Introduction
Autism is a neurodevelopmental disorder characterized by deficits in social behavior, disrupted or abnormal development of verbal and nonverbal communication, repetitive behaviors, and often a restriction of interests. Autism spectrum disorder (ASD) is an umbrella term that encompasses the diagnoses of Aspberger’s disorder and pervasive developmental disorder-not otherwise specified, in addition to classical autism. The constellations of symptoms that present with ASD vary greatly in severity. For instance, delay in development of language presents in only half of patients with ASD (31). Mental retardation similarly presents in only half of this population (5). Interest in the causes and treatment of ASD has spiked in recent years due to an increase in prevalence in children over the last decade, to approximately 3.4 per 1000 children (39).
While the causes of ASD are not yet fully understood, a recent controversial hypothesis that measles-mumps-rubella (MMR) vaccine and thimerosal-containing vaccines cause autism was ruled out by a 2004 Immunization Safety Review (17). A stronger link exists between an individual’s genetic makeup and ASD; one study determined the heritability of autistic disorders to be around 90% (12). In other words, 90% of the difference between individuals with and without ASD is due to the effects of genetic makeup. Genome-wide searches for loci that convey risk for ASD have produced candidate genes on nearly every chromosome (35), though the genetic basis of ASD remains ambiguous and elusive (23).

In order to simplify the analysis in light of the heterogeneity of symptoms, severity, and potential underlying genetic factors of ASD, recent studies have begun to decompose the phenotype into individual heritable components (32). Using this approach, the present study aims to investigate the potential contribution of the oxytocin system to the social deficits observed in patients with ASD.

The following sections present research investigating the role of oxytocin in normal social cognition. Animal research often allows researchers to examine the biological basis of disorders that are difficult to study in humans for logistic and ethical reasons; therefore, after a brief overview of the body’s two oxytocin systems, animal studies will be presented to give the reader a background in the neuroendocrine basis of social behavior as it relates to oxytocin. Following the review of pertinent animal research, a review of the literature examining the role of oxytocin in normally functioning humans and its possible role in the development of ASD will be presented.

Oxytocin

Oxytocin is a nine amino acid neuropeptide unique to mammals. It is most widely known for its hormonal role in activating contractions of the uterus during labor and secretion of milk during lactation (3). Oxytocin achieves hormonal action via magnocellular oxytocinergic neurons originating in the supraoptic and paraventricular nuclei of the hypothalamus projecting to the posterior pituitary, where it is released into the bloodstream. Along with the peripheral effects of oxytocin by secretion along this hypothalamic-neurohypophsial axis, effects in the brain are achieved by neurotransmitter action, with receptor sites located in various species-specific regions of the brain, including but not limited to the amygdala, ventromedial hypothalamus, nucleus acumbens, and medial preoptic area (3). The effects of oxytocin on social cognition involve this centrally acting oxytocin system, which will be elaborated further in the following sections.

Animal Research – Social Motivation

Maternal Behavior

An early study by Pedersen, Ascher, Monroe, and Prange (1982) found that injections of oxytocin into the left lateral ventricle of ovariectomized female rats pretreated with estradiol benzoate rapidly induced full expression of maternal behavior (26). In their study, maternal behavior was measured based on the intensity of five coded behaviors including nest building, grouping and regrouping of pups, crouching over grouped pups, retrieval of pups, and licking of pups. These behaviors are commonly reported in the literature on maternal behavior. Pedersen et al. found that onset to full expression of maternal behavior was induced rapidly in a dose-dependant manner for rats receiving various concentrations of oxytocin, but not rats receiving saline, suggesting oxytocin may be involved in the endogenous expression of maternal behavior (26).

While investigating infanticidal behavior in female mice, McCarthy (1990) came to a similar conclusion (20). Infanticidal mice given subcutaneous injections as well as intracerebroventricular infusions of oxytocin exhibited decreases in pup killing and wounding as well as increases in maternal behavior, suggesting that oxytocin acts centrally on brain tissues to decrease the motivation to kill pups and in some cases to increase motivation to exhibit maternal behavior. This effect was observed equally across intact rats, ovariectomized rats, and ovariectomized rats treated with estradiol benzoate. This suggests that the oxytocin-activated onset of maternal behavior occurs regardless of the mother’s reproductive status. The effect also occurred in the presence of prolactin antagonists, suggesting that the increases in maternal behavior did not arise from the secondary action of oxytocin-dependent increases prolactin, which has been previously implicated in maternal behavior in mice (34), but rather from direct central oxytocinergic action.

