Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities?

BACKGROUND: There is substantial evidence for sex differences in the functioning of one of the most common receptor systems; G protein-coupled receptors (GPCRs). There are many points along the GPCR-mediated molecular signaling pathway at which males and females may differ, one of the first of which, chronologically, is in the stability of the interaction between the ligand and the receptor, or its binding affinity. Here we investigate the binding affinities of oxytocin (OT) and vasopressin (AVP) at the oxytocin receptor (OTR) and the vasopressin V1a receptor (V1aR), both of which are present in numerous in brain regions associated with social behavior. METHOD: In order to investigate sex- and estrous cycle-dependent differences in ligand-receptor binding affinity, male (n = 6) Syrian hamsters (Mesocricetus auratus), females on the day of estrus (E females, n = 6), and females on the second day of diestrus (D2 females n = 6) were chosen for study. Brains from hamsters were mounted on slides and competition and saturation binding assays were conducted. RESULTS: We report a remarkable similarity in the binding affinities of OT and AVP in males and females. Small differences were detected, however, in receptor and ligand specificity in females depending on whether they were in the estrous or diestrous stage of their ovulatory cycle. CONCLUSION: These data suggest that sex differences in binding affinity are not a likely source of the many sex differences that have been observed in the effects of OT and AVP in hamsters and other species.

Sex-dependent regulation of social avoidance by oxytocin signaling in the ventral tegmental area.

It has been hypothesized that oxytocin increases the salience of social stimuli, whether the valence is positive or negative, through its interactions with the ventral tegmental area (VTA). Indeed, oxytocin neurons project to the VTA and activate dopamine neurons that are necessary for social experiences with positive valence. Surprisingly, though, there has not been an investigation of the role of oxytocin in the VTA in mediating social experiences with negative valence (e.g., social stress). Given that there are sex differences in how oxytocin regulates the salience of positively-valenced social interactions, we hypothesized that oxytocin acting in the VTA also alters the salience of social stress in a sex-dependent manner. To test this, female and male Syrian hamsters were site-specifically infused with either saline, oxytocin (9 µM), or oxytocin receptor antagonist (90 µM) into the VTA. Subjects were then exposed to either no defeat or a single, 15 min defeat by one RA. The day following social defeat, subjects underwent a 5 min social avoidance test. There was an interaction between sex and drug treatment, such that the oxytocin antagonist increased social avoidance compared to saline treatment in socially stressed females, while oxytocin decreased social avoidance compared to saline treatment in socially stressed males. Contrary to expectations, these results suggest that oxytocin signaling generally acts to decrease social avoidance, regardless of sex. These sex differences in the efficacy of oxytocin and oxytocin receptor antagonists to alter negatively-valenced social stimuli, however, should be considered when guiding pharmacotherapies for disorders involving social deficits.

Sex differences in the impact of social status on social reward and associated mesolimbic activation.

Social stress plays an important role in the etiology of many neuropsychiatric disorders and can lead to a variety of behavioral deficits such as social withdrawal. One way that social stress may contribute to psychiatric disorders is by reducing social motivation and the rewarding properties of social interactions. We investigated the impact of social stress on social reward in the context of winning versus losing agonistic encounters in Syrian hamsters (Mesocricetus auratus). First, we tested the hypothesis that social stress resulting from either stable low, or subordinate, social status or from social defeat reduces the rewarding properties of social interactions. Using an Operant Social Preference (OSP) task to measure social reward/motivation, we found that both subordinate and socially defeated males made significantly fewer entries into chambers containing novel, same-sex conspecifics compared to males who were dominant (i.e., stably won the agonistic encounters). In females, however, there were no differences in social entries between winners and losers. In a second experiment, we found more activation of the mesolimbic dopamine system (MDS) as assessed with cFos immunohistochemistry in the lateral ventral tegmental area (lVTA) and the nucleus accumbens (NAc) shell of male winners compared to losers. In females, however, there were no differences in activation in the lVTA between winners and losers. Surprisingly, however, winning females displayed significantly more activation in the NAc shell as compared to losing females, despite the lack of behavioral differences. Thus, behavioral and histological data suggest that there are sex differences in the impact of social status on social reward and associated mesolimbic activation.

Embedded macrophages induce intravascular coagulation in 3D blood vessel-on-chip.

