Hormonal Actions in the Medial Preoptic Area Governing Parental Behavior: Novel Insights From New Tools

Abstract

The importance of hormones in mediating a behavioral transition in mammals from a virgin or nonparenting state to parental state was established around 50 years ago. Extensive research has since revealed a highly conserved neural circuit that underlies parental behavior both between sexes and between mammalian species. Within this circuit, hormonal action in the medial preoptic area of the hypothalamus (MPOA) has been shown to be key in timing the onset of parental behavior with the birth of offspring. However, the mechanism underlying how hormones act in the MPOA to facilitate this change in behavior has been unclear. Technical advances in neuroscience, including single cell sequencing, novel transgenic approaches, calcium imaging, and optogenetics, have recently been harnessed to reveal new insights into maternal behavior. This review aims to highlight how the use of these tools has shaped our understanding about which aspects of maternal behavior are regulated by specific hormone activity within the MPOA, how hormone-sensitive MPOA neurons integrate within the wider neural circuit that governs maternal behavior, and how maternal hormones drive changes in MPOA neuronal function during different reproductive states. Finally, we review our current understanding of hormonal modulation of MPOA-mediated paternal behavior in males.

Mammals give birth to altricial or precocial young that are dependent on mothers for nutritional support, shelter, and protection. This substantial investment into parenting requires a profound change in physiology and behavior as mammals switch from a nonparental to a parental state. Diverse examples across the animal kingdom highlight both the costly nature of maternal care, and how motherhood induces behaviors that are distinct from behaviors exhibited in the nonmaternal state. For instance, cheetah (Acinonyx jubatus) mothers move their cubs to new lairs approximately every 5 to 6 days to avoid detection from predators (1), Bornean orangutans (Pongo pygmaeus) have been found to still suckle from their mothers up until 5-8 years of age (2), and killer whale (Orcinus orca) mothers will forgo future reproductive success to care for adult sons (3).

Research undertaken predominantly in rodents has mapped out a neural network that underlies mammalian maternal behavior (4). This complex neural network involves multiple brain regions that regulate a diverse range of behaviors that collectively form maternal behavior. One of the commonalities in these studies has been the identification of the medial preoptic area (MPOA) as a central hub for coordinating maternal behavior (5). Lesions of the MPOA in lactating female rats and mice abolished pup-directed maternal behaviors (such as approach, licking, grooming, kyphosis, and retrieval) (6-9), and disrupted nest-building behavior (6, 10, 11). Specifically, the MPOA appears to regulate pup-directed behaviors, while other maternal behaviors that are indirectly related to pups, such as maternal aggression towards intruders, and altered energy intake to support the metabolic demands of lactation, are regulated by other brain regions (12, 13).

A seminal experiment by Terkel and Rosenblatt in 1972 established hormones as important players in coordinating the onset of maternal behavior with parturition (14). These maternal behavior-promoting hormones have since been shown to include estradiol, progesterone, prolactin (and placental lactogen), and the neuropeptides oxytocin and arginine vasopressin (AVP) (15, 16). The MPOA is well situated to integrate these hormonal cues to communicate a change in reproductive status, with dynamic changes occurring in hormone receptor expression in pregnancy and lactation (Table 1). However, deciphering how different hormones shape MPOA activity to induce the display of maternal behavior at the time of parturition has been a significant challenge in the field. Highlighting the difficulty of this task was single-cell sequencing of the preoptic area that revealed 66 transcriptionally distinct neuronal populations in this region, with high levels of hormone receptor expression in many of these populations (41). Adding to this complexity, the preoptic area is involved in numerous additional physiological roles including in sleep, thermoregulation (42), body weight regulation (43), fertility (44), aggression, sexual behavior, and social behavior (45). Through developments in transgenic, transcriptomic, imaging, and optogenetic technology, significant advances have been made in determining the role of specific hormones within the MPOA in regulating maternal behavior. Here we focus on how these techniques have advanced our current understanding of hormonal modulation of the MPOA in parenting, first in females, and subsequently, how this also might apply to males.

Table 1.

