Nicole M. Cameron

The programming of individual differences in defensive responses and reproductive strategies in the rat through variations in maternal care

There are profound maternal effects on individual differences in defensive responses and reproductive strategies in species ranging literally from plants to insects to birds. Maternal effects commonly reflect the quality of the environment and are most likely mediated by the quality of the maternal provision (egg, propagule, etc.), which in turn determines growth rates and adult phenotype. In this paper, we review data from the rat that suggest comparable forms of maternal effects on both defensive responses to threat and reproductive behavior and which are mediated by variations in maternal behavior. Ultimately, we will need to contend with the reality that neural development, function and health are defined by social and economic influences.

Maternal programming of sexual behavior and hypothalamic-pituitary-gonadal function in the female rat.

Variations in parental care predict the age of puberty, sexual activity in adolescence and the age at first pregnancy in humans. These findings parallel descriptions of maternal effects on phenotypic variation in reproductive function in other species. Despite the prevalence of such reports, little is known about potential biological mechanisms and this especially true for effects on female reproductive development. We examined the hypothesis that parental care might alter hypothalamic-pituitary-ovarian function and thus reproductive function in the female offspring of rat mothers that vary pup licking/grooming (LG) over the first week postpartum. As adults, the female offspring of Low LG mothers showed 1) increased sexual receptivity; 2) increased plasma levels of luteinizing hormone (LH) and progesterone at proestrus; 3) an increased positive-feedback effect of estradiol on both plasma LH levels and gonadotropin releasing-hormone (GnRH) expression in the medial preoptic region; and 4) increased estrogen receptor α (ERα) expression in the anterioventral paraventricular nucleus, a system that regulates GnRH. The results of a cross-fostering study provide evidence for a direct effect of postnatal maternal care as well as a possible prenatal influence. Indeed, we found evidence for increased fetal testosterone levels at embryonic day 20 in the female fetuses of High compared to Low LG mothers. Finally, the female offspring of Low LG mothers showed accelerated puberty compared to those of High LG mothers. These data suggest maternal effects in the rat on the development of neuroendocrine systems that regulate female sexual behaviour. Together with studies revealing a maternal effect on the maternal behavior of the female offspring, these findings suggest that maternal care can program alternative reproductive phenotypes in the rat through regionally-specific effects on ERα expression.

Epigenetic Programming of Phenotypic Variations in Reproductive Strategies in the Rat Through Maternal Care

Studies across multiple organisms reveal considerable phenotypic variation in reproductive tactics. In some species, this variation is associated with maternal effects in which variation in maternal investment results in stable individual differences in reproductive function. Recent studies with the rat suggest that maternal effects can alter the function of neuroendocrine systems associated with female sexual behaviour as well as maternal behaviour. These maternal effects appear to be mediated by epigenetic modifications at the promoter for oestrogen receptor alpha (ERα) and subsequent effects on gene expression. The tissue‐specific nature of such effects may underlie the co‐ordinated variation in multiple forms of reproductive function, resulting in distinct reproductive strategies.

Co-regulation of female sexual behavior and pregnancy induction: an exploratory synthesis.

This paper will review both new and old data that address the question of whether brain mechanisms involved in reproductive function act in a coordinated way to control female sexual behavior and the induction of pregnancy/pseudopregnancy (P/PSP) by vaginocervical stimulation. Although it is clear that female sexual behavior, including pacing behavior, is important for induction of P/PSP, there has been no concerted effort to examine whether or how common mechanisms may control both functions. Because initiation of P/PSP requires that the female receive vaginocervical stimulation, central mechanisms controlling P/PSP may be modulated by or interactive with those that control female sexual behavior. This paper presents a synthesis of the literature and recent data from our lab for the purpose of examining whether there are interactions between behavioral and neuroendocrine mechanisms which reciprocally influence both reproductive functions.

The role of oxytocin in mating and pregnancy.

The hormone oxytocin (OT) is released both centrally and peripherally during and after mating. Although research in humans suggests a central role in sexuality, the most reliable findings to date involve peripheral activation. This review will discuss these results and will particularly focus on understanding the most recent findings from fMRI data and the effects of exogenous peripheral OT administration. We will then consider hypotheses of the roles played by central and systemic OT release as well as their control and modulation in the female, summarizing recent findings from animal research. Finally, we will discuss the contribution of OT to the initiation of pregnancy in rodents. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.

Estrogenic mediation of serotonergic and neurotrophic systems: implications for female mood disorders.

Clinical research has demonstrated a significant sex difference in the occurrence of depressive disorders. Beginning at pubertal onset, women report a higher incidence of depression than men. Women are also vulnerable to the development of depressive disorders such as premenstrual dysphoric disorder, postpartum depression, and perimenopausal depression. These disorders are associated with reproductive stages involving changes in gonadal hormone levels. Specifically, female depression and female affective behaviors are influenced by estradiol levels. This review argues two major mechanisms by which estrogens influence depression and depressive-like behavior: through interactions with neurotrophic factors and through an influence on the serotonergic system. In particular, estradiol increases brain derived neurotrophic factor (BDNF) levels within the brain, and alters serotonergic expression in a receptor subtype-specific manner. We will take a regional approach, examining these effects of estrogens in the major brain areas implicated in depression. Finally, we will discuss the gaps in our current knowledge of the effects of estrogens on female depression, and the potential utility for estrogen receptor modulators in treatment for this disorder.