Macrophages are innate immune cells that prevent infections and help in wound healing and vascular inflammation. While these cells are natural helper cells, they also contribute to chronic diseases, e.g., by infiltrating the endothelial layer in early atherosclerosis and by promoting vascular inflammation. There is a crosstalk between inflammatory pathways and key players in thrombosis, such as platelets and endothelial cells - a phenomenon known as 'thromboinflammation'. The role of the embedded macrophages in thromboinflammation in the context of vascular disease is incompletely understood. Blood vessels-on-chips, which are microfluidic vascular cell culture models, have been used extensively to study aspects of vascular disease, like permeability, immune cell adhesion and thrombosis. Blood perfusion assays in blood vessel-on-chip models benefit from multiple unique aspects of the models, such as control of microvessel structure and well-defined flow patterns, as well as the ability to perform live imaging. However, due to their simplified nature, blood vessels-on-chip models have not yet been used to capture the complex cellular crosstalk that is important in thromboinflammation. Using induced pluripotent stem cell-derived endothelial cells and polarized THP-1 monocytes, we have developed and systematically set up a 3D blood vessel-on-chip with embedded (lipid-laden) macrophages, which is created using sequential cell seeding in viscous finger patterned collagen hydrogels. We have set up a human whole blood perfusion assay for these 3D blood vessels-on-chip. An increased deposition of fibrin in the blood vessel-on-chip models containing lipid-laden macrophages was observed. We anticipate the future use of this advanced vascular in vitro model in drug development for early atherosclerosis or aspects of other vascular diseases.

Distribution of Vasopressin 1a and Oxytocin Receptor Binding in the Basal Forebrain and Midbrain of Male and Female Mongolian Gerbils.

The nonapeptide system modulates a diversity of social behaviors, including aggression, parental care, affiliation, sexual behavior, and pair bonding. Such social behaviors are regulated through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin V1a receptor (AVPR1A) in the brain. Nonapeptide receptor distributions have been mapped for several species, however, studies have demonstrated that there is substantial variation across species. Mongolian gerbils (Meriones unguiculatus) are an excellent organism for studying family dynamics, social development, pair bonding, and territorial aggression. Although an increasing number of studies are examining the neural mechanisms of social behavior in Mongolian gerbils, nonapeptide receptor distributions have yet to be characterized for this species. Here we conducted receptor autoradiography to map distributions of OXTR and AVPR1A binding throughout the basal forebrain and midbrain of female and male Mongolian gerbils. Further, we assessed whether gonadal sex influenced binding densities in brain regions important for social behavior and reward, however, we observed no effects of sex on OXTR or AVPR1A binding densities. These findings provide mapping distributions of nonapeptide receptors in male and female Mongolian gerbils, laying a foundation for future studies that seek to manipulate the nonapeptide system to examine nonapeptide-mediated social behavior.

An AAV-CRISPR/Cas9 strategy for gene editing across divergent rodent species: Targeting neural oxytocin receptors as a proof of concept.

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches, we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.

On the adsorption and reactivity of element 114, flerovium.

Flerovium (Fl, element 114) is the heaviest element chemically studied so far. To date, its interaction with gold was investigated in two gas-solid chromatography experiments, which reported two different types of interaction, however, each based on the level of a few registered atoms only. Whereas noble-gas-like properties were suggested from the first experiment, the second one pointed at a volatile-metal-like character. Here, we present further experimental data on adsorption studies of Fl on silicon oxide and gold surfaces, accounting for the inhomogeneous nature of the surface, as it was used in the experiment and analyzed as part of the reported studies. We confirm that Fl is highly volatile and the least reactive member of group 14. Our experimental observations suggest that Fl exhibits lower reactivity towards Au than the volatile metal Hg, but higher reactivity than the noble gas Rn.

Alpha-melanocyte-stimulating hormone (αMSH) modulates the rewarding properties of social interactions in an oxytocin receptor-dependent manner in Syrian hamsters (Mesocricetus Auratus).

