Progesterone impairs social recognition in male rats

The influence of progesterone in the brain and on the behavior of females is fairly well understood. However, less is known about the effect of progesterone in the male system. In male rats, receptors for progesterone are present in virtually all vasopressin (AVP) immunoreactive cells in the bed nucleus of the stria terminalis (BST) and the medial amygdala (MeA). This colocalization functions to regulate AVP expression, as progesterone and/or progestin receptors (PR)s suppress AVP expression in these same extrahypothalamic regions in the brain. These data suggest that progesterone may influence AVP-dependent behavior. While AVP is implicated in numerous behavioral and physiological functions in rodents, AVP appears essential for social recognition of conspecifics. Therefore, we examined the effects of progesterone on social recognition. We report that progesterone plays an important role in modulating social recognition in the male brain, as progesterone treatment leads to a significant impairment of social recognition in male rats. Moreover, progesterone appears to act on PRs to impair social recognition, as progesterone impairment of social recognition is blocked by a PR antagonist, RU-486. Social recognition is also impaired by a specific progestin agonist, R5020. Interestingly, we show that progesterone does not interfere with either general memory or olfactory processes, suggesting that progesterone seems critically important to social recognition memory. These data provide strong evidence that physiological levels of progesterone can have an important impact on social behavior in male rats.     

Oxytocin and vasopressin are dysregulated in Williams Syndrome, a genetic disorder affecting social behavior

The molecular and neural mechanisms regulating human social-emotional behaviors are fundamentally important but largely unknown; unraveling these requires a genetic systems neuroscience analysis of human models. Williams Syndrome (WS), a condition caused by deletion of ~28 genes, is associated with a gregarious personality, strong drive to approach strangers, difficult peer interactions, and attraction to music. WS provides a unique opportunity to identify endogenous human gene-behavior mechanisms. Social neuropeptides including oxytocin (OT) and arginine vasopressin (AVP) regulate reproductive and social behaviors in mammals, and we reasoned that these might mediate the features of WS. Here we established blood levels of OT and AVP in WS and controls at baseline, and at multiple timepoints following a positive emotional intervention (music), and a negative physical stressor (cold). We also related these levels to standardized indices of social behavior. Results revealed significantly higher median levels of OT in WS versus controls at baseline, with a less marked increase in AVP. Further, in WS, OT and AVP increased in response to music and to cold, with greater variability and an amplified peak release compared to controls. In WS, baseline OT but not AVP, was correlated positively with approach, but negatively with adaptive social behaviors. These results indicate that WS deleted genes perturb hypothalamic-pituitary release not only of OT but also of AVP, implicating more complex neuropeptide circuitry for WS features and providing evidence for their roles in endogenous regulation of human social behavior. The data suggest a possible biological basis for amygdalar involvement, for increased anxiety, and for the paradox of increased approach but poor social relationships in WS. They also offer insight for translating genetic and neuroendocrine knowledge into treatments for disorders of social behavior.     

小型田鼠:研究单配制进化与调控的模型

哺乳动物的单配制通常被认为是社会性单配制,它不是单纯地由性行为来决定,而是由诸多因素,包括长期的pair bond、夫妻双方共同抚育后代、免近亲交配以及雌雄两性相似等来决定的。在这篇综述中,我们论述了如何以啮齿类田鼠属(Microtus)为模型,通过比较研究来帮助我们理解社会性单配制的进化以及其神经调控机制。对田鼠属的研究不仅证实了单配制起源于艰苦的生存条件的假说,而且还证实了雌性性选择可能有利于维持单配制。不仅如此,哺乳动物单配制的进化还需要雄性的prosocial行为的不断强化。例如,亲近行为可以促进pairbond的形成并强化雄性对后代的哺育行为,而这种强化则来源于神经多肽催产素(OT)和加压素(AVP)与类固醇类激素的相互作用。催产素和加压素调控pairbond和双亲哺育行为的表达,而单配制和多配制田鼠的催产素和加压素受体在脑内的分布有显的不同。比较研究揭示了小型田鼠单配制的调控机制,而种内差异和行为上的可塑性则有助于我们进一步理解这种机制。比如,在某些条件下,多配制的草原田鼠(Microtus pennsylvanicu)的雄性个体具有哺育后代的行为。尽管草原田鼠的加压素Vla受体在脑内的分布与其他多配制的田鼠相似,但是如果脑室注射加压素,仍可以诱发其哺育后代的行为。同样是单配制的橙腹田鼠(Microtus ochrogaster),生活在：Illnois的显示出高水平的prosocial行为,而生活在Kansas的则表现出较低水平的社会性行为。即使两个种群的催产素或加压素Vla受体在脑内的分布相同,它们的雌激素受体表达水平显不同,这在雄性个体表现尤其明显。与Kansas的雄性个体相比,在终纹床核(bed rucleus of the stria tenninalis)和杏仁核中区(medial amygdala)这两个调控亲近行为和攻击行为的脑区,Illinois的雄性个体的α雌激素受体的水平要低得多。这些研究表明对雌激素的低敏感程度有利于高水平地表达prosocial行为并降低特定类型的攻击行为。     

