The intertwining of oxytocin's effects on social affiliation and inflammation.

•Oxytocin is an ancient adaptive hormone that promotes social affiliation to maximize fitness and longevity.•Oxytocin is a multifaceted hormone that regulates stress responses at all levels of cellular organization within individuals.•Oxytocin's dual actions on sociability and inflammation highlight its powerful capacity as a modulator of human health.

Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Lasting consequences on physiology and social behavior following cesarean delivery in prairie voles.

Cesarean delivery is associated with diminished plasma levels of several 'birth-signaling' hormones, such as oxytocin and vasopressin. These same hormones have been previously shown to exert organizational effects when acting in early life. For example, our previous work found a broadly gregarious phenotype in prairie voles exposed to oxytocin at birth. Meanwhile, cesarean delivery has been previously associated with changes in social behavior and metabolic processes related to oxytocin and vasopressin. In the present study, we investigated the long-term neurodevelopmental consequences of cesarean delivery in prairie voles. After cross-fostering, vole pups delivered either via cesarean or vaginal delivery were studied throughout development. Cesarean-delivered pups responded to isolation differently in terms of their vocalizations (albeit in opposite directions in the two experiments), huddled in less cohesive groups under warmed conditions, and shed less heat. As young adults, we observed no differences in anxiety-like or alloparental behavior. However, in adulthood, cesarean-delivered voles of both sexes failed to form partner preferences with opposite sex conspecifics. In a follow-up study, we replicated this deficit in partner-preference formation among cesarean-delivered voles and were able to normalize pair-bonding behavior by treating cesarean-delivered vole pups with oxytocin (0.25 mg/kg) at delivery. Finally, we detected minor differences in regional oxytocin receptor expression within the brains of cesarean-delivered voles, as well as microbial composition of the gut. Gene expression changes in the gut epithelium indicated that cesarean-delivered male voles have altered gut development. These results speak to the possibility of unintended developmental consequences of cesarean delivery, which currently accounts for 32.9 % of deliveries in the U.S. and suggest that further research should be directed at whether hormone replacement at delivery influences behavioral outcomes in later life.

Oxytocin and oxygen: the evolution of a solution to the 'stress of life'.

Oxytocin (OT) and the OT receptor occupy essential roles in our current understanding of mammalian evolution, survival, sociality and reproduction. This narrative review examines the hypothesis that many functions attributed to OT can be traced back to conditions on early Earth, including challenges associated with managing life in the presence of oxygen and other basic elements, including sulfur. OT regulates oxidative stress and inflammation especially through effects on the mitochondria. A related nonapeptide, vasopressin, as well as molecules in the hypothalamic-pituitary-adrenal axis, including the corticotropin-releasing hormone family of molecules, have a broad set of functions that interact with OT. Interactions among these molecules have roles in the causes and consequence of social behaviour and the management of threat, fear and stress. Here, we discuss emerging evidence suggesting that unique properties of the OT system allowed vertebrates, and especially mammals, to manage over-reactivity to the 'side effects' of oxygen, including inflammation, oxidation and free radicals, while also supporting high levels of sociality and a perception of safety. This article is part of the theme issue 'Interplays between oxytocin and other neuromodulators in shaping complex social behaviours'.

The Zonulin-transgenic mouse displays behavioral alterations ameliorated via depletion of the gut microbiota.

