James T. Winslow

Social amnesia in mice lacking the oxytocin gene.

The development of social familiarity in rodents depends predominantly on olfactory cues and can critically influence reproductive success. Researchers have operationally defined this memory by a reliable decrease in olfactory investigation in repeated or prolonged encounters with a conspecific. Brain oxytocin (OT) and vasopressin (AVP) seem to modulate a range of social behaviour from parental care to mate guarding. Pharmacological studies indicate that AVP administration may enhance social memory, whereas OT administration may either inhibit or facilitate social memory depending on dose, route or paradigm. We found that male mice mutant for the oxytocin gene (Oxt−/−) failed to develop social memory, whereas wild-type (Oxt+/+) mice showed intact social memory. Measurement of both olfactory foraging and olfactory habituation tasks indicated that olfactory detection of non-social stimuli is intact in Oxt−/− mice. Spatial memory and behavioural inhibition measured in a Morris water-maze, Y-maze, or habituation of an acoustic startle also seemed intact. Treatment with OT but not AVP rescued social memory in Oxt−/− mice, and treatment with an OT antagonist produced a social amnesia-like effect in Oxt+/+ mice. Our data indicate that OT is necessary for the normal development of social memory in mice and support the hypothesis that social memory has a neural basis distinct from other forms of memory.

Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse.

Previous studies have shown that oxytocin (OT)-deficient female mice produced by homologous recombination fail to lactate but exhibit normal parturition and reproductive behaviors. We examined the ultrasonic vocalizations of infant mice and the subsequent aggressive and fear behavior of adult male OT knockout (OT-KO) mice. Infant OT-KO mice were less vocal than wild-type (WT) control mice during separations from the mother and peers. Adult OT-KO males were generally more aggressive in isolation-induced and resident-intruder tests of aggression and less fearful in the plus maze and acoustic startle reflex tests than WT controls. Although the increase in tests of aggression was robust for OT-KO males from obligate litters (progeny of homozygous x homozygous crossings), the increase in aggression was reduced during tests for OT-KO males derived from nonobligate mating (progeny of heterozygous x heterozygous crossings), suggesting that the OT-KO genotype was not, by itself, responsible for the changes in adult behavior. We conclude that the absence of exposure to OT during development was associated with abnormalities in the development of emotional behavior.

Species differences in V1a receptor gene expression in monogamous and nonmonogamous voles: behavioral consequences.

Arginine vasopressin modulates a number of species-typical social behaviors, including social memory in rats, scent marking and aggressive behavior in hamsters, and partner preference formation and paternal behavior in monogamous rodents. The distribution of V1a receptor binding sites in the brain varies greatly among species. Using in situ hybridization in 2 species of voles with strikingly different patterns of V1a binding sites and social behaviors, the authors demonstrate that differences in V1a receptor binding sites are due to species differences in regional V1a receptor gene expression. It is then demonstrated that the differences in receptor gene expression are associated with species differences in behavioral response to centrally administered vasopressin. Together, these data suggest that the phylogenetic plasticity of central neurohypophyseal peptide receptor expression may contribute to the evolution of species-typical social behaviors.

Mating in the monogamous male: Behavioral consequences

In monogamous mammals, males typically show selective affiliation with a single mate, high levels of paternal care, and aggression towards conspecifics to protect male and offspring. We have previously described how selective aggression and affiliation increase after mating in the male prairie vole, Microtus ochrogaster. The current studies further explored the behavioral changes that follow mating in the male of this species. The first set of experiments tested males on several behavioral measures after 24 h of either mating, social (but not sexual) exposure, or no social contact. After 24 h of mating, but not after the other two conditions, aggression and affiliation (partner preference) increased as previously reported. In addition, mated animals showed increased exploration of the open arms of a plus maze, consistent with decreased fearfulness. There were no group differences in paternal behavior (which was high in all three conditions) or analgesia (assessed by tail flick latency). To determine the minimum amount of mating necessary for the induction of aggression, males were tested in a resident-intruder paradigm after 1,6, or 24 h of mating. Although 1 h of mating was associated with a transient increase in the frequency of threats and attacks, the full spectrum of enduring aggression was observed only in the males given 24 h of mating. In a final experiment, the behavioral consequences of mating were studied in males of the closely related montane vole (Microtus montanus) which does not pair bond. Males of this nonmonogamous vole species did not show increased aggression, partner preference, or alterations in plus maze exploration following 24 h of mating. These results demonstrate the importance of prolonged mating for the induction of pair bonding in the monogamous male and they suggest that increases in aggression and affiliation are associated with decreased fearfulness in pair bonded males.

Central administration of oxytocin modulates the infant rats response to social isolation

Several lines of evidence suggest that oxytocin modulates the formation and maintenance of social bonds. In the current experiments we investigated the influence of centrally and peripherally administered oxytocin on the behavior of 6-8 day old rat pups during brief periods of social isolation. Ultrasonic vocalizations emitted by isolated pups were decreased following i.c.v. administration of oxytocin, at doses (500, 1000 ng) which did not affect motor activity. S.c. administered oxytocin (1, 10 micrograms) produced a biphasic change in ultrasonic vocalizations, depending on dose. Central administration of the oxytocin antagonist (d(CH2)5[Tyr(Me)2, Thr4, Tyr-NH2(9)]OVT) (OTA, 500 ng) did not measurably affect pup behavior by itself but did block the decrease in calls following central but not peripheral administration of oxytocin. These data demonstrate that oxytocin via its central receptor can regulate the response to social isolation.