以田鼠作为动物模型来研究社会行为的进化:基因、脑与行为

田鼠属的一些近缘种间具有独特的社会行为多态性。例如Microtusochrogaster和M .pinetorum为一夫一妻制 ,而M .montanus和M .pennsylvanicus则为独居和一夫多妻制。无论是在野外还是人工饲养的条件下 ,单配制的田鼠其雌、雄成年个体一经交配即在两者之间形成长期的配偶关系并且双亲共同哺育后代。已证明神经多肽加压素 (Vasopressin)参与了田鼠单配制行为的神经调控。本篇综述了过去以及近期关于加压素调控田鼠配偶关系形成的研究结果和进展。首先 ,阐述了加压素V1a受体 (V1aR)在脑分布的种间差异 ,并以此来鉴别特定脑区在配偶关系形成中的功能 ;其次 ,探讨了运用V1aR拮抗物的药理学方法来决定究竟哪些脑区参与配偶关系的形成 ,还描述了田鼠种间V1aR基因结构和功能的不同 ,以及这些不同对V1aR在大脑的分布和行为调控潜在的作用机制 ;最后 ,讨论了最新的研究结果 ,即对一夫多妻制田鼠进行脑V1aR基因的改造 ,从而使之表现出一夫一妻制田鼠的行为。总之 ,了解复杂的社会性行为的遗传和神经机制可以加深我们对种间和种内行为分歧进化的理解     

Increased aggression and lack of maternal behavior in Dio3‐deficient mice are associated with abnormalities in oxytocin and vasopressin systems

Thyroid hormones regulate many aspects of brain development and function, and alterations in the levels of thyroid hormone action lead to abnormal anxiety‐ and depression‐like behaviors. A complement of factors in the brain function independently of circulating levels of hormone to strictly controlled local thyroid hormone signaling. A critical factor is the type 3 deiodinase (DIO3), which is located in neurons and protects the brain from excessive thyroid hormone. Here, we examined whether a local increase in brain thyroid hormone action secondary to DIO3 deficiency is of consequence for social behaviors. Although we did not observe alterations in sociability, Dio3?/? mice of both sexes exhibited a significant increase in aggression‐related behaviors and mild deficits in olfactory function. In addition, 85% of Dio3?/? dams manifested no pup‐retrieval behavior and increased aggression toward the newborns. The abnormal social behaviors of Dio3?/? mice were associated with sexually dimorphic alterations in the physiology of oxytocin (OXT) and arginine vasopressin (AVP), 2 neuropeptides with important roles in determining social interactions. These alterations included low adult serum levels of OXT and AVP, and an abnormal expression of Oxt, Avp and their receptors in the neonatal and adult hypothalamus. Our results demonstrate that DIO3 is essential for normal aggression and maternal behaviors, and indicate that abnormal local regulation of thyroid hormone action in the brain may contribute to the social deficits associated with neurodevelopmental disorders.     

