Sex differences in the brain are largely organized by a testicular hormone surge that occurs in males shortly after birth. Although this hormone surge is transient, sex differences in brain and behavior are lasting. Here we describe a sex difference in DNA methylation of the estrogen receptor-alpha (ERalpha) promoter region within the developing rat preoptic area, with males exhibiting more DNA methylation within the ERalpha promoter than females. More importantly, we report that simulating maternal grooming, a form of maternal interaction that is sexually dimorphic with males experiencing more than females during the neonatal period, effectively masculinizes female ERalpha promoter methylation and gene expression. This suggests natural variations in maternal care that are directed differentially at males vs. females can influence sex differences in the brain by creating sexually dimorphic DNA methylation patterns. We also find that the early estradiol exposure may contribute to sex differences in DNA methylation patterns. This suggests that early social interaction and estradiol exposure may converge at the genome to organize lasting sex differences in the brain via epigenetic differentiation.

Steroid receptor activation in developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. We report that estrogen receptors can be activated in a ligand-independent manner within developing brain by membrane dopamine receptors. Neonatal treatment with either estradiol or a dopamine D1 receptor agonist can increase the expression of an estrogen receptor-regulated gene (i.e. progestin receptors) and later juvenile social play. More importantly, increases in social play behavior induced by neonatal treatment with estradiol or a dopamine D1 receptor agonist can be prevented by prior treatment with an estrogen receptor antagonist. This suggests that changes in dopamine transmission in developing brain can activate estrogen receptors in a ligand-independent manner to influence gene expression and have lasting consequences on social behavior.

Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude. In hepatocytes, activated NRF2 bound specific enhancer regions of the core clock repressor gene Cry2, increased Cry2 expression and repressed CLOCK/BMAL1-regulated E-box transcription. Together these data indicate that NRF2 and clock comprise an interlocking loop that integrates cellular redox signals into tissue-specific circadian timekeeping.

Juvenile social play behaviour is regarded as one of the earliest forms of non-mother directed social behaviour in rodents (1). An appealing aspect of juvenile social play behaviour is that it is sexually dimorphic, with males exhibiting higher levels of social play than females, making it an attractive model behaviour to understand both normal juvenile social development and sex differences in social behaviour in a nonreproductive context. It is also becoming clear that, although this sexually dimorphic behaviour is organised by neonatal steroid hormone exposure, the differentiation of social play can be also influenced by the early social environment, such as the amount of maternal care received. Investigations of social play are centered on why and how rats play, brain regions controlling play behaviour, sex differences, and how neurotransmitters and the social environment might influence the organisation of play behaviour. It will be interesting to understand how the social environment impinges on neurotransmitters to influence the steroid-receptor mediated organisation of juvenile social play behaviour. Why do rats play?There are several intriguing concepts with respect to why rats play. Juvenile play behaviour is considered to be rewarding because the opportunity to play can be used as an incentive for maze learning (2, 3) and juvenile rats develop conditioned place preferences for areas associated with play (4). Anticipation of play also elicits 50 kHz ultrasonic vocalisations (5), which are associated with positive affect (6). Indeed, it has been suggested that play is 'joyful' (7) and that some vocalisations during juvenile play might be akin to human laughter (8). Another possible function of play is to establish dominance in the group. After multiple play bouts, juveniles develop dominance hierarchies, which remain relatively stable over the juvenile period (9, 10), although play dominance does not always appear to predict dominance in adulthood (11). Play may also function to better prepare for adult behaviours, such as male sexual and aggressive behaviours (12), because play behaviour predicts adult aggressiveness in males (13). Preventing males from playing has lasting consequences on social (14-16), aggressive (16) and sexual behaviour (16,17). The effect of juvenile isolation on these behaviours appears mainly to be a result of deprivation of play because isolated animals provided with a brief daily period of play do not develop these deficits (16). Therefore, play may serve to prepare for more adaptive social behaviours in adulthood. How do rats play?Juvenile social play behaviour starts to form around 18 days, peaks during the peripubertal period (days 30-40) and wanes after puberty. Play is observed as bites, boxing ⁄ wrestling, pouncing and pinning. Pouncing, the act of jumping on or attacking the nape of a Juvenile social play behaviour is one of the earliest forms of non-mother directed social behaviour in rodents. Juvenile social play behaviour is sexually dimorphic, with males exhibiting ...

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