The gut-brain axis hypothesis suggests that interactions in the intestinal milieu are critically involved in regulating brain function. Several studies point to a gut-microbiota-brain connection linking an impaired intestinal barrier and altered gut microbiota composition to neurological disorders involving neuroinflammation. Increased gut permeability allows luminal antigens to cross the gut epithelium, and via the blood stream and an impaired blood-brain barrier (BBB) enters the brain impacting its function. Pre-haptoglobin 2 (pHP2), the precursor protein to mature HP2, is the first characterized member of the zonulin family of structurally related proteins. pHP 2 has been identified in humans as the thus far only endogenous regulator of epithelial and endothelial tight junctions (TJs). We have leveraged the Zonulin-transgenic mouse (Ztm) that expresses a murine pHP2 (zonulin) to determine the role of increased gut permeability and its synergy with a dysbiotic intestinal microbiota on brain function and behavior. Here we show that Ztm mice display sex-dependent behavioral abnormalities accompanied by altered gene expression of BBB TJs and increased expression of brain inflammatory genes. Antibiotic depletion of the gut microbiota in Ztm mice downregulated brain inflammatory markers ameliorating some anxiety-like behavior. Overall, we show that zonulin-dependent alterations in gut permeability and dysbiosis of the gut microbiota are associated with an altered BBB integrity, neuroinflammation, and behavioral changes that are partially ameliorated by microbiota depletion. Our results suggest the Ztm model as a tool for the study of the cross-talk between the microbiome/gut and the brain in the context of neurobehavioral/neuroinflammatory disorders.

Altered cleavage plane orientation with increased genomic aneuploidy produced by receptor-mediated lysophosphatidic acid (LPA) signaling in mouse cerebral cortical neural progenitor cells.

The brain is composed of cells having distinct genomic DNA sequences that arise post-zygotically, known as somatic genomic mosaicism (SGM). One form of SGM is aneuploidy-the gain and/or loss of chromosomes-which is associated with mitotic spindle defects. The mitotic spindle orientation determines cleavage plane positioning and, therefore, neural progenitor cell (NPC) fate during cerebral cortical development. Here we report receptor-mediated signaling by lysophosphatidic acid (LPA) as a novel extracellular signal that influences cleavage plane orientation and produces alterations in SGM by inducing aneuploidy during murine cortical neurogenesis. LPA is a bioactive lipid whose actions are mediated by six G protein-coupled receptors, LPA1-LPA6. RNAscope and qPCR assessment of all six LPA receptor genes, and exogenous LPA exposure in LPA receptor (Lpar)-null mice, revealed involvement of Lpar1 and Lpar2 in the orientation of the mitotic spindle. Lpar1 signaling increased non-vertical cleavage in vivo by disrupting cell-cell adhesion, leading to breakdown of the ependymal cell layer. In addition, genomic alterations were significantly increased after LPA exposure, through production of chromosomal aneuploidy in NPCs. These results identify LPA as a receptor-mediated signal that alters both NPC fate and genomes during cortical neurogenesis, thus representing an extracellular signaling mechanism that can produce stable genomic changes in NPCs and their progeny. Normal LPA signaling in early life could therefore influence both the developing and adult brain, whereas its pathological disruption could contribute to a range of neurological and psychiatric diseases, via long-lasting somatic genomic alterations.

Is Oxytocin "Nature's Medicine"?

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Seasonal patterns of melatonin alter aggressive phenotypes of female Siberian hamsters.

Many animal species exhibit year-round aggression, a behaviour that allows individuals to compete for limited resources in their environment (eg, food and mates). Interestingly, this high degree of territoriality persists during the non-breeding season, despite low levels of circulating gonadal steroids (ie, testosterone [T] and oestradiol [E2 ]). Our previous work suggests that the pineal hormone melatonin mediates a 'seasonal switch' from gonadal to adrenal regulation of aggression in Siberian hamsters (Phodopus sungorus); solitary, seasonally breeding mammals that display increased aggression during the short, 'winter-like' days (SDs) of the non-breeding season. To test the hypothesis that melatonin elevates non-breeding aggression by increasing circulating and neural steroid metabolism, we housed female hamsters in long days (LDs) or SDs, administered them timed or mis-timed melatonin injections (mimic or do not mimic a SD-like signal, respectively), and measured aggression, circulating hormone profiles and aromatase (ARO) immunoreactivity in brain regions associated with aggressive or reproductive behaviours (paraventricular hypothalamic nucleus [PVN], periaqueductal gray [PAG] and ventral tegmental area [VTA]). Females that were responsive to SD photoperiods (SD-R) and LD females given timed melatonin injections (Mel-T) exhibited gonadal regression and reduced circulating E2 , but increased aggression and circulating dehydroepiandrosterone (DHEA). Furthermore, aggressive challenges differentially altered circulating hormone profiles across seasonal phenotypes; reproductively inactive females (ie, SD-R and Mel-T females) reduced circulating DHEA and T, but increased E2 after an aggressive interaction, whereas reproductively active females (ie, LD females, SD non-responder females and LD females given mis-timed melatonin injections) solely increased circulating E2 . Although no differences in neural ARO abundance were observed, LD and SD-R females showed distinct associations between ARO cell density and aggressive behaviour in the PVN, PAG and VTA. Taken together, these results suggest that melatonin increases non-breeding aggression by elevating circulating steroid metabolism after an aggressive encounter and by regulating behaviourally relevant neural circuits in a region-specific manner.

