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Program in Neuroscience, Department of Psychology, Michigan State University, East Lansing, Michigan 48824
Address all correspondence and requests for reprints to: Joseph S. Lonstein, Program in Neuroscience, Department of Psychology, Giltner Hall, Michigan State University, East Lansing, Michigan 48824. E-mail: lonstein{at}msu.edu.
For many scientists, the bane of their existence is often the inherent variability that exists in the biological systems they investigate. Indeed, one can pick up any statistics text and without fail find an abundance of pages devoted not only to the measurement and interpretation of variability within and across samples, but also to a variety of ways to reduce it. A different mindset, however, views individual differences in physiology or behavior not as a potential foil, but rather as a unique opportunity to gather information about the system under examination. Why a minority of subjects is either behaviorally hyper- or hyporesponsive under identical conditions can be as interesting as determining what the majority of subjects will do under these circumstances, and focusing on individual differences has provided important insight into the neural and hormonal mechanisms underlying a variety of complex processes in animals including anxiety, stress responsiveness, and sexual behavior.
It has long been known that even apparently subtle manipulations of the perinatal environment produce notable changes in the physiology and behavior of rats and some other animals when they are adults. Many of these effects are thought to be due, at least in part, to subsequent changes in mother-infant interactions. The resulting differences in the amount or type of maternal care received during infancy can be an important source of individual differences in adulthood (1, 2). For over two decades, the work of Michael Meaney and members of his laboratory has focused on how manipulations of the neonatal environment, often including changes in maternal care, alter brain development and resulting individual differences in stress responsiveness, anxiety, and cognition. In a novel twist, their most recent work has been examining how differences in early maternal care influences the later expression of this same behavior in the female offspring when they themselves are adults.
Meaney and his colleagues have previously demonstrated (reviewed in Ref. 3) that female rats having mothers that naturally lick and nurse them more often grow up to also lick and nurse their own offspring more. This phenomenon is not passed down genetically because when pups born to mothers that show relatively low maternal care are fostered to high-licking and nursing dams, the female pups also grow up to be high-licking and nursing mothers. This line of research is particularly interesting when one considers the fact that some characteristics of mother-infant interactions can be passed down from human mothers to their daughters (4).
The neural basis of these differences in the display of maternal care in lactating rats appears to be related to differences in oxytocin receptor (OTr) content in numerous areas of the brain known to be important for the display of maternal behaviors. Among its many roles, oxytocin is well known to facilitate a variety of social behaviors, including the interactions between mothers and their infants (e.g. Ref. 5). Not only do lactating females that received more maternal care as infants have greater OTr binding in the preoptic area (POA), lateral septum, and bed nucleus of the stria terminalis, but administration of an oxytocin antagonist into the cerebral ventricles reduces maternal care in high-licking and nursing dams to the levels displayed by less-nurturing mothers (3, 6). Given that OTr expression is potently induced by estrogens, it was a logical extension for Meaney’s group to find that exogenous estradiol increased OTr expression in the POA and lateral septum only in the females that received relatively high amounts of maternal care during infancy (6).
In the present issue of this journal, Champagne et al. (7) expand upon these findings and show in the brains of high and low maternal females and their daughters further differences that might be related to individual differences in their responding toward pups. First, they demonstrate that high-licking and nursing dams have higher levels of estrogen receptor 
(ER), but not ERß, mRNA expression in some regions of the POA compared with low-licking and nursing dams. Similarly, virgin female offspring of high-licking and nursing dams were found to have higher levels of ER mRNA and protein expression compared with offspring of less maternal dams. Secondly, they demonstrate that treatment with estradiol increases activity of the immediate-early gene c-fos in some regions of the POA of virgin daughters of high-licking and nursing mothers, but not those raised by less-responsive mothers.
These results have some important implications. First, it seems that individual differences in sensitivity to estradiol in virgin female rats are at least partly mediated by basal differences in neural ER, but not ERß, expression that can be transmitted from one generation to the next. It is likely that many of the cells that express ER in the POA of high-licking and nursing females are the same cells that also express high levels of OTr, thereby specifically implicating ER in the regulation of the individual differences in OTr expression previously observed by Meaney and colleagues. Although individual differences in sensitivity to estradiol might explain why there might be variability in females’ initial responsiveness to pups at parturition, the authors note that estradiol levels are very low thereafter, when individual differences in maternal care are still evident and are sensitive to manipulations of oxytocin. The authors suggest that the behavior of high- and low-responding females differs after the periparturitional period not because of differences in neural ER activity and subsequent OTr expression resulting from exposure to circulating estradiol itself. Rather, they propose that female rats might differ in the amount of ER and OTr activity that can be stimulated in a ligand-independent manner through activation of neurotransmitter systems during interactions with pups. That is, ER may be stimulated by neurotransmitters or neuromodulators, even in the absence of circulating estradiol, when dams interact with and receive sensory stimuli from their offspring. This hypothetical neurotransmitter-induced ER activity might be capable of increasing neural OTr expression in the dams and maintaining high levels of ongoing maternal care.
Ligand-independent activation of steroid hormone receptors is known to influence sexual behavior in female rats, such that dopamine can alter neural progestin receptor activity in the complete absence of progesterone to influence copulation (8). Ligand-independent activation of ER has been suggested, although not yet demonstrated, to be somehow involved in the general maintenance of maternal behavior throughout lactation in rats, which is not dependent on circulating hormones but instead on the dam’s continuous exposure to sensory cues from pups (9). The possibility of ligand-independent mechanisms also acting ultimately through the OTr to generate individual differences in maternal care is highly intriguing. If future experiments demonstrate that ligand-independent activation of steroid or peptide hormone receptors is relevant for the display of maternal behavior in lactating rats, then an important mystery in the neurobiology of nurturance will have been solved.
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Footnotes |
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Received August 1, 2003.
Accepted for publication August 4, 2003.
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 Top References |
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expression and estrogen sensitivity in the medial preoptic area. Endocrinology 144:4720–4724-containing neurons in lactating rats. Neuroendocrinology 72:91–101[CrossRef][Medline]
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