Neuroendocrine basis of social recognition

All social relationships are dependent on an organisms ability to remember conspecifics. Social memory may be a unique form of memory, critical for reproduction, territorial defense, and the establishment of dominance hierarchies in a natural context. In the laboratory, social memory can be assessed reliably by measuring the reduction in investigation of a familiar partner relative to novel conspecifics. The neurohypophyseal neuropeptides oxytocin and vasopressin have been shown to influence a number of forms of social behavior, including affiliation, aggression, and reproduction. This article reviews vasopressin and oxytocin effects on social cognition, particularly the acquisition and retention of social recognition in rats and mice. Studies in rats have demonstrated that vasopressin in specific neural pathways, such as the lateral septum, is necessary for social recognition. As vasopressin facilitates recall when given after an initial encounter, the peptide appears important for the consolidation not the acquisition of a social memory. Although oxytocin has complex effects on social memory in rats, mice with a null mutation of the oxytocin gene are completely socially amnestic without other cognitive deficits evident. As oxytocin given centrally before but not after the initial encounter restores social recognition in these mutant mice, the neuropeptide appears critical for the acquisition rather than the consolidation phase of memory. Oxytocins effects on social memory are mediated via a discrete cell population in the medial amygdala. These findings support the hypothesis that vasopressin and oxytocin are essential for social memory, although they appear to influence different cognitive processes and may modulate different neural systems. (c) Elsevier Science.

Neural correlates of maternal separation in rhesus monkeys

BACKGROUND The neurobiological basis of stress and anxiety in primates remains poorly understood. In this study, we examined the neural response to a naturalistic social stressor: maternal separation. We used rhesus monkeys as an animal model because of their close phylogenetic affinity with humans. METHODS Six juvenile rhesus monkeys received [(18)F]-fluorodeoxyglucose positron emission tomography scans following 1) a period together with their mothers and again after separation from their mothers 2) with or 3) without visual contact. Image subtraction revealed brain regions that exhibited altered activity during separation. In addition, plasma cortisol concentrations obtained following each condition were tested for correlations with regional brain activity. RESULTS Maternal separation activated the right dorsolateral prefrontal cortex and the right ventral temporal/occipital lobe. There was also decreased activity in left dorsolateral prefrontal cortex associated with separation stress. Correlational analyses demonstrated these activated and deactivated regions to be positively and negatively correlated with cortisol, respectively. Additionally, correlational analyses revealed cortisol-related activation in brainstem areas previously implicated in stress and anxiety. CONCLUSIONS In juvenile rhesus monkeys, the stress of maternal separation is associated with activation in the right dorsolateral prefrontal cortex and ventral temporal/occipital lobes and decreased activity in the left dorsolateral prefrontal cortex.

Gene Targeting Approaches to Neuroendocrinology: Oxytocin, Maternal Behavior, and Affiliation

Transgenic technology affords exciting new opportunities in the field of behavioral neuroendocrinology. We have extended our research into the behavioral function of oxytocin in maternal and social behavior using two transgenic approaches: (i) targeted deletion of the oxytocin gene in mice and (ii) augmented oxytocin receptor expression in the brain. Mice genetically deficient in oxytocin can mate, give birth, and display normal maternal behavior; however, milk ejection and certain aspects of social behavior are affected. Comparative studies of oxytocin receptors have led to the observation that species differences in social organization are associated with differences in receptor distribution. Specifically, monogamous prairie voles and nonmonogamous, asocial montane voles exhibit different patterns of OT receptor expression in the brain. Transgenic mice have been created with a reporter gene driven by the prairie vole oxytocin receptor gene promoter. Analysis of the expression pattern suggests that it should be possible to manipulate receptor expression in the vole brain in order to examine the effects of receptor distribution on behavior.

Serotonin and neuropeptides in affiliative behaviors.

The neuropharmacological study of serotonin and behavior has followed two fundamentally different strategies. One approach has used behavior as a dependent variable for assaying drug effects. To characterize serotonergic drugs, most studies have used relatively simple behaviors, such as locomotor activity, startle, exploration, operant responses, and sleep. A second approach has focused on behavior, with drugs used as tools to elucidate the physiological role of serotonin. These studies have increasingly focused on behaviors of ethological importance, including aggression, sexual behavior, and other forms of social interaction. Here we review studies using this approach to focus on one particular kind of social interaction: affiliation.

Effects of central vasopressin administration to infant rats

The neurohypophyseal peptide hormone arginine-vasopressin functions as a neuropeptide in several brain areas in addition to its role as a posterior pituitary hormone. Several studies indicate that arginine-vasopressin and arginine-vasopressin receptors appear early in the infant rat brain. To determine if arginine-vasopressin receptors in the infant were responsive to exogenous peptides, we compared the behavioral effects of central or peripheral administration of arginine-vasopressin, arginine vasotocin, the oxytocin precursor oxytocin-Gly-Lys-Arg, and arginine-vasopressin receptor antagonists in socially isolated rat pups. Central administration of arginine-vasopressin decreased the number of rat pup ultrasonic vocalizations, reduced locomotor activity and decreased the latency to express a response to negative geotaxis. Temperature was also reduced at all doses tested. Co-administration of arginine-vasopressin and receptor antagonists suggested that changes in vocal behavior were mediated by the V1 receptor subtype. Changes in core temperature appeared to be mediated by a V2 receptor subtype. Peripheral arginine-vasopressin administration increased calling and decreased core body temperature. Neither effect was blocked by central receptor antagonist administration. The results are consistent with the hypothesis that arginine-vasopressin receptors in the infant rat brain are functional.