Neonatal immune challenge induces female-specific changes in social behavior and somatostatin cell number.

Decreases in social behavior are a hallmark aspect of acute "sickness behavior" in response to infection. However, immune insults that occur during the perinatal period may have long-lasting consequences for adult social behavior by impacting the developmental organization of underlying neural circuits. Microglia, the resident immune cells of the central nervous system, are sensitive to immune stimulation and play a critical role in the developmental sculpting of neural circuits, making them likely mediators of this process. Here, we investigated the impact of a postnatal day (PND) 4 lipopolysaccharide (LPS) challenge on social behavior in adult mice. Somewhat surprisingly, neonatal LPS treatment decreased sociability in adult female, but not male mice. LPS-treated females also displayed reduced social interaction and social memory in a social discrimination task as compared to saline-treated females. Somatostatin (SST) interneurons within the anterior cingulate cortex (ACC) have recently been suggested to modulate a variety of social behaviors. Interestingly, the female-specific changes in social behavior observed here were accompanied by an increase in SST interneuron number in the ACC. Finally, these changes in social behavior and SST cell number do not appear to depend on microglial inflammatory signaling, because microglia-specific genetic knock-down of myeloid differentiation response protein 88 (MyD88; the removal of which prevents LPS from increasing proinflammatory cytokines such as TNFα and IL-1ß) did not prevent these LPS-induced changes. This study provides novel evidence for enduring effects of neonatal immune activation on social behavior and SST interneurons in females, largely independent of microglial inflammatory signaling.

The inflammatory event of birth: How oxytocin signaling may guide the development of the brain and gastrointestinal system.

The role of oxytocin (OT) as a neuropeptide that modulates social behavior has been extensively studied and reviewed, but beyond these functions, OT's adaptive functions at birth are quite numerous, as OT coordinates many physiological processes in the mother and fetus to ensure a successful delivery. In this review we explore in detail the potential adaptive roles of oxytocin as an anti-inflammatory, protective molecule at birth for the developing fetal brain and gastrointestinal system based on evidence that birth is a potent inflammatory/immune event. We discuss data with relevance for a number of neurodevelopmental disorders, as well as the emerging role of the gut-brain axis for health and disease. Finally, we discuss the potential relevance of sex differences in OT signaling present at birth in the increased male vulnerability to neurodevelopmental disabilities.

Mitochondria, Oxytocin, and Vasopressin: Unfolding the Inflammatory Protein Response.

Neuroendocrine and immune signaling pathways are activated following insults such as stress, injury, and infection, in a systemic response aimed at restoring homeostasis. Mitochondrial metabolism and function have been implicated in the control of immune responses. Commonly studied along with mitochondrial function, reactive oxygen species (ROS) are closely linked to cellular inflammatory responses. It is also accepted that cells experiencing mitochondrial or endoplasmic reticulum (ER) stress induce response pathways in order to cope with protein-folding dysregulation, in homeostatic responses referred to as the unfolded protein responses (UPRs). Recent reports indicate that the UPRs may play an important role in immune responses. Notably, the homeostasis-regulating hormones oxytocin (OXT) and vasopressin (AVP) are also associated with the regulation of inflammatory responses and immune function. Intriguingly, OXT and AVP have been linked with ER unfolded protein responses (UPRER), and can impact ROS production and mitochondrial function. Here, we will review the evidence for interactions between these various factors and how these neuropeptides might influence mitochondrial processes.