精氨酸加压素对大鼠抗体产生和淋巴细胞增殖的上调作用

大鼠侧脑室注射１００ｎｇ精氨酸加压素（ＡＶＰ）,用ＥＬＩＳＡ法检测血中对鸡卵白 白抗原产生的ＩｇＧ抗体水平。结果显示,ＩｇＧ水平高于对照,而ＡＶＰ的Ｖ１受体阻断剂ＤＰＡＶＰ则可阻断此作用;ｉｃｖ８００ｎｇＡＶＰ,大鼠的ＳＲＢＣ溶血素 水平高于对照;ｉｃｖ１００ｎｇ、８００ｎｇＡＶＰ２ｈ后,脾淋巴细胞对ＭＴＴ产生的颜色反应均比对照增加,而ＤＰＡＶＰ可阻断之;ｉｃｖ８００ＡＶＰ２ｈ后,脾淋巴细胞对ＭＴ     

Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine

The neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are evolutionarily highly conserved mediators in the regulation of complex social cognition and behaviour. Recent studies have investigated the effects of OXT and AVP on human social interaction, the genetic mechanisms of inter-individual variation in social neuropeptide signalling and the actions of OXT and AVP in the human brain as revealed by neuroimaging. These data have advanced our understanding of the mechanisms by which these neuropeptides contribute to human social behaviour. OXT and AVP are emerging as targets for novel treatment approaches--particularly in synergistic combination with psychotherapy--for mental disorders characterized by social dysfunction, such as autism, social anxiety disorder, borderline personality disorder and schizophrenia.     

Arginine vasotocin neuronal phenotypes, telencephalic fiber varicosities, and social behavior in butterflyfishes (Chaetodontidae): potential similarities to birds and mammals

The neuropeptide arginine vasopressin (AVP) influences many social behaviors through its action in the forebrain of mammals. However, the function of the homologous arginine vasotocin (AVT) in the forebrain of fishes, specifically the telencephalon remains unresolved. We tested whether the density of AVT-immunoreactive (-ir) fiber varicosities, somata size or number of AVT-ir neuronal phenotypes within the forebrain were predictive of social behavior in reproductive males of seven species of butterflyfishes (family Chaetodontidae) in four phylogenetic clades. Similar to other fishes, the aggressive (often territorial) species in most cases had larger AVT-ir cells within the gigantocellular preoptic cell group. Linear discriminant function analyses demonstrated that the density of AVT-ir varicosities within homologous telencephalic nuclei to those important for social behavior in mammals and birds were predictive of aggressive behavior, social affiliations, and mating system. Of note, the density of AVT-ir varicosities within the ventral nucleus of the ventral telencephalon, thought to be homologous to the septum of other vertebrates, was the strongest predictor of aggressive behavior, social affiliation, and mating system. These results are consistent with the postulate that AVT within the telencephalon of fishes plays an important role in social behavior and may function in a similar manner to that of AVT / AVP in birds and mammals despite having cell populations solely within the preoptic area.     

The contribution of oxytocin and vasopressin to mammalian social behavior: potential role in autism spectrum disorder

Oxytocin (OT) and arginine-vasopressin (AVP) are 2 peptides that are produced in the brain and released via the pituitary gland to the peripheral blood, where they have diverse physiological functions. In the last 2 decades it has become clear that these peptides also play a central role in the modulation of mammalian social behavior by their actions within the brain. Several lines of evidence suggest their involvement in autism spectrum disorder (ASD), which is known to be associated with impaired social cognition and behavior. Recent clinical trials using OT administration to autistic patients have reported promising results. Here, we aim to describe the main data that suggest a connection between these peptides and ASD. Following a short illustration of several major topics in ASD biology we will (a) briefly describe the oxytocinergic and vasopressinergic systems in the brain, (b) discuss a few compelling cases manifesting the involvement of OT and AVP in mammalian social behavior, (c) describe data supporting the role of these peptides in human social cognition and behavior, and (d) discuss the possibility of the involvement of OT and AVP in ASD etiology, as well as the prospect of using these peptides as a treatment for ASD patients.     

Species differences in paternal behavior and aggression in peromyscus and their associations with vasopressin immunoreactivity and receptors.