A reduction in the rewarding properties of social interactions is frequently a key contributor to neuropsychiatric disorders. Although much remains to be learned about the neural mechanisms governing social reward, numerous studies have found that oxytocin can enhance the salience of rewarding social interactions. As a result, oxytocin has been suggested as a pharmacotherapy for disorders characterized by a dampening of social motivation. However, exogenous oxytocin does not cross the blood-brain barrier effectively, which has led to the investigation of alternative approaches to induce central oxytocin release, such as pharmaceuticals targeting melanocortins. Although oxytocin treatment is widely viewed to increase social reward, there is also recent evidence that high concentrations of oxytocin can decrease social reward. In the present study we tested the hypothesis that alpha-melanocyte-stimulating hormone (αMSH) influences the rewarding properties of social interactions by acting on oxytocin receptors. Male and female Syrian hamsters were given intracerebroventricular infusions of saline, αMSH, or a cocktail containing αMSH and an oxytocin receptor antagonist during social conditioning with a same-sex hamster and then tested for a conditioned place preference. αMSH decreased preference for the socially-paired chamber compared to saline treatment, and administration of the oxytocin antagonist concurrent with αMSH administration returned subjects' preference to control levels. Importantly, αMSH treatments did not affect any measures of body composition or the specific social behaviors displayed during conditioning. These data suggest that melanocortin-targeting drugs should be administered carefully to avoid the possibility of decreasing the rewarding properties of social interactions.

CRISPR-Cas9 editing of the arginine-vasopressin V1a receptor produces paradoxical changes in social behavior in Syrian hamsters.

Studies from a variety of species indicate that arginine­vasopressin (AVP) and its V1a receptor (Avpr1a) play a critical role in the regulation of a range of social behaviors by their actions in the social behavior neural network. To further investigate the role of AVPRs in social behavior, we performed CRISPR-Cas9­mediated editing at the Avpr1a gene via pronuclear microinjections in Syrian hamsters (Mesocricetus auratus), a species used extensively in behavioral neuroendocrinology because they produce a rich suite of social behaviors. Using this germ-line gene-editing approach, we generated a stable line of hamsters with a frame-shift mutation in the Avpr1a gene resulting in the null expression of functional Avpr1as. Avpr1a knockout (KO) hamsters exhibited a complete lack of Avpr1a-specific autoradiographic binding throughout the brain, behavioral insensitivity to centrally administered AVP, and no pressor response to a peripherally injected Avpr1a-specific agonist, thus confirming the absence of functional Avpr1as in the brain and periphery. Contradictory to expectations, Avpr1a KO hamsters exhibited substantially higher levels of conspecific social communication (i.e., odor-stimulated flank marking) than their wild-type (WT) littermates. Furthermore, sex differences in aggression were absent, as both male and female KOs exhibited more aggression toward same-sex conspecifics than did their WT littermates. Taken together, these data emphasize the importance of comparative studies employing gene-editing approaches and suggest the startling possibility that Avpr1a-specific modulation of the social behavior neural network may be more inhibitory than permissive.

Sex and social status modify the effects of fluoxetine on socioemotional behaviors in Syrian hamsters and rhesus macaques.

Social subordination increases risk for psychiatric disorders, while dominance increases resilience to these disorders. Fluoxetine, a selective serotonin (5HT) reuptake inhibitor whose actions are mediated in part by the 5HT1A receptor (5HT1AR), has sex- and social status-specific effects on socioemotional behavior and aggressive behavior. However, the impact of social status on these sex-specific effects remains unclear. The current study evaluated the impact of acute fluoxetine treatment and social status on dominance-related behaviors in female and male hamsters, and the impact of chronic fluoxetine treatment on socioemotional behavior and 5HT1AR binding potential (5HT1ARBP) in female rhesus macaques. We hypothesized that sex differences in the effects of fluoxetine on aggression in hamsters would be diminished in dominant and enhanced in subordinate males and that aggression in female hamsters would be enhanced in dominants and diminished in subordinates. In female rhesus macaques, we hypothesized that chronic fluoxetine would alter socioemotional behaviors and site-specific 5HT1ARBP in a status-dependent manner. Male (n = 46) and female (n = 56) hamsters were paired with conspecifics for three days to establish social rank. Hamsters received a single dose of 20 mg/kg fluoxetine or vehicle two-hours prior to a test with a non-aggressive intruder. Female rhesus monkeys (n = 14) housed were administered fluoxetine (2.8 mg/kg/day) or vehicle injections chronically for 14-days, separated by a three-week washout period. On Day 15, positron emission tomography neuroimaging for 5HT1ARBP was conducted. Fluoxetine treatment decreased aggression in subordinate female monkeys and subordinate female hamsters but not in dominant females of either species. Fluoxetine decreased aggression in dominant but not in subordinate male hamsters. Fluoxetine also reduced and increased prefrontal 5HT1ARBP in dominant and subordinate females, respectively. Taken together, these results provide cross-species evidence that social status and sex impact how increased 5HT modulates agonistic behavior.