Increased oxytocin receptor binding in the ventral tegmental and preoptic areas was observed in rats during pregnancy compared to levels measured before and after (27). Interestingly, the onset of normal maternal behaviors following pregnancy, including pup retrieval and crouching over grouped pups, was blocked when oxytocin antagonists were infused into either of these areas, further implicating oxytocinergic action in central nervous tissue in the initiation of this crucial social behavior. Fahrbach, Morrell, and Pfaff (1985) found that oxytocin antagonists’ inhibition of maternal behavior was ineffective when administered to rats five days after pregnancy, after the behaviors had already been initiated (6). This finding suggests that oxytocin may be specifically involved in the initiation but not maintenance of maternal behavior.

Compelling evidence from a cross-species study of oxytocin receptor (OTR) density in various brain regions suggests that variations in OTR expression may also underlie behavioral differences in presentation of maternal behavior across different species (24). Maternal behavior towards young that are not the rodent’s offspring is spontaneous in juvenile female prairie voles, may take several days to develop in juvenile rats, and is absent in juvenile mice and meadow voles. Olazabal and Young found the highest OTR density in the nucleus acumbens and caudate putamen of prairie voles, intermediate densities in both structures in rats, and lowest density of OTR in mice and meadow voles in these structures, while OTR binding showed the opposite pattern in the lateral septum (24; Figure 1). The researchers also found that patterns of OTR density predicted behavior; time spent crouching over pups was positively correlated with OTR binding in the nucleus acumbens and caudate putamen, and negatively correlated with OTR binding in the lateral septum.

Olazabal and Young (2006b) then showed in a separate experiment that an OTR antagonist infused into the nucleus acumbens, but not the caudate putamen, eliminated spontaneous maternal behavior in prairie voles compared to control prairie voles infused with cerebrospinal fluid (25). These findings suggest that variations in OTR expression in the nucleus acumbens may underlie a common mechanism of initiating and motivating maternal behavior across different rodent species. Since the nucleus acumbens is known to be involved in reward and reinforcement pathways in the brain, the results further implicate a relationship between oxytocin activity and this particular facet of social motivation.

There is evidence in support of an epigenetic mode of inheritance of maternal behavior, which may be mediated by changes in the expression of OTR. One study found that rat pups reared by mothers who licked, groomed, and nursed pups often displayed higher licking, grooming, and nursing when they subsequently become mothers, whereas pups reared by mothers who did not lick and groom pups often displayed less of these behaviors when they became mothers (11). Maternal behavior was highly heritable, but was not attributable to differences in genotype as the maternal behavior of rats’ biological mothers had no effect. Francis, Champagne, and Meaney (2000) found that these differences in maternal behavior were associated with differences in OTR levels in the central nucleus of the amygdala, suggesting that OTR regulation may underlie the epigenetic mechanism of inheritance (10).

Offspring Behavior

Mouse offspring who lack OTR or oxytocin genes have been found to show decreased social motivation as well. Takayanagi et al. (2005) found that infant OTR knockout mice showed deficits in social discrimination and emitted fewer ultrasonic vocalizations than wild type infant mice following separation from their mothers (33). Ultrasonic vocalizations are usually indicative of emotional distress, suggesting that infant OTR knockout mice are less distressed by social isolation than normal infant mice. This pattern of behavior was also found in a study examining the behavior of infant mice with a null mutation in the gene coding for oxytocin itself (37), suggesting that abnormalities in the oxytocin system underlie deficits in social emotional regulation.

Though the findings of the Takayanagi et al. (2005) and Winslow et al. (2000) studies may indicate oxytocin-related decreases in overall anxiety, the decrease in vocalizations observed for oxytocin-KO and OTR-KO mouse pups may also reflect a lack of motivation to be near their mothers (33, 37). Studies conducted with rats support this motivation interpretation. Rat pups trained to associate a scent with their mother approached the scent quicker than did rat pups not trained to associate the same scent with their mother (22). Following intracerebroventricular administration of an oxytocin antagonist, this decrease in latency to approach the mother-associated odor was eliminated, though odor aversion learning and interactions with the anesthetized mother were unaffected. These results suggest that interference with the brain oxytocin system may result in decreased social motivation of approach, independent of olfactory or learning impairments.

