational transfer of behavioral traits. Advances during each research phase are highlighted and future directions in the field of behavioral neuroendocrinology and endocrine neurobiology are set forth in a final section. Note that the overall relationships among the factors that govern the expression of maternal behavior are illustrated in Figure 1. A recent review of the neuroendocrine regulation of maternal behavior provides a more comprehensive report on this topic (Bridges, 2015).

Figure 1:

Schematic representation of factors regulating the expression of maternal behavior. There are rich and complex exchanges among hormones, genes, the brain, and behavioral events, all of which are influenced by environmental, developmental and experiential factors. The regulation of maternal behavior involves both underlying capacities or nature and the influences of nurturing factors such as experience and the environment.

Stage One: The Early Period - The involvement of Hormones in Stimulating Maternal Behavior

The first paper that examined the relationship between pregnancy and maternal behavior in Hormones and Behavior measured maternal nest building in rabbits treated with androgens during gestation (Anderson et al., 1970). A subsequent paper reported the involvement of the pituitary gland in maternal nest building in hypophysectomized rabbits (Anderson et al., 1971). Shortly thereafter Terkel and Rosenblatt using a cross-transfusion parabiotic system in rats reported that a factor present in the newly periparturient rat was able to stimulate aspects of maternal care in recipient virgin rats (Terkel and Rosenblatt, 1972). These findings drew upon the seminal finding of Rosenblatt (1967) that there exists a basic nonhormonal basis for maternal behavior in female rats. This latter finding provided an important foundation used to subsequently examine the direct effects of hormonal manipulations on maternal behavior in rats.

The first replicable study that demonstrated the ability of exogenous hormone treatment to stimulate the onset of maternal behavior utilized a regimen consisting of estrogen, progesterone and prolactin (Moltz et al.,1970). The ability of a similar hormone regimen to induce maternal behavior in virgin rats was confirmed by Zarrow and colleagues (1971). Studies establishing the importance of estrogens in stimulating maternal care were then reported by Siegel and Rosenblatt using a hysterectomize-dovariectomized virgin rat preparation (Siegel & Rosenblatt, 1975). As technology drives research approaches, the development of radioimmunoassays in the 1970s and 1980s facilitated the measurement of hormone levels in various reproductive models and allowed for more physiological evaluations of the role for hormones in motherhood. For example, a role for the decline in progesterone prepartum in the expression of the onset of maternal behavior in rats was identified. Physiological treatment with progesterone in pregnancy-terminated rats delayed the onset of maternal care (Bridges et al., 1978). In the mid-1980s a quantitative assessment of the roles of estradiol and progesterone in the stimulation of maternal behavior in rats was developed using a combination of Silastic steroid-containing subcutaneous implants (Bridges, 1984). This treatment model produced circulating hormone levels that mimicked the patterns of steroid concentrations found during pregnancy and provided an important model for the subsequent evaluations of the roles for both pituitary (prolactin) and placental (lactogens) hormones in the regulation of maternal behavior in rats.

Stage Two: Identification of the Neural Basis of Maternal Behavior

The contributions of Dr. Michael Numan to our understanding of the neural bases underlying the regulation of maternal behavior merit significant recognition. Numan’s initial contribution identified the medial preoptic area as a key neural region in the expression of maternal behavior in the female rat (Numan, 1974). He further demonstrated that implants of estradiol into the MPOA of pregnancy-terminated rats stimulated a more rapid onset of maternal care towards foster young (Numan & Rosenblatt, 1977). Using a combination of surgical and anatomical approaches over the following years, Numan developed an integrated model of a “maternal neural network” that linked neural motivational regions and motor control regions with the operations of the MPOA (Numan, 2012).

The MPOA thus became the focus of neurochemical investigations of maternal behavior. Using the early oncogene protein c-Fos as a marker for neural activation Fleming and Walsh (1994) examined c-Fos activity in maternal versus non-maternal subjects. Increased activation of c-Fos neurons was consistently identified in the MPOA of maternal lactating rats, indicating that maternal care was associated with increases in the expression of the c-Fos gene. Other work focused on brain regions involved in motivational aspects of maternal behavior. Li and Fleming (2003) identified a key role for the nucleus accumbens shell in the display of maternal memory. More recently, Numan and Stolzenberg (2009) demonstrated a relationship between neural dopamine and the nucleus accumbens in the regulation of maternal motivation within the maternal neural network.