Acute administration of fluoxetine increases social avoidance and risk assessment behaviors in a sex- and social stress-dependent manner in Syrian hamsters (Mesocricetus auratus).

Most studies investigating the effects of acute administration of selective serotonin reuptake inhibitors (SSRI) on responses to social stress have been conducted with males. This is despite the fact that SSRIs remain the primary pharmacotherapy for social stress-related disorders for both sexes and that the prevalence of these disorders is twofold higher in women than in men. To determine whether acute treatment with the SSRI, fluoxetine, alters behavioral responses to social defeat stress in a sex- or social stress-dependent manner, male and female Syrian hamsters were subjected to one of three social defeat conditions: no defeat (placed into an empty resident aggressor (RA) cage), a single defeat by one RA for 15 min, or three consecutive defeats using different RAs for 5 min each. The day following social defeat, subjects were infused with either vehicle or fluoxetine (20 mg/kg, I.P.) 2 h prior to a 5 min social avoidance test. Overall, we found that fluoxetine increased social vigilance regardless of sex or defeat condition. We also found that fluoxetine affected social avoidance in a sex by stress intensity interaction, such that fluoxetine increased avoidance in no defeat males and in males defeated once but significantly increased avoidance in females only after three defeats. These data suggest that treatment with an SSRI could initially exacerbate the effects of social stress in both sexes. These data also emphasize the importance of including sex as a biological variable when investigating the efficacy of pharmacotherapy for stress-related disorders.

Spectroscopy along Flerovium Decay Chains: Discovery of

A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions ^{48}Ca+^{242}Pu and ^{48}Ca+^{244}Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to ^{286}Fl and ^{288}Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely ^{282}Cn. Spectroscopy of ^{288}Fl decay chains fixed Q_{α}=10.06(1) MeV. In one case, a Q_{α}=9.46(1)-MeV decay from ^{284}Cn into ^{280}Ds was observed, with ^{280}Ds fissioning after only 518 µs. The impact of these findings, aggregated with existing data on decay chains of ^{286,288}Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.

Estrogen Withdrawal Increases Postpartum Anxiety via Oxytocin Plasticity in the Paraventricular Hypothalamus and Dorsal Raphe Nucleus.

BACKGROUND: Estrogen increases dramatically during pregnancy but quickly drops below prepregnancy levels at birth and remains suppressed during the postpartum period. Clinical and rodent work suggests that this postpartum drop in estrogen results in an estrogen withdrawal state that is related to changes in affect, mood, and behavior. How estrogen withdrawal affects oxytocin (OT) neurocircuitry has not been examined. METHODS: We used a hormone-simulated pseudopregnancy followed by estrogen withdrawal in Syrian hamsters, a first for this species. Ovariectomized females were given daily injections to approximate hormone levels during gestation and then withdrawn from estrogen to simulate postpartum estrogen withdrawal. These hamsters were tested for behavioral assays of anxiety and anhedonia during estrogen withdrawal. Neuroplasticity in OT-producing neurons in the paraventricular nucleus of the hypothalamus and its efferent targets was measured. RESULTS: Estrogen-withdrawn females had increased anxiety-like behaviors in the elevated plus maze and open field tests but did not differ from control females in sucrose preference. Furthermore, estrogen-withdrawn females had more OT-immunoreactive cells and OT messenger RNA in the paraventricular nucleus of the hypothalamus and an increase in OT receptor density in the dorsal raphe nucleus. Finally, blocking OT receptors in the dorsal raphe nucleus during estrogen withdrawal prevented the high-anxiety behavioral phenotype in estrogen-withdrawn females. CONCLUSIONS: Estrogen withdrawal induces OT neuroplasticity in the paraventricular nucleus of the hypothalamus and dorsal raphe nucleus to increase anxiety-like behavior during the postpartum period. More broadly, these experiments suggest Syrian hamsters as a novel organism in which to model the effects of postpartum estrogen withdrawal on the brain and anxiety-like behavior.

Sex-dependent effects of social status on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT), and serotonin (5-HT) 1A receptor binding and aggression in Syrian hamsters (Mesocricetus auratus).

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.