Neural responses to familiar conspecifics are modulated by a nonapeptide receptor in a winter flocking sparrow.

The social behavior network, a collection of reciprocally connected areas within the basal forebrain and midbrain, plays a conserved role in the regulation of vertebrate social behavior. Specific behaviors are associated with patterns of activity across the network, and these activity profiles vary with species and context. We investigated how the social behavior network responds to familiar social stimuli in a seasonally flocking songbird. Further, we explored how socially-induced neural responses are modulated by endogenous nonapeptide receptor blockade. Winter flocking dark-eyed juncos were exposed to either familiar conspecifics or a familiar empty aviary following a peripheral injection of either saline or [desGly-NH2,d(CH2)5, Tyr(Me)2,Thr4]-ornithine vasotocin, an VT3 receptor antagonist. Socially-exposed animals exhibited greater Fos induction across the social behavior network. Sex and drug effects were site-specific, with females tending to exhibit greater Fos responses to social stimuli and a greater sensitivity to VT3 antagonism. We suggest that in flocking animals, VT3 activation during social interaction may shift the pattern of neural activity towards the dorsocaudal lateral septum and rostral arcopallium and away from the extended amygdala, anterior and ventromedial hypothalamus, and the caudal ventral/ventrolateral lateral septum.

The Role of VIP in Social Behavior: Neural Hotspots for the Modulation of Affiliation, Aggression, and Parental Care.

Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core "social behavior network" (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural "hotspots" in the SBN that relate to avian affiliative behavior, as well as neural "hotspots" that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus-caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential "hotspots" for the modulation of affiliation, aggression, and parental care.

Seasonal Variation in Group Size Is Related to Seasonal Variation in Neuropeptide Receptor Density.

In many species, seasonal variation in grouping behavior is widespread, with shifts towards territoriality in the breeding season and grouping in the winter. Compared to the hormonal and neural mechanisms of seasonal territorial aggression, the mechanisms that promote seasonal grouping have received little attention. We collected brains in spring and winter from wild-caught males of two species of emberizid sparrows that seasonally flock (the field sparrow, Spizella pusilla, and the dark-eyed junco, Junco hyemalis) and two species that do not seasonally flock (the song sparrow, Melospiza melodia, and the eastern towhee, Pipilo erythrophthalmus). We used receptor autoradiography to quantify seasonal plasticity in available binding sites for three neuropeptides known to influence social behavior. We examined binding sites for 125I-vasoactive intestinal polypeptide (VIP), 125I-sauvagine (SG, a ligand for corticotropin-releasing hormone receptors) and 125I-ornithine vasotocin analog (OVTA, a ligand for the VT3 nonapeptide). For all species and ligands, brain areas that exhibited a seasonal pattern in binding density were characterized by a winter increase. Compared to nonflocking species, seasonally flocking species showed different binding patterns in multiple brain areas. Furthermore, we found that winter flocking was associated with elevated winter 125I-VIP binding density in the medial amygdala, as well as 125I-VIP and 125I-OVTA binding density in the rostral arcopallium. While the functional significance of the avian rostral arcopallium is unclear, it may incorporate parts of the pallial amygdala. Our results point to this previously undescribed area as a likely hot spot of social modulation.

Oxytocin mechanisms of stress response and aggression in a territorial finch.