Previous comparative studies have suggested that the distribution of arginine vasopressin (AVP) pathways within the brain is associated with species-typical patterns of social behavior. In the current study, male parental behavior and aggression were compared in two species of Peromyscus. As predicted based on other studies, male mice from a monogamous species, the California mouse Peromyscus californicus, spent more time providing parental care to offspring than males from a polygamous species, the white-footed mouse Peromyscus leucopus. Sexually naive male California mice also attacked opponents more rapidly than white-footed mice during resident-intruder and neutral aggression tests. Since AVP has been shown to modulate these behaviors, we compared the distribution of vasopressinergic neurons and receptors. We predicted that greater AVP-immunoreactive (AVP-ir) staining in the bed nucleus of the stria terminalis and AVP receptor density in the lateral septum would occur in the species with low levels of paternal care because this pattern was found in similar comparisons with sexually naive monogamous and polygamous voles. In contrast, in our study, monogamous male mice showed more AVP-ir staining in the bed nucleus of the stria terminalis than the polygamous species, as well as more AVP receptors in the lateral septum. Parental behavior therefore does not appear to predict differences in patterns of AVP-ir staining and receptor distribution across species or vice versa. We propose the hypothesis that aggression may be better correlated with species patterns of AVP-ir staining density and receptor distribution.     

Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways

In adult male rats, vasopressin (AVP) facilitates social recognition via activation of V1a receptors within the lateral septum. Much less is known about how AVP affects social recognition in adult females or in juvenile animals of either sex. We found that administration of the specific V1a receptor antagonist d(CH(2))(5)[Tyr(Me)(2)]AVP into the lateral septum of adult rats impaired, whereas AVP extended, social discrimination in both sexes. In juveniles, however, we detected a sex difference, such that males but not females showed social discrimination. Interestingly, administration of the V1a receptor antagonist to juveniles (either intracerebroventricularly or locally in the lateral septum) did not prevent social discrimination, but instead significantly decreased the investigation of a novel as opposed to a familiar animal in both sexes, with stronger effects in males. V1a receptors were found to be abundantly expressed in the lateral septum with higher binding density in females than in males. These findings demonstrate that activation of V1a receptors in the lateral septum is important for social recognition in both sexes, and that the roles of septal V1a receptors in social recognition change during development.     

Central cardiovascular actions of vasopressin in the rat

Arginine vasopressin (AVP) containing neurones and pathways have been localized in various cardiovascular control centers of the central nervous system in rats. AVP influences cardiovascular regulation when injected into various areas of the central nervous system. The blood pressure increases in response to central AVP injections were shown to be initiated by stimulation of central V1-AVP receptors and mediated by stimulation of sympathetic outflow to the periphery. On the other hand, AVP has also been shown to attenuate the pressor responses to electrical stimulation of the mesencephalic reticular formation when injected into the brain ventricular system. In addition, AVP can participate in cardiovascular regulation by modulating baroreceptor reflex sensitivity. We have shown that in rats peripheral (hormonal) AVP can sensitize the heart rate component of the baroreceptor reflex by acting on V2-AVP receptors accessible from the blood, while at the same time central (neuronal) AVP can attenuate the baroreceptor reflex through brain V1-AVP receptors that cannot be reached from the blood. Binding and functional studies favour the existence of V1-AVP receptors in the central nervous system, whereas evidence for central V2-AVP receptors is still scarce. The role of AVP in hypertension remains controversial, but recent evidence suggests that a discordance between the various central and peripheral cardiovascular actions of AVP, rather than its hormonal vasopressor effects, may contribute to the pathogenesis of hypertension.     