Changes in hormone receptor expression in the MPOA across reproduction in female and male rodents (compared with virgin levels)

	Pregnancy (D: day of pregnancy)	Parturition	Lactation (L: day postpartum, ND: L not defined)	Fathers (PP: day postpartum, ND: PP not defined)	Species	mRNA/protein	Study
Estrogen receptor Esr1	Up (>D10)	—	—	—	Rat	Esr1 binding	Giordano et al 1990 (17)
		—	Up (L6)	—	Rat	Esr1 mRNA	Champagne et al 2003 (18)
	Up (D8)	—	—	—	Rat	Esr1 mRNA	Wagner and Morrell 1995 (19)
	Up (D8, 16)	No change	—	—	Rat	Esr1 mRNA	Rosenblatt et al 1994 (20)
	—	—	—	No change (PP2-4)	California mouse	Esr1 mRNA	Perea-Rodriguez et al 2015 (21)
	—	—	No change (L3)	No change (PP3)	Dwarf hamster	Esr1 protein	Timonin et al 2008 (22)
	—	—	—	Up (PP1)	Dwarf hamster	Esr1 protein	Romero-Morales et al 2020 (23)
Progesterone receptor	Up (D21)	Up	—	—	Rat	Pgr protein	Francis et al 2002 (24)
	Down (D3)	—	Down (L3)	—	Rat	Pgr protein	Numan et al 1999 (25)
	—	Up	Down (L7-18)	—	Rat	Pgr protein	Grieb et al 2017 (26)
	—	—	—	Down (PP2-4)	California mouse	Pgr mRNA	Perea-Rodriguez et al 2015 (21)
Oxytocin receptor	Up (D15, D20)	—	—	—	Rat	OXTR binding	Bealer et al 2006 (27)
	Up (D21, D22)	Up	No-change	—	Rat	OXTR mRNA	Meddle et al 2007 (28)
	Up (D13-15)	No-change	—	—	Rat	OXTR mRNA	Young et al 1997 (29)
	—	—	Up (L5)	—	Rat	OXTR binding	Bosch et al 2010 (30)
	—	—	Up (L8)	—	Rat	OXTR mRNA	Naik and de Jong 2017 (31)
	—	—	Up (ND)	—	Mouse	OXTR protein	Hidema et al 2023 (32)
	—	—	—	No change (PP2-4)	California mouse	OXTR mRNA	Perea-Rodriguez et al 2015 (21)
	—	—	—	Up (ND)	Mandarin Vole	OXTR mRNA, OXTR protein	Yuan et al 2019 (33)
Vasopressin receptor Avpr1	—	—	No-change (ND)	—	Rat	Avpr1 mRNA	Bayer et al 2016 (34)
	—	—	No change (L8, L21)	—	Rat	Avpr1 mRNA	Naik and de Jong 2017 (31)
	—	—	—	No change (PP2-4)	California mouse	Avpr1 mRNA	Perea-Rodriguez et al 2015 (21)
	—	—	—	No change (ND)	Mandarin vole	Avpr1 mRNA, Avpr1 protein	Yuan et al 2019 (33)
Prolactin receptor	Up (D12)	Up (2 hours)	Up	—	Rat	Prlr mRNA	Mann and Bridges 2002 (35)
	—	—	Up (L7-10)	—	Rat	Prlr protein	Pi and Grattan 1999 (36)
	—	—	Up	—	Rat	pSTAT5 protein	Sjoeholm et al 2011 (37)
	—	—	Up (L7)	—	Mouse	pSTAT5 protein	Brown et al 2011 (38)
	—	—	No change	—	Mouse	Prlr mRNA	Brown et al 2011 (38)
	No change (D17)	—	No change (L1-5)	No change (PP1, PP5)	Hamster	Prlr mRNA	Ma et al 2005 (39)
Androgen receptor	—	—	—	Up (PP1, PP6)	Mongolian gerbil	AR protein	Martínez et al 2019 (40)

 

Determining the Role of Hormones Within the MPOA

The original identification of which hormones regulate maternal behavior arose through manipulation of circulating hormone levels, followed by central administration of hormones or hormone receptor antagonists (15). More recently, a refined approach using targeted deletion of hormone receptors from the MPOA has revealed hormone-specific roles in regulating different aspects of maternal behavior. Here, we focus on hormones for which there is evidence of direct action at the level of the MPOA being required for normal postpartum behavior specifically, estrogen, progesterone, oxytocin, AVP, and prolactin.