Inter-Adult Behavior

Oxytocin appears to be involved in social motivation among adult animals as well. Chronic intracerebroventricular infusion of oxytocin in male rats was found to double the time spent in direct nonsexual physical contact with females when compared to chronic cerebrospinal fluid infusion (38). This effect of chronic oxytocin, which was not influenced by the reproductive status of the female, was accompanied by increased levels of anogenital investigation of females, as well as increases in grooming behavior. These results suggest that chronic oxytocin may enhance social motivation by increasing the magnitude of positive reinforcement gained by somatosensory and/or olfactory stimuli.

Rosenblum et al. (2002) found that behavioral differences in affiliation across species of macaque monkeys were associated with differences in cerebrospinal fluid concentrations of oxytocin and corticotrophin-releasing factor (CRF; 29). Highly social bonnet macaques had higher oxytocin levels and lower CRF levels, measured by radioimmunoassay, whereas socially withdrawn pigtail macaques showed the opposite pattern (29; Figure 2).

These results, though correlational, provide evidence, in light of converging support from rodent models, for a role of the brain oxytocin system in facilitating social motivation in a wide range of animal species.

Animal Research – Pair Bonding

Oxytocin plays a crucial role in the development of pair bonding in female prairie voles. Ovariectomized females who received intracerebroventricular infusions of oxytocin during a 6 hour nonsexual exposure to a stimulus male prairie vole developed pair bonding, operationalized as the ratio of time spent with the partner during exposure versus time spent with a novel stimulus male (36). Control females who received infusions of cerebrospinal fluid did not show partner preference. An oxytocin antagonist administered concurrently with the oxytocin infusions eliminated pair bonding, suggesting a direct oxytocinergic action. This oxytocin-initiated pair bonding can be attributed to central effects of oxytocin, since subcutaneous injections of oxytocin were without effect.
Similar to the previously mentioned interspecies differences in maternal behavior linked to OTR expression (24), a study conducted by Young, Lim, Gingrich, and Insel (2001) found a higher density of OTR expression in the nucleus acumbens in monogamous female prairie voles compared to polygamous montane voles, suggesting a potential link between OTR levels and the formation of pair bonds (40). When an oxytocin antagonist was injected into the nucleus acumbens or the prefrontal cortex, partner preference was blocked, providing additional evidence that functioning oxytocin pathways are required for the expression normal afflilative behaviors across species.

A recently published study found that female prairie voles injected with adeno-associated viral vectors containing the OTR gene into the nucleus acumbens, resulting in a local increase in OTR expression, exhibited accelerated partner preference (30). The increase in OTR expression in the nucleus acumbens was not sufficient to induce pair bonding in polygamous prairie voles, and did not affect maternal behaviors, however. These results provide strong support for the direct role of OTR binding in the nucleus acumbens in facilitating pair bonding in prairie voles, though they also suggest that differences in OTR expression in the nucleus acumbens alone do not account for all oxytocin system-related social behaviors, or for differences in pair bonding between species. Further research examining OTR expression is needed and should provide further insight into the complex interactions of the oxytocin system among multiple brain regions in multiple species.

Animal Research – Social Memory

The effect of intracerebroventricular infusions of oxytocin on social memory in rats appears to be very dependent on the dose of oxytocin administered. Benelli et al. (1995) found that low doses of oxytocin that approximated endogenous levels reduced the time that males spent investigating a familiar female compared to a novel female, a decrease thought to reflect recognition of the female (2). High doses of oxytocin increased the time investigating a familiar female, reflecting an impairment of social memory. When an oxytocin antagonist was administered at equal concentrations of oxytocin five minutes before each dose, the improvement in social memory observed for the low dose was eliminated. This suggests that the improvement in social memory observed for the lower dose of oxytocin is likely mediated by direct binding of oxytocin to the OTR.

Surprisingly, the impairment in social memory observed in the rats receiving the high dose of oxytocin was reversed with an equal concurrent administration of oxytocin antagonist, indicating slightly improved social recognition. The experimenters suggest that this reversal may have been due to oxytocin displacement of the antagonist that mimicked the action of the lower, endogenous dose of oxytocin.