Maternal care associates with play dominance rank among adult female rats

Variations in maternal care influence important life history traits that determine reproductive fitness. The adult female offspring of mothers that show reduced levels of pup licking/grooming (LG; i.e., low-LG mothers) show increased defensive responses to stress, accelerated pubertal development, and greater sexual receptivity than the female offspring of high-LG mothers. Amongst several species an accelerated pattern of reproductive development is associated with increased dominance-related behaviors and higher social rank. We hypothesize that rats from low-LG dams may thus also secure higher social rank as a means to compete for limited resources with conspecifics. In this study, social interactions were observed in triads of adult female rats aged p90 that received low, mid, and high levels of pup LG over the first week of life. Low- and mid-LG females had the highest pinning scores and high-LG rats the lowest, showing that low- and mid-LG adult females engage in greater play dominance-related behavior. Likewise, low- and mid-LG rats spent significantly more time drinking following 24 hr of water deprivation in a water competition test thus allowing them to secure a limited resource more easily than high-LG rats. Interestingly, pinning by play dominant females was increased when subordinates were sexually receptive (proestrus/estrus), suggestive of a process of reproductive suppression. Some evidence suggests that low-LG and mid-LG rats also show greater fecundity than high-LG rats. Variations in maternal care may thus have a long-term influence on the development of play dominance and possibly social rank in the female rat, which might contribute to reproductive success within a competitive environment.

Deficits in male sexual behavior in adulthood after social instability stress in adolescence in rats

There is increasing evidence that exposure to stressors in adolescence has long-lasting effects on emotional and cognitive behavior, but little is known as to whether reproductive functions are affected. We investigated appetitive and consummatory aspects of sexual behavior in male rats that were exposed to chronic social instability stress (SS, n=24) for 16 days in mid-adolescence compared to control rats (CTL, n=24). Over five sexual behavior test sessions with a receptive female, SS rats made fewer ejaculations (p=0.02) and had longer latencies to ejaculation (p=0.03). When only data from rats that ejaculated in the fifth session were analyzed, SS rats (n=18) had reduced copulatory efficiency (more mounts and intromissions before ejaculation) compared to CTL rats (n=19) (p=0.004), and CTL rats were twice as likely as SS rats to make more than one ejaculation in the fifth session (p=0.05). Further, more CTL (14/24) than SS (5/25) rats ejaculated in four or more sessions (p=0.05). SS rats had lower plasma testosterone concentrations than CTL rats (p=0.05), but did not differ in androgen receptor, estrogen receptor alpha, or Fos immunoreactive cell counts in the medial preoptic area. The groups did not differ in a partner preference test administered between the fourth and fifth sexual behavior session. The results suggest that developmental history contributes to individual differences in reproductive behavior, and that stress exposures in adolescence may be a factor in sexual sluggishness.

Variation in maternal care influences ventromedial hypothalamus activation in the rat.

Natural variation in maternal care in the rat is an important source of individual differences in the female neuroendocrine system and sexual behaviours. Thus, females reared by low licking and grooming (LG) mothers are sexually more receptive to males, showing higher lordosis ratings, and are more motivated to mate compared to female offspring of high LG mothers. In the present study, we investigated the effect of natural variations in maternal care on the ventrolateral part of the ventromedial hypothalamus (VMHvl) cell population and on the reproductive success of the female rat. Immunohistochemistry for phosphorylated oestrogen‐receptor (pER) α and progesterone receptor (PR) were used to study the VMHvl of female offspring of high and low LG mothers at pro‐oestrus and dioestrus. A second experiment investigated sexual behaviour and the effect of mating on c‐Fos expression in the VMHvl of pro‐oestrus and ovariectomised high and how female offspring. Lastly, we investigated the maternal effect on the establishment of the progestational state. A greater number of VMHvl pERα immunoreactive cells was found in the pro‐oestrous female offspring of low LG mothers and PR was most abundant at pro‐oestrus compared to dioestrus in both high and low LG females. Interestingly it is the less receptive high females that show the greater c‐Fos expression in the VMH after mating in the pro‐oestrous group. The difference in c‐Fos expression after mating disappeared when the two groups were ovariectomised and received steroid replacement. Finally, low LG female offspring reached pseudopregnancy more often when receiving only seven intromissions at a 5‐min interval compared to high LG females. Lower levels of maternal care may favour the reproductive success of low LG offspring by increasing pERα and oestrogen‐dependent lordosis behaviour and lowering c‐Fos after mating, resulting in inhibition of termination of oestrus.

Maternal Programming of Reproductive Function and Behavior in the Female Rat

Parental investment can be used as a forecast for the environmental conditions in which offspring will develop to adulthood. In the rat, maternal behavior is transmitted to the next generation through epigenetic modifications such as methylation and histone acetylation, resulting in variations in estrogen receptor alpha expression. Natural variations in maternal care also influence the sexual strategy adult females will adopt later in life. Lower levels of maternal care are associated with early onset of puberty as well as increased motivation to mate and greater receptivity toward males during mating. Lower levels of maternal care are also correlated with greater activity of the hypothalamus–pituitary–gonadal axis, responsible for the expression of these behaviors. Contrary to the transition of maternal care, sexual behavior cannot simply be explained by maternal attention, since adoption studies changed the sexual phenotypes of offspring born to low caring mothers but not those from high caring dams. Indeed, mothers showing higher levels of licking/grooming have embryos that are exposed to high testosterone levels during development, and adoption studies suggest that this androgen exposure may protect their offspring from lower levels of maternal care. We propose that in the rat, maternal care and the in utero environment interact to influence the reproductive strategy female offspring display in adulthood and that this favors the species by allowing it to thrive under different environmental conditions.