Estrogens acting through estrogen receptor ERα/Esr1 are important for maternal behavior (46). Knockdown of Esr1 MPOA expression in mice using si-RNAs confirmed the MPOA as a key region facilitating estrogen's actions on pup retrieval, nursing, and pup-licking aspects of maternal behavior (47). More recently, Esr1 knockout using adeno-associated virus-Cre recombinase administration into the MPOA of adult Esr1 flox mice demonstrated that estrogen action in the MPOA is required for the emergence of pup-directed maternal behavior in late pregnancy (48). Progesterone acts synergistically with estrogen to promote maternal behaviors, with progesterone sensitizing females to the behavioral effects of estradiol (49, 50). Progesterone has a complicated role in maternal behavior, needing to both be elevated during pregnancy (51), and subsequently suppressed at parturition to enable the onset of postpartum maternal behavior (52). Consistent with a synergistic role with estradiol, around 50% of MPOA neurons coexpress progesterone receptor (Pgr) and Esr1 (48). A 2023 study recently confirmed the requirement of progesterone activity in the MPOA for maternal behavior, with MPOA-specific deletion of Pgr blocking the increased pup retrieval and nursing behavior observed in late pregnant mice (48).

Oxytocin and AVP are derived from a common ancestral gene, and with >80% homology between the oxytocin receptor (Oxtr) and the AVP receptor 1a (Avpr1a), there is significant cross-activation on receptors by both peptides (53). Discovery of an important role for oxytocin in mediating the onset of maternal behavior arose from studies that showed global oxytocin (Oxt) or Oxtr deletion in mice resulted in extremely low survival rates of litters (54-57). However, it was unclear whether this was due to the requirement for oxytocin in parturition and milk production rather than a role for the oxytocin-AVP system per se in regulating maternal behavior. Recently, global deletion of both Oxtr and Avpr1a (and Avpr1b) in mice suggested that oxytocin-AVP is only important in regulating maternal behavior under conditions of stress or anxiety (58). Whereas no deficits in pup sniffing, or pup retrieval behavior were observed in virgin or mother mice under standard housing conditions, restraint stress delayed pup retrieval in virgin female mice with deletion of Oxtr (58). It should be noted that this study involved the developmental deletion of receptors, and compensation may occur during development in this transgenic model to mask the role of these receptors in maternal behavior. In support of this, deletion of Oxtr specifically from the MPOA of adult female mice resulted in reduced litter survival under standard housing conditions, although retrieval behavior was unaffected (32). Additional data to support a role for AVP in maternal behavior in nonstressed conditions has been provided in rats, where downregulation of Avpr1a expression in adult rats decreased postpartum nursing and pup retrieval behavior, and central AVP infusion enhanced maternal behavior in rat dams selectively bred to show low anxiety–like behavior (59). A recent study by Hidema et al raised the possibility that oxytocin action in the MPOA indirectly regulates maternal behavior through altering pituitary secretion of prolactin (32), another key regulator of MPOA-mediated maternal behavior discussed below. The action of oxytocin in the MPOA is also regulated by other hormones, with peripheral estradiol administration suppressing Oxtr expression in the MPOA of ovariectomized female mice (60). Conceptually, the parturition-associated drop in circulating estradiol may enable increased Oxtr MPOA expression during lactation (Table 1), thereby facilitating oxytocin's role in postpartum maternal behavior.

Prolactin and placental lactogen act through the prolactin receptor (Prlr), with elevated levels of Prlr expression or Prlr signaling occurring in the MPOA during lactation (Table 1). The MPOA was identified as a key brain region mediating the maternal behavior actions of prolactin, with prolactin or placental lactogen infusion into the MPOA inducing maternal responses in steroid-primed female rats at significantly lower doses than peripheral or intracerebroventricular administration (61). Subsequently, a critical role for prolactin action in the MPOA for the onset of postpartum maternal behavior was established with MPOA-specific deletion of the Prlr in adult female mice leading to abandonment of offspring after parturition (62). There is also likely to be significant hormonal coordination in the MPOA regulation of maternal behavior that involves prolactin. Many MPOA neurons coexpress Prlr, Pgr, and Esr1 (Fig. 1), but how these hormones work synergistically on different MPOA neuronal populations to promote maternal behavior is not currently known. The development of hormone receptor flox mice and stereotaxic delivery of adeno-associated virus-Cre recombinase has been particularly useful in confirming the MPOA as a mediator of important roles of estradiol, progesterone, prolactin, oxytocin, and AVP in promoting postpartum maternal behavior. However, given the high levels of neuronal heterogeneity with the MPOA, complementary strategies have been and will be necessary to further determine how hormones are shaping parental behavior through this region.