Search for Electron-Capture Delayed Fission in the New Isotope

The electron-capture decay followed by a prompt fission process was searched for in the hitherto unknown most neutron-deficient Md isotope with mass number 244. Alpha decay with α-particle energies of 8.73-8.86 MeV and with a half-life of 0.30_{-0.09}^{+0.19} s was assigned to ^{244}Md. No fission event with a similar half-life potentially originating from spontaneous fissioning of the short-lived electron-capture decay daughter ^{244}Fm was observed, which results in an upper limit of 0.14 for the electron-capture branching of ^{244}Md. Two groups of fission events with half-lives of 0.9_{-0.3}^{+0.6} ms and 5_{-2}^{+3} ms were observed. The 0.9_{-0.3}^{+0.6} ms activity was assigned to originate from the decay of ^{245}Md. The origin of eight fission events resulting in a half-life of 5_{-2}^{+3} ms could not be unambiguously identified within the present data while the possible explanation has to invoke previously unseen physics cases.

Binding affinities of oxytocin, vasopressin and Manning compound at oxytocin and V1a receptors in male Syrian hamster brains.

Oxytocin (OT) and arginine vasopressin (AVP), as well as synthetic ligands targeting their receptors (OTR, V1aR), are used in a wide variety of research contexts, although their pharmacological properties are determined in only a few species. Syrian hamsters (Mesocricetus auratus) have a long history of use as a behavioural and biomedical model for the study of OT and AVP and, more recently, hamsters have been used to investigate behavioural consequences of OT-mediated activation of V1aR. We aimed to determine the binding affinities of OT, AVP and the selective V1aR antagonist, Manning compound, for OTR and V1aR in hamster brains. We performed saturation binding assays to determine the Kd values for the selective OTR and V1aR radioligands, [125 I]ornithine vasotocin analogue and [125 I]linear vasopressin antagonist. We then performed competition binding assays to determine Ki values for OT, AVP and Manning compound at both the OTR and V1aR. We found that OT and AVP each had the highest affinity for their canonical receptors (OT-OTR Ki = 4.28 [95% confidence interval (CI) = 2.9-6.3] nmol L-1 ; AVP-V1ar Ki = 4.70 [95% CI = 1.5-14.1] nmol L-1 ) and had the lowest affinity for their non-canonical ligands (OT-V1aR = 495.2 [95% CI = 198.5-1276] nmol L-1 ; AVP-OTR Ki = 36.1 [95% CI = 12.4-97.0] nmol L-1 ). Manning compound had the highest affinity for the V1aR (MC-V1aR Ki = 6.87 [95% CI = 4.0-11.9] nmol L-1 ; MC-OTR Ki = 213.8 [95% CI = 117.3-392.7] nmol L-1 ), although Manning compound was not as selective for the V1aR in hamsters as has been reported for the receptor in rats. When comparing these data with previously published work, we found that the promiscuity of the V1aR in hamsters with respect to OT and AVP binding is more similar to the promiscuity of the human V1aR than to the rat V1aR receptor. Moreover, the selectivity of OT at hamster receptors is more similar to the selectivity of OT at human receptors than the selectivity of OT at rat receptors. These data highlight the importance of determining the pharmacological properties of behaviourally relevant compounds in diverse model species.

The Excitatory Effects of GABA within the Suprachiasmatic Nucleus: Regulation of Na-K-2Cl Cotransporters (NKCCs) by Environmental Lighting Conditions.

The suprachiasmatic nucleus (SCN) contains a pacemaker that generates circadian rhythms and entrains them with the 24-h light-dark cycle (LD). The SCN is composed of 16,000 to 20,000 heterogeneous neurons in bilaterally paired nuclei. γ-amino butyric acid (GABA) is the primary neurochemical signal within the SCN and plays a key role in regulating circadian function. While GABA is the primary inhibitory neurotransmitter in the brain, there is now evidence that GABA can also exert excitatory effects in the adult brain. Cation chloride cotransporters determine the effects of GABA on chloride equilibrium, thereby determining whether GABA produces hyperpolarizing or depolarizing actions following activation of GABAA receptors. The activity of Na-K-2Cl cotransporter1 (NKCC1), the most prevalent chloride influx cotransporter isoform in the brain, plays a critical role in determining whether GABA has depolarizing effects. In the present study, we tested the hypothesis that NKCC1 protein expression in the SCN is regulated by environmental lighting and displays daily and circadian changes in the intact circadian system of the Syrian hamster. In hamsters housed in constant light (LL), the overall NKCC1 immunoreactivity (NKCC1-ir) in the SCN was significantly greater than in hamsters housed in LD or constant darkness (DD), although NKCC1 protein levels in the SCN were not different between hamsters housed in LD and DD. In hamsters housed in LD cycles, no differences in NKCC1-ir within the SCN were observed over the 24-h cycle. NKCC1 protein in the SCN was found to vary significantly over the circadian cycle in hamsters housed in free-running conditions. Overall, NKCC1 protein was greater in the ventral SCN than in the dorsal SCN, although no significant differences were observed across lighting conditions or time of day in either subregion. These data support the hypothesis that NKCC1 protein expression can be regulated by environmental lighting and circadian mechanisms within the SCN.