During the late 1970s and 1980s major findings identifying roles for the hormones, oxytocin and prolactin, in the stimulation of the onset of maternal behavior emerged. Cort Pedersen’s group reported that oxytocin when infused into the cerebrospinal fluid of virgin rats stimulated a rapid onset of maternal behavior (Pedersen and Prange, 1979). His group identified sites of central oxytocin action both in the ventral tegmental area and medial preoptic area (Pedersen et al., 1994). Their work led to numerous studies on the actions of this neuropeptide on maternal and other behavioral responses, including pair bonding in voles (Insel and Young, 2001; Young, 2015) and social responsiveness (Pohl et al., 2019). The work of Oliver Bosch and Inga Neumann further elucidated the roles of oxytocin and vasopressin in maternal care and aggression in rodents (Bosch and Neumann, 2012). In addition to the involvement of neural peptides and pregnancy hormones in maternal care, a role for the serotonergic system in maternal aggression in rodents was identified which led to proposed treatments of postpartum disorders with serotoninergic inhibitors (Pawluski et al., 2019). Clinical studies drew upon these sets of findings and led to studies on the actions of oxytocin in human affective states. One such study found that oxytocin enhanced the feeling of trust in humans (Kosfeld et al., 2005).

A definitive role for prolactin in the induction of maternal behavior in the rat was established using a combination of hormone replacement and ectopic pituitary transplants (Bridges et al., 1985). Inhibition of prolactin secretion with the dopamine agonist, bromocriptine, was found to delay the expression of maternal care in steroid-primed virgin rats (Bridges & Ronsheim,1990). Central infusions of prolactin into the MPOA of steroid-primed virgin rats, in contrast, stimulated a rapid onset maternal behavior (Bridges et al., 1990). Likewise, other lactogenic hormones, including placental lactogens I and II, when infused into the MPOA stimulated maternal behavior (Bridges et al., 1996). These findings indicate that hormonal signals from both the mother and conceptus prime the maternal brain to result in full activation at birth to promote immediate care for the newborn. Overall, these neurochemical and hormonal studies support the idea that a complement of factors, not just a single factor, work in consort to stimulate maternal behavior as well as to regulate parturition and lactation.

Stage Three: Developmental Aspects of Maternal Care

The expression of maternal behaviors varies and is modified both as a function of developmental events and prior maternal experience (see Figure 1). Over the course of development in the rat, high levels of maternal-like behaviors are present when testing begins around day 24 of life during the juvenile, prepubertal period (Bridges et al., 1974). This rapid onset of responsiveness declines when exposure to foster young starts at 30 days of age and beyond. As an adult, the rate of onset of maternal behavior shifts from a basal 5 to 7-day latency in the nulliparous female (Rosenblatt, 1967) to a fast onset just prior to parturition (Slotnick et al., 1973). Quite strikingly, once the new mother rat interacts with her young postpartum, she retains or remembers how to behave maternally (Bridges, 1975). This maternal memory persists for many months (Scanlan et al., 2006). Repeated parity can also affect maternal care. Primiparous and multiparous rats, for example, respond differently towards young following caesarean delivery (Moltz et al., 1966). Whereas the effects of experience are most pronounced in so-called “biological” mothers, pup-induced maternal nulliparous rats also exhibit experiential effects when retested for maternal memory (Scanlan et al., 2006). When neural activation patterns in response to pup exposure are compared between re-induced primiparous and nulliparous maternal rats, c-Fos-labeled cell numbers are more abundant in the non-lactating maternal primiparous subjects in both the cortical amygdala and shell region of the nucleus accumbens. Li and Fleming’s earlier seminal research (2003) identified the shell region of the nucleus accumbens as a key neural region that motivated the display of maternal memory in the rat. Fleming’s research also characterized the impact of reproductive and maternal experience on neural astrocyte numbers (Featherstone and Fleming, 2000; see Fleming et al., 2008). It is noted that since the MPOA is a prolactin responsive neural substrate that regulates the initial onset of maternal behavior (Bridges et al., 1990) as well as a site of enhanced prolactin gene expression and responsiveness to prolactin in previously parous rats (Anderson et al., 2006; Sjöeholm et al., 2011; Sapsford et al., 2012), the MPOA is an attractive neural site that is also involved in some aspect of maternal memory. Changes in this neural site that sensitize the female to sensory properties produced by young.

Stage Four: Neuroplasticity and Mothering

The possible alterations in the female’s brain as a function of motherhood has received considerable attention in recent years. Kinsley et al. (1999) found that motherhood results in enhanced learning during the postpartum period. That is, motherhood increases the new mother’s ability to effectively adapt to the demands of her young and changes in the environment. They also found that motherhood altered dendritic spine concentrations in the mother’s hippocampus (Kinsley et al., 2006). In related experiments Galea and colleagues explored how pregnancy and lactation affect hippocampal neurogenesis, identifying changes in the rate of neurogenesis as a function of parity (Pawluski and Galea, 2007; Duarte-Guterman et al., 2019). Whereas the relationship between shifts in new neuron formation or neuronal death and maternal care remains to be defined, it appears that motherhood is certainly associated with changes in neuronal structure and function. In other studies Shingo et al. (2003) reported increased neurogenesis in pregnant mice, an increase associated with exposure to prolactin. Subsequent work by Larsen et al. (2010) showed that reduced prolactin exposure during early pregnancy in mice increased postpartum depressive-like behaviors. A similar partial suppression of prolactin during early pregnancy in rats reduced maternal care in a novel environment (Price & Bridges, 2014). In ewes, shifts in olfactory neurogenesis during the peri-parturitional period has been proposed to play a role in maternal acceptance of young by the newly parturient ewe (Levy et al., 2011). Finally, in nulliparous rats the induction of maternal care by pup exposure is associated with increases in neurogenesis (Furuta & Bridges, 2009). Overall, these studies demonstrate that the maternal neural state is dynamic and accompanied by a range of modifications in neuronal expression. Functionally, maternal neuroplasticity appears to promote increased behavioral and physiological adaptations that facilitate offspring survival and growth.