Figure 1.

Significant coexpression of prolactin receptor (Prlr; yellow), estrogen receptor 1 (Esr1; magenta), and progesterone receptor (Pgr; cyan) and in the medial preoptic area (MPOA) of virgin female mice. RNA Scope in situ hybridization for Prlr (Advanced Cell Diagnostics (ACDBio); Probe-Mm-Prlr, 430791), Esr1 (ACDBio; Probe-Mm-Esr1, 47801), and Pgr (ACDBio; Probe-Mm-Pgr, 318921). Low-powered representative image of Prlr, Esr1, and Pgr in the MPOA (A), and high-powered representative images of Prlr (B), Esr1 (C), Pgr (D), merged image of all labels (E, white arrows indicate examples of triple-labeled neurons in the MPOA). Images sourced from unpublished data.

Identifying Parenting Neurons in the MPOA

Single-cell spatial transcriptomics has enabled the identification of specific neuronal populations within the MPOA that regulate parental behavior. Through combining markers for distinct neuronal populations (identified by single-cell sequencing) with the marker of neuronal activity, cFos, Moffitt et al have shown that only a few preoptic area neuronal clusters are active during parenting behavior in female and male mice (41). The highest levels of parenting-induced neuronal activation was observed in an inhibitory neuronal population (I-14) that coexpressed the neuropeptide galanin (Gal), calcitonin receptor (Calcr), bombesin receptor subunit 3 (Brs3), and high levels of Esr1, Pgr, and Prlr (as well as lower levels of Avpr1a) (41). The importance of these neurons for maternal behavior is supported by separate studies that have ablated either Gal- or Calcr-expressing neurons in the MPOA and found disrupted maternal behavior (63, 64). A separate neuronal cluster, I-10, that also showed significant parenting-induced cFos was enriched for Oxtr expression (and Esr1, Prlr, and Pgr) but did not show Gal expression (41), highlighting that there are other important neuronal populations in the MPOA involved in parenting. To investigate the role of hormones on particular neuronal subpopulations will require an intersectional genetic strategy to delete individual hormone receptors from MPOA neurons that coexpress distinct combinations of genetic markers. With developments in Cre/lox and FLP/FRT (recombinase flippase/FLP recombinase recognition target) technology, future experiments will likely enable a much more precise understanding of hormones shape neuronal function in this region.

Other technical approaches have also been key in revealing how the hormone-sensitive MPOA circuit is regulating parental behavior. In vivo calcium imaging of specific neuronal populations within the MPOA has enabled activity of neuronal populations to be correlated with specific aspects of maternal behavior. Using fiber photometry, it has been shown that MPOA neurons expressing Esr1 are preferentially activated when a female approaches and retrieves pups (65). Similarly, Kohl et al (66) showed that MPOA galanin neurons, many of which express Esr1, Pgr, and Prlr (41), display high levels of neuronal activity during pup-directed parenting behavior in virgin female mice, dams, and fathers. These experiments to correlate behavior with activity of specific neuronal populations have paved the way for functional optogenetic interrogation of whether these hormone-sensitive neurons are necessary and/or sufficient for the display of parental behavior.

