The formation of social attachments is a critical component of human relationships. Infants begin to bond to their caregivers from the moment of birth, and these social bonds continue to provide regulatory emotional functions throughout adulthood. It is difficult to examine the interactions between social experience and the biological origins of these complex behaviors because children undergo both brain development and accumulate social experience at the same time. We had a rare opportunity to examine children who were reared in extremely aberrant social environments where they were deprived of the kind of care-giving typical for our species. The present experiment in nature provides insight into the role of early experience on the brain systems underlying the development of emotional behavior. These data indicate that the vasopressin and oxytocin neuropeptide systems, which are critical in the establishment of social bonds and the regulation of emotional behaviors, are affected by early social experience. The results of this experiment suggest a potential mechanism whose atypical function may explain the pervasive social and emotional difficulties observed in many children who have experienced aberrant care-giving. The present findings are consistent with the view that there is a critical role for early experience in the development of the brain systems underlying basic aspects of human social behavior.attachment ͉ emotion ͉ oxytocin ͉ vasopressin ͉ child abuse T he social attachments formed between human infants and their caregivers begin very early in postnatal life and play a critical role in children's survival and healthy adaptation. Typically, adults provide infants with a social environment that is fairly consistent. Caregivers learn how to recognize and respond to the infants' needs, thereby creating predictable contingencies in the environment; these regularities, in turn, make the infant's environment secure and conducive to further social learning (1, 2). Multiple perceptual, sensory, cognitive, and affective systems must become synchronized so that a social bond can develop between an infant and caregiver; this bond is then reflected in the child's adaptive behavioral responses to the environment. The goal of this experiment was to address a fundamental evolutionary and developmental question: To what extent are the neurobiological systems that regulate affiliative behaviors dependent on the social experiences afforded to most infants by their caregivers?It is difficult to evaluate the effects of early social experience on the organization of the developing brain because, within seconds of postnatal life, the human infant experiences a vast amount of emotional input. In this regard, the maturation of the brain is confounded with the accumulation of social experience. One way to address this problem is to experimentally manipulate the social environment. Although this approach is successful with nonhuman animals, such studies are neither possible nor desirable to undertake with human children. There...

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.

Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b 5 reductase and cytochrome b 5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b 5 reductase and cytochrome b 5 , expressed in Escherichia coli, efficiently catalyzed the reduction of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and benzamidoxime, with apparent K m values similar to those found in human liver microsomes and specific activities (V max ) 74 to 235 times higher than in microsomes. Minimal activity was seen with either protein alone, and microsomal protein did not enhance activity other than additively. All three reduction activities were significantly correlated with immunoreactivity for cytochrome b 5 in individual human liver microsomes. In addition, polyclonal antibodies to both NADH cytochrome b 5 reductase and cytochrome b 5 significantly inhibited reduction activity for sulfamethoxazole hydroxylamine. Finally, fibroblasts from a patient with type II hereditary methemoglobinemia (deficient in NADH cytochrome b 5 reductase) showed virtually no activity for hydroxylamine reduction, compared with normal fibroblasts. These results indicate a novel direct role for NADH cytochrome b 5 reductase and cytochrome b 5 in xenobiotic metabolism and suggest that pharmacogenetic variability in either of these proteins may effect drug reduction capacity.Hydroxylamine and amidoxime compounds are metabolized in humans by an as yet incompletely characterized NADH-dependent reductase system. Hydroxylamine metabolites have been implicated in dose-dependent and idiosyncratic drug toxicity from sulfamethoxazole, dapsone, procainamide, and other arylamine drugs (Uetrecht, 2002). Amidoximes and other hydroxylated amines have been developed as prodrugs to enhance the absorption of a wide range of antihypertensive, antiprotozoal, and antithrombotic drugs (Weller et al

Release of gonadotropin releasing hormone (GnRH) from the medial basal hypothalamus (MBH)/median eminence region (S-ME) is essential for normal reproductive function. GnRH release is profoundly regulated by the negative and positive feedback effects of ovarian estradiol (E 2 ). Here we report that neuroestradiol, released in the S-ME, also directly influences GnRH release in ovariectomized female monkeys, in which the ovarian source of E 2 is removed. We found that (1) brief infusion of E 2 benzoate (EB) to the S-ME rapidly stimulated release of GnRH and E 2 in the S-ME of ovariectomized monkeys, (2) electrical stimulation of the MBH resulted in GnRH release as well as E 2 release, and (3) direct infusion of an aromatase inhibitor to the S-ME suppressed spontaneous GnRH release as well as the EB-induced release of GnRH and E 2 . These findings reveal the importance of neuroestradiol as a neurotransmitter in regulation of GnRH release. How circulating ovarian E 2 interacts with hypothalamic neuroestrogens in the control of GnRH release remains to be investigated.

Methyl-CpG-binding protein 2 (MeCP2) binds methylated DNA and recruits corepressor proteins to modify chromatin and alter gene transcription. Mutations of the MECP2 gene can cause Rett syndrome, whereas subtle reductions of MeCP2 expression may be associated with male-dominated social and neurodevelopmental disorders. We report that transiently decreased amygdala Mecp2 expression during a sensitive period of brain sexual differentiation disrupts the organization of sex differences in juvenile social play behavior. Interestingly, neonatal treatment with Mecp2 small interfering RNA within the developing amygdala reduced juvenile social play behavior in males but not females. Reduced Mecp2 expression did not change juvenile sociability or anxiety-like behavior, suggesting that this disruption is associated with subtle behavioral modification. This suggests that Mecp2 may have an overlooked role in the organization of sexually dimorphic behaviors and that male juvenile behavior is particularly sensitive to Mecp2 disruption during this period of development.