Stage Five: Genes and Maternal Care

Research on the involvement of genes in maternal care has gained impetus with the development of a range of genetic tools, including the measurement of gene activity, the development of selective gene knockouts, neural tracking technologies, and optogenetics. The work of Meaney (2001) and Champagne et al. (2003) initially identified alterations in the neural expression of the estrogen receptor alpha gene (Esr1) that served as the basis for intergenerational modifications in maternal care. Their research provided a novel linkage between the type of maternal behavior that offspring received and their subsequent expression of mothering. Champagne et al. (2006) subsequently identified that this linkage was mediated through the methylation in the MPOA of the estrogen receptor-α1b promoter and the Esr1 gene. Recent studies that have examined the role of Esr1 in the induction of maternal care in adult nulliparous female rats, in contrast, found that Esr1 knockouts do not display significant deficits in induction rates (Gallagher et al., 2019). Likewise, both female and male juvenile Esr1 knockouts displayed rapid onsets of maternal-like behaviors when tested at 24 days of age, responses comparable to wild-type subjects (Moran et al., 2020). Thus, the involvement of the estrogen receptor-alpha in maternal behavior while significant in given contexts may not be universal in regulating aspects of maternal care.

The more recent research on the role of galanin in mice by Kohl et al (2018) provides an intricate exploration and demonstration of the role of galanin and its connectivity within the medial preoptic and related brain regions in parental responsiveness. They reported that MPOA galanin neurons are active during all episodes of parental behavior, while individual subsets of galanin neurons are associated with specific aspects of parental care. The use of sophisticated neurobiological methodologies involving genetic expression in maternal care such as those utilized by Champagne’s and Dulac’s groups provide novel avenues to explore the relationships among specific genes, related sets of neuro-molecules, hormones, and specific groupings of neurons in brain regions identified as part of a maternal neural network. These approaches will help to more precisely identify the relationships between sites and neurochemical regulators of maternal behavior.

Future Directions for Research in the Neurobiology of Maternal Behavior

Future areas of research that increase our understanding of the neurobiology of maternal behavior will occur in distinct research areas. First, the technological approaches, such as optogenetics, will provide experimental tools to address more refined topics in the field. Much like the recent development of tools that silence gene activation, new technologies will provide tools to ask address questions on topics related to nature/nurture and the maintenance of allostasis (Russell and Brunton, 2019). Next, a greater integration of neuromodulators and endocrine factors and how they function physiologically within given neural networks will continue to develop. It is important to understand if and how individual identified factors, such as oxytocin, prolactin, dopamine, galanin, steroids, and other identified factors, interact to mediate specific aspects maternal care. Third, our understanding of the substrates underlying the experiential modifications of maternal care and how developmental processes impact these substrates is needed to enrich our understanding of how behaviors and experience themselves may impact brain functions both acutely and on a long-term basis. Similarly, given that maternal care provides a rich format for physiological and behavioral actions, our understanding of how gene expression affects maternal care and is related by other substances, including hormones, will provide a rich platform that contributes to our knowledge of the maternal brain. Finally, identification of improved animal models for behavioral disorders associated with motherhood, as well as fatherhood, should emerge based upon effective comparative studies. Understanding basic biology, while enriching our appreciation of normative processes, provides an empirical basis for evaluating clinical disorders, including postpartum depression and maternal aggression. It certainly will be fascinating to witness progress in the neuroendocrinology/neurobiology of maternal care in the upcoming decades.

Highlights.

• Hormones and peptides stimulate the initiation of maternal behavior.

• A key brain site mediating active maternal care and its hormonal stimulation is the medial preoptic area.

• Maternal experience modifies subsequent parental care through alterations in neural activity.

• Pregnancy and lactation enhance neurogenesis and learning in new mothers.

• Estrogen receptor-alpha plays a key role in regulating the maternal care of subsequent generations.

• Sophisticated identification of neural network connectivity provides greater understanding of the functions of the maternal network.

• Understanding basic brain mechanisms will lead to novel clinical models.