Studies examining oxytocin knockout mice have given less ambiguous results as to the role of oxytocin in social memory. Wild type mice exhibit a characteristic decrease in olfactory investigation of a stimulus conspecific with repeated exposure. This is thought to reflect recognition of the stimulus mouse. Ferguson et al. (2000) found that male oxytocin knockout mice exhibited social amnesia; these mice failed to show a decrease in olfactory investigation of female mice after repeated exposure (9). These mice were still able to locate buried food by scent and showed normal habituation to olfactory and acoustic stimuli, suggesting that failure to habituate to the scent of females reflects social amnesia per se, rather than impairments in general memory or olfactory function. Spatial memory was also indistinguishable between knockout and wild type mice, further supporting that the impairment was specific to social memory.
Ferguson et al. (2000) also found that social memory was completely restored to oxytocin knockout males after intracerebroventricular infusion of oxytocin, while infusion of oxytocin antagonists in wild type mice delayed the normal decrease in investigation normally observed, suggesting a modest amnesic effect (9). These effects were also not due to differences in OTR expression. These results suggest that oxytocin is crucial to normally functioning social memory. Since the impairment was fully restored following central administration of oxytocin, it appears to be a result of activational rather than organizational effects.

Along this line of investigation, Ferguson, Aldag, Insel, and Young (2001) replicated the effects of social amnesia in oxytocin knockout mice and found that c-Fos immunoreactivity (Fos-IR) was indistinguishable between oxytocin knockouts and wild type mice in the olfactory bulbs (8). However, Fos-IR was observed in the medial amygdala in wild type mice but was absent in the medial amygdala and its projection sites throughout the brains of oxytocin knockout mice. These findings suggest that the medial amygdala may play a crucial role in normal processing of social memory in the mouse. Fos-IR was observed in the somatosensory cortex and hippocampi of oxytocin knockout mice but not wild type mice, suggesting that alternative processing strategies may mediate social cognition in oxytocin knockout mice.

Ferguson et al. (2001) also found that infusions of oxytocin into the medial amygdala before, but not after, the initial encounter with a female facilitated social recognition in male oxytocin knockout mice (8). This suggests that oxytocinergic action in the medial amygdala is necessary and sufficient for olfactory recognition. The role of oxytocin in the medial amygdala may be the formation/coding of social memories rather than memory recall, which may be mediated by oxytocinergic action at separate brain nuclei.

Implications for Humans

The extensive animal literature suggests a role for oxytocin in human social functioning, especially motivation, pair bonding, and memory. Though far less investigation has gone into human research with respect to oxytocin, evidence in support of this role in humans exists. Feldman, Weller, Zagoory-Sharon, and Levine (2007) examined plasma oxytocin levels and infant interactions of pregnant women during the first and last trimesters and first postpartum month (7). They found that oxytocin levels during this period were correlated with maternal behaviors, such as gaze at the child’s face, positive affect, affectionate touch, and vocalizations. They also found that oxytocin levels were correlated with a mental component of human bonding, including attachment-related thoughts and frequent checking of the child. Though correlational, these results provide converging evidence with animal research that oxytocin may be important in humans for the motivation of maternal behaviors. Though strong evidence is lacking, it is conceivable that oxytocin-mediated maternal behavior may provide an epigenetic mode of inheritance of social behavior in humans, analogous to the findings in studies of inheritance of maternal behavior in rats (11).

The formation and strengthening of pair bonds in humans may be related to oxytocin release at orgasm. Carmichael et al. (1987) took continuous blood samples from both males and females during sexual self-stimulation and found increased oxytocin plasma levels during sexual arousal, as well as a significant increase from baseline during orgasm (4). These findings suggest that oxytocinergic action may mediate pair bonding after copulation in humans. This interpretation is limited by the study’s correlational approach, as well as the measurement of peripheral levels of oxytocin rather than levels of central oxytocin.

An interesting study examining trusting behavior in humans found that double blind administration of intranasal oxytocin prevented subjects from reducing trust of others in the face of betrayal (1). In this study, subjects received either intranasal oxytocin or placebo and played two economic strategy games; one in which the payoff for trusting a computer was random (risk game) and one in which the payoff depended on participants’ trust of another player to act unselfishly (trust game). Participants receiving placebo adjusted their strategy to the trust game by decreasing trusting behavior in the face of betrayal by the other player. Participants receiving oxytocin, however, continued to trust their opponent (1; Figure 3).