Optogenetics has been a particularly valuable tool to enable subpopulations of MPOA neurons to be studied that are defined by the regions in the brain to which they project. Using this approach, it was found that MPOA galanin neurons can be categorized into projection region–defined subpopulations, with optogenetic activation of different subpopulations stimulating specific aspects of behavior (66). For instance, activation of periaqueductal gray–projecting MPOA galanin neurons stimulated maternal grooming of pups while activation of ventral tegmental area (VTA)–projecting MPOA galanin neurons resulted in increased barrier climbing behavior to access pups but did not alter the level of pup interactions (66). Interestingly, optogenetic stimulation of VTA-projecting Esr1-expressing neurons reduced the latency to approach and retrieve pups, suggesting that the VTA-projecting Esr1-expressing neuronal population is distinct from the VTA-projecting galanin population (65). A separate study using neurotensin as a cellular marker in the MPOA (the majority of neurotensin-expressing neurons coexpress Esr1) showed that activation of VTA-projecting neurotensin MPOA neurons results in dopamine release in the nucleus accumbens (67). With the mesolimbic dopaminergic system known to be important for maternal behavior (68-70), this study shows how estrogen-sensitive (neurotensin) MPOA neurons can alter the output of this system to shape maternal behavior. Together, these studies provide strong evidence that hormone-sensitive MPOA neurons can drive aspects of maternal behavior, and incorporate into the wider neural network that drives maternal behavior. While functional circuit mapping has begun to define the role of estrogen-sensitive MPOA neurons, it is yet to be determined whether populations of neurons defined by expression of other hormone receptors (eg, Pgr, Prlr, Oxtr, or Avpr1a) have similar or distinct effects on maternal behavior.

An important question for the parental behavior field is how hormones alter the function of MPOA neurons to enable the reproductive state-dependent display of behavior. In other words, how do stimuli from pups differentially evoke responses in MPOA neurons between the virgin and lactating state? We and others have demonstrated that even though virgin female mice display some maternal behavior, full maternal behavior is only seen following parturition (71, 72), implying that some sort of neuronal remodeling most be occurring in pregnancy and/or lactation. A recent study by Ammari et al provided some of the first insights into how hormones alter both the structure and function of MPOA galanin neurons in reproduction. Although a greater proportion of MPOA galanin neurons are silent during pregnancy than in virgins, they are also more excitable than in virgins (48). Targeted deletion of Pgr or Esr1 from MPOA galanin neurons revealed that progesterone acts to increase the density of excitatory spines on galanin neurons while estradiol increases the excitability of these neurons in pregnancy (48). This study provides a potential template by which reproduction state-driven functional changes might be explored for additional MPOA neuronal populations, as well as examining the role of other important hormones such as prolactin, oxytocin, and AVP, in this remodeling.

The Role of Hormonal Action in MPOA-Facilitated Paternal Behavior

Although dependence on lactation for nutritional requirements necessitates that all mammalian mothers invest in maternal care of young, in around 5% to 10% of mammalian species, including some primate, rodent, and canid species, males demonstrate paternal care (73). The house mouse (Mus musculus) provides one of the greatest contrasts in young-directed behavior between the nonpaternal and paternal states that can be observed in the laboratory. Prior to and in the first few days after mating, around 80% of male mice will display infanticide behavior towards pups, with less than 20% of males showing paternal care (74). However, 2 weeks after mating, infanticide is reduced to 10% of males, with 80% now demonstrating paternal care (74). How these profound changes in parental behavior are coordinated in males is a fascinating question.

Hormonal changes in fathers are often overlooked; however, work from biparental rodent and primate species has indicated that hormonal profiles in males change during their mates' pregnancy and lactation (75-80). Similar to females, the MPOA of males in some species has also been shown to express the hormone receptors Esr1, Pgr, Prlr, Oxtr, and Avpr1a (21, 81-84) (Table 1). There are limited studies that have undertaken global or MPOA-targeted deletion of hormone receptors in males and assessed paternal behavior. Mice with a global deletion of Esr1 displayed higher levels of infanticide than wildtype male mice, suggesting that estradiol may promote paternal behavior in males (85). In support of this, peripheral estradiol administration to castrated Dwarf hamsters (Phodopus campbelli) or Mongolian gerbils (Meriones unguiculatus) facilitated paternal behavior in nonpaternal males (86, 87). These actions of estradiol may be mediated by the MPOA, with estradiol administered directly into the MPOA of gonadectomized, estradiol- and progesterone-primed male rats reducing latencies to retrieve, crouch, and lick pups (88). In contrast to estradiol, there is evidence to suggest that progesterone plays an inhibitory role in paternal behavior. Virgin male mice with global Pgr knockout did not exhibit virgin-typical infanticide behavior, while fathers displayed elevated paternal behavior (89). Similarly, elevated paternal behavior was observed in wildtype male mice following peripheral administration of a Pgr antagonist (89). Whether these inhibitory effects of progesterone on paternal behavior are mediated at the level of the MPOA is currently unknown.