AVP and Glu systems interact to regulate levels of anxiety in BALB/cJ mice

While the roles of glutamic acid(Glu), arginine vasopressin(AVP) and their respective receptors in anxiety have been thoroughly investigated, the effects of interactions among Glu, N-methyl-D-aspartic acid(NMDA) receptor, AVP and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid(AMPA) receptor on anxiety are still unclear. In the present study, the agonist and antagonist of the NMDA receptor and AMPA receptor, as well as the antagonist of AVP V1 receptor(V1aR) were introduced into BALB/cJ mice by intracerebroventricular microinjection, and the anxiety-like behaviors of the mice were evaluated by open field and elevated plus-maze tests. Compared with C57BL/6 mice, BALB/cJ mice displayed higher levels of anxiety-like behavior. Significant anxiolytic effects were found in the NMDA receptor antagonist(MK-801) and the AMPA receptor or V1 aR antagonist(SSRI49415), as well as combinations of AVP/MK-801 and SSRI49415/DNQX. These results indicated that anxiety-like behaviors expressed in BALB/CJ mice may be due to a coordination disorder among glutamate, NMDA receptor, AMPA receptor, AVP and V1 aR, resulting in the up-regulation of the NMDA receptor and V1 aR and down-regulation of the AMPA receptor. However, because the AMPA receptor can execute its anxiolytic function by suppressing AVP and V1 aR, we cannot exclude the possibility of the NMDA receptor being activated by AVP acting on V1 aR.     

Violating social norms when choosing friends: how rule-breakers affect social networks

Social networks rely on basic rules of conduct to yield functioning societies in both human and animal populations. As individuals follow established rules, their behavioral decisions shape the social network and give it structure. Using dynamic, self-organizing social network models we demonstrate that defying conventions in a social system can affect multiple levels of social and organizational success independently. Such actions primarily affect actors' own positions within the network, but individuals can also affect the overall structure of a network even without immediately affecting themselves or others. These results indicate that defying the established social norms can help individuals to change the properties of a social system via seemingly neutral behaviors, highlighting the power of rule-breaking behavior to transform convention-based societies, even before direct impacts on individuals can be measured.     

Exogenous vasotocin alters aggression during agonistic exchanges in male Amargosa River pupfish (Cyprinodon nevadensis amargosae)

Pupfishes in the Death Valley region have rapidly differentiated in social behaviors since their isolation in a series of desert streams, springs, and marshes less than 20,000 years ago. These habitats can show dramatic fluctuations in ecological conditions, and pupfish must cope with the changes by plastic physiological and behavioral responses. Recently, we showed differences among some Death Valley populations in brain expression of arginine vasotocin (AVT). As AVT regulates both hydromineral balance and social behaviors in other taxa, these population differences may indicate adaptive changes in osmoregulatory and/or behavioral processes. To test whether AVT is relevant for behavioral shifts in these fish, here we examined how manipulations to the AVT system affect agonistic and reproductive behaviors in Amargosa River pupfish (Cyprinodon nevadensis amargosae). We administered exogenous AVT (0.1, 1, and 10 microg/g body weight) and an AVP V1 receptor antagonist (Manning compound, 2.5 microg/g body weight) intraperitoneally to males in mixed-sex groups in the laboratory. We found that AVT reduced the initiation of aggressive social interactions with other pupfish but had no effect on courtship. The effects of AVT were confirmed in males in the wild where AVT (1 microg/g body weight) reduced the aggressive initiation of social interactions and decreased aggressive responses to the behavior of other males. Combined, these results show that AVT can modulate agonistic behaviors in male pupfish and support the idea that variation in AVT activity may underlie differences in aggression among Death Valley populations.     

Central vasopressin V1-blockade prevents salicylate but not acetaminophen antipyresis

Recent evidence has suggested that the endogenous antipyretic arginine vasopressin (AVP) may participate in drug-induced antipyresis. This study sought to further those investigations by comparing the effects of two other antipyretic drugs, sodium salicylate and acetaminophen, administered intraperitoneally, during AVP V1-receptor blockade within the ventral septal area (VSA) of the rat brain. During endotoxin-evoked fever, V1-receptor blockade within the VSA of the conscious unrestrained rat significantly antagonized the antipyretic effects of salicylate. The effects of the V1-antagonist on salicylate-induced antipyresis were dose related. In contrast, the antipyresis elicited by acetaminophen was unaffected by VSA V1-antagonist pretreatment. Neither saline nor the V1-antagonist microinjected into the VSA of febrile or nonfebrile rats had any significant effects on the normal progression of endotoxin fever or normal core temperature, respectively. These data suggest that the mechanism of action of salicylate-induced antipyresis includes activation of AVP V1-type receptors within the VSA, as has been shown for indomethacin. However, the lack of effect of the V1-antagonist on antipyresis induced by acetaminophen indicates that not all antipyretic drugs act through the same mechanism in the brain.     