This oxytocin-induced failure of extinction of trust may play a physiological role in pair bonding in humans. Reduced activation measured by functional magnetic resonance imaging was found in the amygdala, midbrain, and dorsal striatum of participants administered oxytocin compared to participants administered placebo (1). The results of this fMRI study compare well with the animal literature reporting reduced OTR expression in rats within the central nucleus of the amygdala (10).

Rimmele, Hediger, Heinrichs, and Klaver (2009) demonstrated the interspecies role of oxytocin in social memory (28). Intranasal administration of oxytocin improved correct recognition of previously presented faces compared to a placebo group, but had no effect on recollection of previously presented nonsocial stimuli. This finding directly mimics the extensive animal literature implicating oxytocin in the formation of social recognition memory and provides strong evidence of an analogous role of oxytocin in human social cognition.

Relevance to Autism Spectrum Disorders

It is clear that oxytocin plays an important role in normal social cognition in many animal species, including humans. Because autism and its close phenotypic relatives, Aspberger’s syndrome and pervasive developmental disorder-not otherwise specified, show such marked impairments in social cognition, it is likely that these deficits may be a result of impaired functioning of the oxytocin system. Until recently, the role of oxytocin system dysfunction in the etiology of ASD was highly speculative. Recent evidence suggests that oxytocin may play a very direct role in the social impairments associated with ASD, however.

A study by Hollander et al. (2003) found that intranasal administration of oxytocin was effective in reducing the number and severity of repetitive behaviors over a 4 hour period in patients diagnosed with ASD (16). This suggests that abnormal function of the brain oxytocin system may play a role in the development of the ASD phenotype, though outside of the domain of social cognition. In line with this idea, recent studies have found that oxytocin administered intranasally was effective in improving the processing of emotional cues conveyed by faces (14) and oxytocin administered intravenously was also effective in improving comprehension of affective content of speech (15) in patients diagnosed with ASD. These studies found that administration of oxytocin reduced the symptoms of ASD in a clinical population, providing support for the role of abnormal oxytocin binding in the expression of these symptoms.

Additionally, intranasal oxytocin may prove to be a promising medical treatment of the deficits in social cognition accompanying ASD.
Though Freitag (2007) estimated the heritability of autistic disorders to be around 90%, specific genetic causes of ASD remain elusive (11, 23). Three separate studies examining differences in single-locus alleles and haplotype frequencies between patients with ASD and healthy controls have found single nucleotide polymorphisms (SNPs) and haplotypes conveying heightened risk for autism within the 3p25 region, containing the gene for the oxytocin receptor (21, 18, 19). These studies suggest that a genetic cause with respect to mutations on or near the oxytocin receptor may be relevant to at least a subset of the ASD population. The findings of these studies are complicated by the fact that candidate genes have been identified on nearly every chromosome (35). Thus, specific genetic causes of autism appear highly varied and complex, and have not been exclusively correlated to genes coding for a functioning oxytocin system.
Gregory et al. (2009) have unveiled compelling evidence suggesting that overregulation of the oxytocin receptor gene may underlie an epigenetic mechanism by which ASD may be transmitted (13). They examined the genome of a patient with ASD who directly inherited a null mutation on the oxytocin gene from his mother (essentially a naturally occurring human OTR knockout). The researchers also examined the genome of his sister, who was also diagnosed with ASD. It was found that the sister had an intact OTR gene, but that the gene promoter region was highly hypermethylated, essentially silencing the gene.

Since the ASD phenotype was not due to direct genetic inheritance in the sister, Gregory et al. (2009) examined if overregulation of the OTR gene could be common among ASD patients (13). They found significant increases in methylation within the promoter region of ASD patients compared to controls. This hypermethylation was correlated with decreases in OTR expression determined by reduced brain and blood OTR mRNA levels in ASD patients compared to controls matched for age and gender. These findings lend genetic support to the role of oxytocin signaling in the development of ASD. They also provide a plausible epigenetic mechanism of inheritance of ASD. This hypothesis receives support from the animal literature, which provides evidence of epigenetic inheritance of other oxytocin-mediated behavioral traits, such as maternal behavior (11). The results of the Gregory et al. study demand replication on a larger scale (13). Investigation into the behavioral and cognitive consequences of inadequate expression of the OTR gene, as well as the specificity of this hypermethylation to the OTR gene promoter region will hopefully begin to reveal the etiology of ASD and the mechanisms by which the oxytocin system operates in normal and dysfunctional human brains.

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