Research investigating potential paternal behavior roles for oxytocin has been undertaken in the MPOA, where there are species-specific differences in MPOA Oxtr expression in fathers (Table 1). In the biparental Mandarin vole (Microtus mandarinus), fathers have elevated serum levels of oxytocin, increased Oxtr expression in the MPOA, and MPOA infusion of an Oxtr antagonist slowed the initiation of pup-directed paternal behavior (33). Alongside oxytocin, manipulation of Prlr expression in the MPOA has also been undertaken in males. In male mice, prolactin has an analogous role to females in inducing paternal care, with MPOA-specific deletion of the Prlr disrupting paternal behavior in mated male mice (90). Interestingly, this study showed that differential levels of prolactin secretion can, at least in part, account for the presence or absence of paternal behavior in mouse (high prolactin) and rat (low prolactin) fathers, respectively (90). These 2 studies looking at oxytocin and prolactin signaling in the MPOA reveal that our understanding of these important roles for hormones acting in the MPOA to facilitate paternal behavior are starting to emerge.

With androgens playing a key role in modulating social behavior in males, there is also scope for further studies to interrogate how androgen action in the MPOA regulates paternal behavior. Circulating androgens generally (but not always (91)) decline in both rodent and primate fathers (76, 92-94), suggesting in these species that suppression of androgenic actions might facilitate paternal behavior. There is significant androgen receptor (AR) expression in the male MPOA, which is mostly coexpressed with Esr1, and present in the majority of Gal-expressing neurons (81). Similar to females, stimulation of MPOA galanin neurons can induce paternal behaviors in virgin male mice (66), but whether a change in AR expression in MPOA galanin neurons occurs in mouse fathers and whether this facilitates the virgin to paternal shift in care-giving behavior is not yet known. The role of androgens in paternal behavior appears to be highly variable even between rodent species. For instance, in Mongolian gerbils, higher testosterone levels are associated with paternal care, and higher levels of AR immunoreactivity in the MPOA of fathers (40, 95) (Table 1).

It is important to highlight that testosterone may be an important source of estradiol in the MPOA of males, and contribute to paternal behavior through that route in some species. For instance, in the California mouse, testosterone promotes paternal behavior (96) through aromatase-mediated conversion of testosterone to estradiol, and not by the nonaromatizable androgen, dihydrotestosterone (97). In support of this, aromatase activity is higher in the MPOA of California mouse fathers than in mated males without pups (98), and aromatase knockout C57BL/6 male mice display increased infanticide (99). It would be valuable to further explore how androgens, AR expression, and aromatase expression collectively shape nurturing behavior towards pups across different species that display paternal behavior.

Challenges and Future Directions

Collectively, MPOA-specific deletion of hormone receptors, spatial transcriptomics, calcium imaging, and optogenetics have led to significant strides in our understanding of how hormonal action in the MPOA induces maternal behavior (Fig. 2). These studies have also highlighted significant gaps in our knowledge (Fig. 2). Much of this work has focused on galanin neurons, and a couple of their projection sites, with differing proportions of these neurons expressing Esr1, Pgr, and Prlr (Fig. 2). While galanin neurons are clearly important for maternal behavior, the majority of maternal hormone receptor expression in the MPOA is not seen in Gal-expressing neurons. Many additional neuronal populations express at least 1, but more likely, combinations of these hormone receptors, and the identity and specific roles in maternal behavior of these neuronal populations are yet to be determined (Fig. 2). For instance, little Oxtr expression is observed in galanin neurons (41), and yet blockade of Oxtr in the MPOA has a significant effect on maternal behavior (32). Applying similar technical approaches that have been harnessed to investigate galanin neurons to other genetically defined populations, and incorporating interrogation of hormonal cues has the potential to transform our understanding of the mechanisms by which hormones induce MPOA-mediated maternal behavior.

Figure 2.