Neurohypophysial hormones and renal function in fish and mammals

The two major basic neurohypophysial peptides, arginine vasopressin (AVP) of mammals and arginine vasotocin (AVT) of all non-mammalian vertebrates, share common structure and major roles in regulating renal function. In this review the complexity of AVP actions within the mammalian kidney is discussed and comparisons are made with the emerging picture of AVT's renal effects in fish. It has become apparent that the antidiuretic action of the neurohypophysial hormones is an ancient phylogenetic phenomenon, although this is based upon reduced glomerular filtration in fish by comparison with predominant tubular effects in mammals. Nonetheless, there appears to be retention of AVP effects upon the functional heterogeneity of nephron populations in mammals. Preliminary evidence for the possible existence of V(2)-type (tubular) neurohypophysial hormone receptors in fish, implies possible AVT actions which parallel those in mammals on tubular ion transport. Further insight from recent mammalian tubule microperfusion studies suggests that in teleost fish both apical (tubular lumen) and basolateral (blood borne) AVT have the potential to modulate renal function, though this remains to be examined.     

Multiple mechanisms of phenotype development in the bluehead wrasse

Despite having detailed information on mechanisms mediating sex-typical behavior in many species, we have little understanding of whether the same mechanisms regulate these behaviors when they are performed in the same species under different social contexts. In the five field experiments of this study of bluehead wrasses (Thalassoma bifasciatum), a sex-changing fish, we examined the roles of arginine vasotocin (AVT) and the potent teleost androgen 11-ketotestosterone (11KT) in mediating sexual and aggressive behaviors typical of dominant males. We demonstrated that AVT appears necessary for the assumption of dominant territorial status in males and females, but is sufficient only in the socially dominant terminal phase (TP) male phenotype. Specifically, an AVP V(1) receptor antagonist prevented both TP males and females from gaining dominance over recently vacated territories. However, unlike TP males in a previous study, neither females nor initial phase males responded to AVT treatment with increases in display of TP male typical behaviors when under social conditions that inhibit sex change. Treating females with 11KT did not alter responsiveness to AVT, but did induce male coloration and courtship behavior that was not observed in oil-treated females. Combined with the results of a previous study, these results indicate that the ability of AVT to induce male-typical behavior differs among sexual phenotypes and that this differential responsiveness appears to be dependent on social context and not directly on exposure to 11KT. Furthermore, since 11KT can induce courtship behavior in females that is not affected by AVT, there may be different hormonal mechanisms mediating courtship behavior under different social contexts.     

Repeated agonistic encounters in hamsters modulate AVP V1a receptor binding

Arginine vasopressin (AVP) regulates aggression in male Syrian hamsters. In this study, we used radioligand receptor autoradiography to examine whether changes in agonistic behavior following acute and repeated social defeat are accompanied by changes in AVP V1a receptor binding. Social defeat produced high levels of submissive behavior and a loss of territorial aggression when hamsters were subsequently tested with a novel intruder, and repeated agonistic encounters produced similar behavioral changes in subordinates. AVP V1a receptor binding was not reduced by acute social defeat but was affected by repeated agonistic encounters. Dominants had significantly more AVP V1a receptor binding in lateral portions of the ventromedial hypothalamus (VMHL) than did their subordinate opponents, but subordinates were no different from controls. In contrast, receptor binding did not differ in most other brain regions examined. The changes in receptor binding appear to be independent of testosterone levels, as testosterone levels did not differ among dominants, subordinates, and controls. Our results suggest that changes in AVP V1a receptors do not account for the changes in agonistic behavior produced by acute social defeat but AVP V1a binding in the VMHL correlates with, and may modulate, the behavioral changes that occur following repeated experiences of victory.