All jawed vertebrates produce a form of oxytocin (OT), and in birds, mammals and fish, OT is strongly associated with affiliation. However, remarkably few data are available on the roles of OT and OT receptors (OTRs) in aggression. Because OT and OTRs exert anxiolytic effects in mammals (although context-specific) and modulate stress coping, we hypothesized that OTR activation is at least permissive for territorial aggression. Indeed, we find that peripheral injections of an OTR antagonist significantly reduce male-male and female-female aggression in a highly territorial finch. This finding suggests the hypothesis that aggression is accompanied by an increase in transcriptional (Fos) activity of OT neurons, but contrary to this hypothesis, we find that dominant male residents do not elevate OT-Fos colocalization following an aggressive encounter and that OT-Fos colocalization in the preoptic area and hypothalamus correlates negatively with aggression. Furthermore, OT-Fos colocalization increases dramatically in males that were aggressively subjugated or pursued by a human hand, likely reflecting OT modulation of stress response. Because OT inhibits the hypothalamo-pituitary-adrenal axis, the antagonist effects may reflect the fact that aggressive birds and mammals tend to be hyporesponsive to stress. If this is correct, then 1) the observed effects of OTR antagonism may reflect alterations in corticosterone feedback to the brain rather than centrally mediated OTR effects, and 2) the negative correlation between OT-Fos colocalization and aggression may reflect the fact that more aggressive, stress hyporesponsive males require less inhibition of the hypothalamo-pituitary-adrenal axis than do less aggressive males, despite the requirement of that inhibition for the normal display of aggression.

Nesting behavior is associated with VIP expression and VIP-Fos colocalization in a network-wide manner.

Many species, including humans, engage in a series of behaviors that are preparatory to the arrival of offspring. Such "nesting behaviors" are of obvious importance, but relevant neuroendocrine mechanisms remain little studied. We here focus on the potential roles of vasoactive intestinal polypeptide (VIP) in the performance of appetitive and consummatory nesting behaviors in male and female zebra finches (Taeniopygia guttata). Using combined immunocytochemistry for Fos and in situ hybridization for VIP, we now show that many VIP cell groups show increased transcriptional activity in response to nest building in male and female zebra finches. Particularly strong data come from the preoptic area (medial preoptic area and medial preoptic nucleus), where VIP-Fos co-expression correlates positively with three different measures of nesting behavior, as does the number of VIP-expressing cells. Remarkably, we find that VIP mRNA and/or VIP-Fos co-expression is correlated with nesting behavior in virtually every brain area that we examined, including the medial amygdala (anterior and posterior), medial bed nucleus of the stria terminalis, medial preoptic area, medial preoptic nucleus, anterior hypothalamus, ventromedial hypothalamus, periaqueductal gray complex (central gray and nucleus intercollicularis), and ventral tegmental area. Near-significant effects are also obtained in the tuberoinfundibular hypothalamus. Although most correlations are positive, negative correlations are observed for the VIP cell group of the anterior hypothalamus, a population that selectively promotes aggression, and also the periaqueductal gray complex. These data demonstrate a network-wide relationship between peptide production and social behavior that is, to our knowledge, unparalleled by other peptidergic modulators.

New perspectives on vasoactive intestinal polypeptide as a widespread modulator of social behavior.

In terms of reproductive and social functions, vasoactive intestinal polypeptide (VIP) is best known as a major regulator of prolactin secretion in vertebrates and hence, as an essential contributor to parental care. However, VIP and its cognate VPAC receptors are distributed throughout the social behavior network in the brain, suggesting that VIP circuits may play important roles in a variety of behaviors. With the exception of VIP neuronal populations in the suprachiasmatic nucleus and tuberal hypothalamus (which regulate circadian rhythms and prolactin secretion, respectively), we have known very little about the functional properties of VIP circuits until recently. The present review highlights new roles for VIP signaling in avian social behaviors such as affiliation, gregariousness, pair bonding and aggression, and discusses recent advances in VIP's role as a regulator of biological rhythms, including the potential timing of ovulation, photoperiodic response and seasonal migration.

Pair bond formation is impaired by VPAC receptor antagonism in the socially monogamous zebra finch.