Hormonal modulation of MPOA neuronal populations in maternal behavior. Although estradiol, progesterone, prolactin, vasopressin, and oxytocin are all known to act directly in the MPOA to regulate maternal behavior, it is yet to be determined how these neurons alter the functioning of specific neuronal populations in different reproductive states (A). Recently it has been shown that progesterone and estradiol increase galanin neuronal excitability during pregnancy (A), but the role of these hormones on other neuronal populations that regulate maternal behavior is unknown. Different populations of MPOA neurons project to specific regions of the maternal neural circuit to regulate different aspects of maternal behavior (B, C). While specific projection targets of MPOA galanin neurons, and a subpopulation of Esr1-expressing neurons, have been mapped to correspond with specific aspects of maternal behavior (C), this is yet to be undertaken for other neuronal populations involved in mediating maternal behavior (B, C).

Abbreviations: PAG, periaqueductal gray; VTA, ventral tegmental area; MEA, medial amygdala; VMH, ventromedial hypothalamus; PVN, paraventricular nucleus; BNST, bed nucleus of the stria terminalis; LS, lateral septum.

One of the biggest challenges in the field of parental behavior is the investigation of hormonal roles on parental behavior using a reductionist approach. While this is often necessary for practical reasons, it inevitably creates barriers in identifying how hormones collectively work together to orchestrate parental behavior. Clearly, these hormones do not act within narrow temporal windows to influence discrete aspects of parental behavior. Rather, there is significant overlap in the pregnancy/parturition/lactation or parenting continuum during which hormone secretion and/or receptor expression may be altered, with multiple hormones affecting specific aspects of parental behavior. The elegant study by Ammari et al (48) to show how progesterone and estradiol together alter galanin neuronal function during pregnancy, highlights how much can be learnt through looking at the combinatory actions of maternal hormones.

While significant advances have been made towards identifying how hormones shape maternal behavior, there is a marked lag in the development of understanding of the mechanisms underlying the hormonal control of paternal behavior. Research is lacking in this area, from understanding how circulating levels of hormones change in males at mating, through to the role of hormones in facilitating active paternal involvement once offspring are born. Much has been learnt about paternal behavior by applying knowledge gained from studies in females. However, given that the MPOA itself is sexually dimorphic (100), there are likely to be important sex differences that are not yet fully understood, and this may involve, yet to be described, sexually dimorphic hormonal actions upon parental behavior. Adding to the complexity of investigating the mechanisms driving paternal behavior is significant variation between species in the role of hormones on paternal behavior. While this can be seen even between rodent species, it is likely that even more variation will exist between higher-order taxa.

It is also important to acknowledge that while this review has focused on the MPOA, it is but part of a complex neural circuit that regulates parental behavior. Hormonal action at multiple levels of this circuit is important for the regulation of parental behavior, and this is reflected by the high degree of hormone receptor expression in many parts of the circuit. For instance, modulation of maternal aggressive behavior has recently been found to be mediated through Prlr expression in the ventromedial nucleus (101). The MPOA in turn regulates the release dynamics of hormones that are important for maternal behavior, as illustrated by deletion of Oxtr from the MPOA leading to a suppression of circulating prolactin in postpartum rats (32). In summary, our current understanding of the neural circuitry regulating parental behavior continues to evolve, with novel research tools being used to highlight both the presence of new pathways and revealing how hormones modulate the activity of this circuitry to orchestrate the timely display of parental behavior.

Abbreviations

AR

androgen receptor

AVP

arginine vasopressin

Avpr

arginine vasopressin receptor

brs3

bombesin receptor subunit 3

Calcr

calcitonin receptor

Esr1

estrogen receptor 1

Gal

galanin

MPOA

medial preoptic area of the hypothalamus

Oxtr

oxytocin receptor

Pgr

progesterone receptor

Prlr

prolactin receptor

pSTAT5

phosphorylated signal transducer and activator of transcription 5

VTA

ventral tegmental area

Funding

Marsden Fund Grant from the Royal Society of New Zealand and the Health Research Council of New Zealand Project Grant.

Disclosures

The authors have nothing to disclose.

Data Availability

The data set associated with this review is not available at this time as the data also forms part of an ongoing study.