Social experience and sex-dependent regulation of aggression in the lateral septum by extrasynaptic δGABAA receptors.

RATIONALE: Understanding the neurobiological mechanisms mediating dominance and competitive aggression is essential to understanding the development and treatment of various psychiatric disorders. Previous research suggests that these mechanisms are both sexually differentiated and influenced substantially by social experience. In numerous species, GABAA receptors in the lateral septum have been shown to play a significant role in aggression in males. However, very little is known about the role of these GABAA receptors in female aggression, the role of social experience on GABAA receptor-mediated aggression, or the roles of different GABAA subtypes in regulating aggression. OBJECTIVES: Thus, in the following set of experiments, we determined the role of social experience in modulating GABAA receptor-induced aggression in both male and female Syrian hamsters, with a particular focus on the GABAA receptor subtype mediating these effects. RESULTS: Activation of GABAA receptors in the dorsal lateral septum increased aggression in both males and females. Social housing, however, significantly decreased the ability of GABAA receptor activation to induce aggression in males but not females. No significant differences were observed in the effects of GABAA receptor activation in dominant versus subordinate group-housed hamsters. Finally, examination of potential GABAA receptor subtype specificity revealed that social housing decreased the ratio of δ extrasynaptic to γ2 synaptic subunit GABAA receptor mRNA expression in the anterior dorsal lateral septum, while activation of δ extrasynaptic, but not γ2 synaptic, GABAA receptors in the dorsal lateral septum increased aggression. CONCLUSIONS: These data suggest that social experience can have profound effects on the neuronal mechanisms mediating aggression, especially in males, and that δ extrasynaptic GABAA receptors may be an important therapeutic target in disorders characterized by high levels of aggression.

Sex-dependent effects of social isolation on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5HT) 1a receptor binding and aggression.

It is widely held that social isolation produces higher rates of mortality and morbidity and has deleterious effects on an individual's sociality. Relatedly, it is widely observed that socially isolated adult rodents display significantly higher levels of aggression when placed in a social situation than do their conspecifics living in social groups. In the following study, we investigated the effects of social isolation on several neurochemical signals that play key roles in the regulation of social behavior in adults. More specifically, we examined the effects of social isolation on vasopressin (AVP) V1a, oxytocin (OT) and serotonin (5-HT)1a receptor binding within the neural circuit controlling social behavior. Male and female Syrian hamsters were housed individually or with two other hamsters for four weeks and were then tested with a same-sex nonaggressive intruder in a neutral arena for 5 min. Social isolation significantly increased aggression in both males and females and altered receptor binding in several brain regions in a sex-dependent manner. For example, V1a receptor binding was greater in socially isolated males in the anterior hypothalamus than it was in any other group. Taken together, these data provide substantial new support for the proposition that the social environment can have a significant impact on the structural and neurochemical mechanisms regulating social behavior and that the amount and type of social interactions can produce differential effects on the circuit regulating social behavior in a sex-dependent manner.

Sex-dependent regulation of social reward by oxytocin: an inverted U hypothesis.

The rewarding properties of social interactions are essential for the expression of social behavior and the development of adaptive social relationships. Here, we review sex differences in social reward, and more specifically, how oxytocin (OT) acts in the mesolimbic dopamine system (MDS) to mediate the rewarding properties of social interactions in a sex-dependent manner. Evidence from rodents and humans suggests that same-sex social interactions may be more rewarding in females than in males. We propose that there is an inverted U relationship between OT dose, social reward, and neural activity within structures of the MDS in both males and females, and that this dose-response relationship is initiated at lower doses in females than males. As a result, depending on the dose of OT administered, OT could reduce social reward in females, while enhancing it in males. Sex differences in the neural mechanisms regulating social reward may contribute to sex differences in the incidence of a large number of psychiatric and neurodevelopmental disorders. This review addresses the potential significance of a sex-dependent inverted U dose-response function for OT's effects on social reward and in the development of gender-specific therapies for these disorders.