Naturally occurring variations in maternal behavior in the rat are associated with differences in estrogen-inducible central oxytocin receptors

Abstract

Naturally occurring variations in maternal licking͞grooming influence neural development and are transmitted from mother to female offspring. We found that the induction of maternal behavior in virgin females through constant exposure to pups (pup sensitization) was significantly shorter in the offspring of High compared with Low licking͞grooming mothers, suggesting differences in maternal responsivity. In randomly selected females screened for individual differences in maternal responsivity and subsequently mated, there was a significant and negative correlation (r ‫؍‬ ؊0.73) between the latency to exhibit maternal behavior in the pup sensitization paradigm and the frequency of pup licking͞grooming during lactation. Females that were more maternally responsive to pups and that showed increased levels of pup licking͞grooming also showed significantly higher oxytocin receptor levels in the medial preoptic area, the lateral septum, the central nucleus (n.) of the amygdala, the paraventricular n. of the hypothalamus, and the bed n. of the stria terminalis. Intracerebroventricular administration of an oxytocin receptor antagonist to mothers on postpartum day 3 completely eliminated the differences in pup licking͞grooming, suggesting that differences in oxytocin receptor levels are functionally related to maternal behavior. Finally, estrogen treatment of virgin females significantly increased oxytocin receptor binding in the medial preoptic area and lateral septum of female offspring of High, but not Low, licking͞grooming mothers. These findings suggest that maternal licking͞grooming influences the development of estrogen sensitivity in brain regions that regulate maternal behavior, providing a potential mechanism for the intergenerational transmission of individual differences in maternal behavior. N aturally occurring variations in maternal care influence the development of behavioral, endocrine, and cognitive stress responses in the rat (1-4). As adults, the offspring of mothers that show increased levels of pup licking͞grooming and archedback nursing (i.e., High LG-ABN mothers) exhibit more modest hypothalamic-pituitary-adrenal and behavioral responses to stress, and are more proficient in learning to navigate an escape path in the Morris water maze compared with the offspring of Low LG-ABN mothers. The results of cross-fostering studies suggest that the differences in maternal behavior are critical: On each of the measures mentioned above, the biological offspring of Low LG-ABN mothers reared by High LG-ABN dams resembled the normal offspring of High LG-ABN mothers (3, 4). Individual differences in maternal behavior show a comparable pattern of transmission across generations. Thus, the adult, female offspring of High LG-ABN mothers are, themselves, High LG-ABN mothers, whereas those of Low LG-ABN dams are Low LG-ABN mothers. The pattern is reversed with crossfostering (3). These findings suggest that individual differences in stress reactivity and maternal care can be transmitted across generations through a be...

Epigenetic mechanisms and the transgenerational effects of maternal care

“…Thus, offspring of Low LG dams have reduced oxytocin receptor binding during the postpartum period. Moreover, offspring of Low LG dams that have been ovarietomized and given a high dose of estrogen do not have elevated oxytocin receptor binding in the MPOA [51]. Initially this finding was somewhat puzzling and contrary to what would be predicted based on previous research of estrogen-oxytocin interactions.…”

“…As is the case with High and Low LG dams, the offspring of these females display altered levels of hypothalamic oxytocin receptor binding [51]. Thus, offspring of Low LG dams have reduced oxytocin receptor binding during the postpartum period.…”

Oxytocin pathways in the intergenerational transmission of maternal early life stress

“…Extensive research in rodents indicates that OTRs are abundantly expressed within this network rendering it sensitive to the effects of OT (Love, 2014; Numan and Stolzenberg, 2009). Already during the gestational period, the MPOA, which is thought to constitute the core of this network, is hormonally primed, likely through an estrogen (E)-induced upregulation of OTR expression (Bealer et al, 2006; Champagne et al, 2001; Meddle et al, 2007; Numan and Stolzenberg, 2009). This E-primed network is then “triggered” by pup stimuli after parturition to result in immediate onset of maternal behavior, which is then maintained in the postpartum period (Numan and Stolzenberg, 2009; Pedersen, 1997).…”

“…The effects of ELS on key regions of the neural circuits that underlie parenting have been most rigorously studied in animal models (Champagne, 2008; Champagne et al, 2001; Pena et al, 2014). In female offspring of rats, a low level of maternal care (LG) is associated with lower OTR expression in the MPOA, PVN, the central nucleus of the amygdala, and the lateral septum (Champagne et al, 2001). Moreover, downstream targets of hypothalamic OT projections in the mesolimbic system, i.e., the VTA and the nAcc, are equally affected by early rearing experiences.…”

“…These experience-induced differences in OT-DA neural circuits that underlie parenting correspond to observable parenting behaviors. Lower levels of OTR expression are associated with less maternal responsiveness towards pups (Champagne, 2008; Champagne et al, 2001). This intergenerational transmission of maternal behavior in rats is partly mediated by epigenetic modifications of the estrogen receptor α with downstream effects on OTR expression regulation in the brain, which will be further described below (see section 3.2.2).…”