A variety of recent data demonstrate that vasoactive intestinal polypeptide (VIP) and VPAC receptors (which bind VIP, and to a lesser extent, pituitary adenylatecyclase activating peptide) are important for numerous social behaviors in songbirds, including grouping and aggression, although VIP relates to these behaviors in a site-specific manner. In order to determine the global effects of central VPAC receptor activation on social behavior, we here infused a VPAC receptor antagonist or vehicle twice daily into the lateral ventricle of colony-housed male and female zebra finches and quantified a wide range of behaviors. Aggressive behaviors were not altered by ventricular infusions, consistent with known opposing, site-specific relationships of VIP innervation to aggression. Courtship and self-maintenance behaviors were likewise not altered. However, VPAC antagonism produced significant deficits in pair bonding. Antagonist subjects took longer to form a pair bond and were paired for significantly fewer observation sessions relative to control subjects (median 1.5 of 6 observation sessions for antagonist subjects versus 4 for control subjects). Antagonist subjects were also significantly less likely to be paired in the final observation session. Based on the known distribution of VPAC receptors in finches and other vertebrates, we propose that VPAC receptors may mediate pair bonding via a variety of brain areas that are known to be important for the establishment of partner preferences in voles, including the lateral septum, ventral tegmental area, nucleus accumbens and ventral pallidum.

VPAC receptor signaling modulates grouping behavior and social responses to contextual novelty in a gregarious finch: a role for a putative prefrontal cortex homologue.

In both mammals and birds, vasoactive intestinal polypeptide (VIP) neurons and fibers are present in virtually every brain area that is important for social behavior. VIP influences aggression in birds, social recognition in rodents, and prolactin secretion in both taxa, but other possible functions in social modulation remain little explored. VIP effects are mediated by VPAC receptors, which bind both VIP and pituitary adenylate cyclase activating peptide. Within the lateral septum and medial bed nucleus of the stria terminalis, VPAC receptors are found at higher densities in gregarious finch species relative to territorial species, suggesting that VPAC receptor activation promotes social contact and/or preference for larger groups. Here we here test this hypothesis in zebra finches (Taeniopygia guttata), and also examine the relevance of VPAC receptors to anxiety-like processes. Intraventricular infusions of the VPAC receptor antagonist, neurotensin6-11 mouseVIP7-28, strongly reduce social contact when animals are tested in a novel environment, and exert sex-specific effects on grouping behavior. Specifically, VPAC receptor antagonism reduces gregariousness in females but increases gregariousness in males. Interestingly, VPAC antagonism in the medial pallium (putative prefrontal cortex homologue) significantly reduces gregariousness in both sexes, suggesting site-specific effects of VIP signaling. However, VPAC antagonism does not modulate novel-familiar social preferences in a familiar environment or general anxiety-like behaviors. The current results suggest that endogenous activation of VPAC receptors promotes social contact under novel environmental conditions, a function that may be accentuated in gregarious species. Moreover, endogenous VIP modulates gregariousness in both males and females.

What's in a name? Considerations of homologies and nomenclature for vertebrate social behavior networks.

Behavioral neuroendocrinology is an integrative discipline that spans a wide range of taxa and neural systems, and thus the appropriate designation of homology (sameness) across taxa is critical for clear communication and extrapolation of findings from one taxon to another. In the present review we address issues of homology that relate to neural circuits of social behavior and associated systems that mediate reward and aversion. We first address a variety of issues related to the so-called "social behavior network" (SBN), including homologies that are only partial (e.g., whereas the preoptic area of fish and amphibians contains the major vasopressin-oxytocin cell groups, these populations lie in the hypothalamus of other vertebrates). We also discuss recent evidence that clarifies anterior hypothalamus and periaqueductal gray homologies in birds. Finally, we discuss an expanded network model, the "social decision-making network" (SDM) which includes the mesolimbic dopamine system and other structures that provide an interface between the mesolimbic system and the SBN. This expanded model is strongly supported in mammals, based on a wide variety of evidence. However, it is not yet clear how readily the SDM can be applied as a pan-vertebrate model, given insufficient data on numerous proposed homologies and a lack of social behavior data for SDM components (beyond the SBN nodes) for amphibians, reptiles or fish. Functions of SDM components are also poorly known for birds. Nonetheless, we contend that the SDM model provides a very sound and important framework for the testing of many hypotheses in nonmammalian vertebrates.