Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report.

22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common genetic disorder and is characterized by an elevated risk for immune dysfunction, up to 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1ß, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r=0.851, p=0.004; r=0.580, p=0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r=0.795, p=0.033; r=0.774, p=0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive association between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.

Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior.

Oxytocin is produced in the hypothalamus and released into the circulation through the neurohypophyseal system. Peripherally released oxytocin facilitates parturition and milk ejection during nursing. Centrally released oxytocin coordinates the onset of maternal nurturing behavior at parturition and plays a role in mother-infant bonding. More recent studies have revealed a more general role for oxytocin in modulating affiliative behavior in both sexes. Oxytocin regulates alloparental care and pair bonding in female monogamous prairie voles. Social recognition in male and female mice is also modulated by oxytocin. In humans, oxytocin increases gaze to the eye region of human faces and enhances interpersonal trust and the ability to infer the emotions of others from facial cues. While the neurohypopheseal oxytocin system has been well characterized, less is known regarding the nature of oxytocin release within the brain. Here we review the role of oxytocin in the regulation of prosocial interactions, and discuss the neuroanatomy of the central oxytocin system.

Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles.

Oxytocin receptors in the nucleus accumbens have been implicated in the regulation of alloparental behavior and pair bond formation in the socially monogamous prairie vole. Oxytocin receptor density in the nucleus accumbens is positively correlated with alloparenting in juvenile and adult female prairie voles, and oxytocin receptor antagonist infused into the nucleus accumbens blocks this behavior. Furthermore, prairie voles have higher densities of oxytocin receptors in the accumbens than nonmonogamous rodent species, and blocking accumbal oxytocin receptors prevents mating-induced partner preference formation. Here we used adeno-associated viral vector gene transfer to examine the functional relationship between accumbal oxytocin receptor density and social behavior in prairie and meadow voles. Adult female prairie voles that overexpress oxytocin receptor in the nucleus accumbens displayed accelerated partner preference formation after cohabitation with a male, but did not display enhanced alloparental behavior. However, partner preference was not facilitated in nonmonogamous meadow voles by introducing oxytocin receptor into the nucleus accumbens. These data confirm a role for oxytocin receptor in the accumbens in the regulation of partner preferences in female prairie voles, and suggest that oxytocin receptor expression in the accumbens is not sufficient to promote partner preferences in nonmonogamous species. These data are the first to demonstrate a direct relationship between oxytocin receptor density in the nucleus accumbens and variation in social attachment behaviors. Thus, individual variation in oxytocin receptor expression in the striatum may contribute to natural diversity in social behaviors.

Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice.

The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr(-/-)) and compared them with OXT-deficient (Oxt(-/-)) mice. Oxtr(-/-) mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr(-/-) dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr(-/-) males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr(-/-) males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt(-/-) males from Oxt(-/-) dams, but not from Oxt(+/-) dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT/OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior.

Circadian regulation of gonadotropin-releasing hormone neurons and the preovulatory surge in luteinizing hormone in the diurnal rodent, Arvicanthis niloticus, and in a nocturnal rodent, Rattus norvegicus.

Daily rhythms in the timing of the preovulatory surge and the display of reproductive behavior are reversed in diurnal and nocturnal rodents, but little is known about the neural mechanisms underlying these differences. We examined this issue by comparing a diurnal murid rodent, Arvicanthis niloticus (the grass rat), to a nocturnal one, Rattus norvegicus (the lab rat). In the first study, we established that sequential estradiol and progesterone treatment induces a proestrous-like rise in LH secretion and in the percentage of GnRH neurons that express Fos in grass rats, as is the case in lab rats. Next, we tested the hypothesis that differences in the timing of estrus-related events in diurnal and nocturnal species are caused by differences in rhythms in responsiveness to steroid hormones. We found rhythms in GnRH neuron activity, as indicated by Fos, that were 12 hours out of phase in grass rats and lab rats. These patterns persisted in both species when animals were housed in constant darkness for 5 days, suggesting that they are driven by an endogenous circadian mechanism. These results indicate that steroid-primed grass rats and lab rats are similar with respect to the temporal relationship among estrus-related events, but that the timing of these events relative to the light-dark cycle is dramatically different and that this difference is caused by endogenous circadian mechanisms.

Aging and the perception of speed.

Two experiments were conducted to explore the potential effects of aging upon the perception and discrimination of speed. In the first experiment, speed difference thresholds were obtained for younger and older observers for a variety of standard speeds ranging from slow to fast. The second experiment was designed to evaluate the observers' ability to discriminate differences in the speed of moving patterns in the presence of significant amounts of noise (the noise was manipulated by limiting the lifetimes of individual moving stimulus elements). The results of both experiments revealed a significant deterioration in the ability of the older observers to perceive or detect differences in speed. While the presence of noise was found to affect the observers' discrimination performance, it affected both younger and older observers' thresholds in a proportionally equivalent manner-the older observers were no more affected by noise than the younger observers.