Testosterone facilitates nonreproductive, context-appropriate pro- and anti-social behavior in female and male Mongolian gerbils.

A growing body of literature suggests that testosterone (T) rapidly modulates behavior in a context-specific manner. However, the timescales in which T can rapidly mediate distinct types of behavior, such as pro- vs. anti- social responses, has not been studied. Thus, here we examined acute T influences on social behavior in male and female Mongolian gerbils in nonreproductive contexts. Females and males received an injection of either saline or T and were first tested in a social interaction test with a same-sex, familiar peer. 5 min after the peer interaction, subjects then underwent a resident-intruder test with a novel, same-sex conspecific. After another 5 min, gerbils were tested in a novel object task to test context-specificity (i.e., social vs. nonsocial) of T effects on behavior. Within 1 h, males and females injected with T exhibited more huddling with a peer but more active avoidance of and less time spent in proximity of an intruder than did animals injected with saline. T effects on behavior were specific to social contexts, such that T did not influence investigation of the novel object. Together these findings show that T rapidly promotes pro-social responses to a familiar peer and anti-social responses to an intruder in the same individuals within 5 min of experiencing these disparate social contexts. This demonstrates that T rapidly facilitates behavior in a context-appropriate manner outside the context of reproduction and reveals that rapid effects of T on behavior are not restricted to males.

An update on oral cavity cancer: epidemiological trends, prevention strategies and novel approaches in diagnosis and prognosis.

In the UK, the incidence of oral cavity cancer continues to rise, with an increase of around 60% over the past 10 years. Many patients still present with advanced disease, often resulting in locoregional recurrence and poor outcomes, which has not changed significantly for over four decades. Changes in aetiology may also be emerging, given the decline of smoking in developed countries. Therefore, new methods to better target prevention, improve screening and detect recurrence are needed. High-throughput 'omics' technologies appear promising for future individual-level diagnosis and prognosis. However, given this is a relatively rare cancer with significant intra-tumour heterogeneity and variation in patient response, reliable biomarkers have been difficult to elucidate. From a public health perspective, implementing these novel technologies into current services would require substantial practical, financial and ethical considerations. This may be difficult to justify and implement at present, therefore focus remains on early detection using new patient-led follow-up strategies. This paper reviews the latest evidence on epidemiological trends in oral cavity cancer to help identify at risk groups, population-based approaches for prevention, in addition to potential cutting-edge approaches in the diagnosis and prognosis of this disease.

Beyond sex and aggression: testosterone rapidly matches behavioural responses to social context and tries to predict the future.

Although androgens are widely studied in the context of aggression, androgenic influences on prosocial behaviours have been less explored. We examined testosterone's (T) influence on prosocial and aggressive responses in a positively valenced social context (interacting with a pairbond partner) and a negatively valenced context (interacting with an intruder) in socially monogamous Mongolian gerbils. T increased and decreased prosocial responses in the same individuals towards a pairbond partner and an intruder, respectively, both within 30 min, but did not affect aggression. T also had persistent effects on prosocial behaviour; males in which T initially increased prosocial responses towards a partner continued to exhibit elevated prosocial responses towards an intruder male days later until a second T injection rapidly eliminated those responses. Thus, T surges can rapidly match behaviour to current social context, as well as prime animals for positive social interactions in the future. Neuroanatomically, T rapidly increased hypothalamic oxytocin, but not vasopressin, cellular responses during interactions with a partner. Together, our results indicate that T can facilitate and inhibit prosocial behaviours depending on social context, that it can influence prosocial responses across rapid and prolonged time scales, and that it affects oxytocin signalling mechanisms that could mediate its context-dependent behavioural influences.

An updated field guide for snark hunting: Comparative contributions to behavioral neuroendocrinology in the era of model organisms.

Studying neuroendocrine behavioral regulatory mechanisms in a variety of species across vertebrate groups is critical for determining how they work in natural contexts, how they evolved, and ultimately what can be generalized from them, potentially even to humans. All of the above are difficult, at best, if work within our field is exclusively done in traditional laboratory organisms. The importance of comparative approaches for understanding the relationships between hormones and behavior has been recognized and advocated for since our field's inception through a series of papers centered upon a poetic metaphor of Snarks and Boojums, all of which have articulated the benefits that come from studying a diverse range of species and the risks associated with a narrow focus on "model organisms." This mini-review follows in the footsteps of those powerful arguments, highlighting some of the comparative work since the latest interactions of the metaphor that has shaped how we think about three major conceptual frameworks within our field, two of them formalized - the Organization/Activation Model of sexual differentiation and the Social Brain Network - and one, context-dependency, that is generally associated with virtually all modern understandings of how hormones affect behavior. Comparative approaches are broadly defined as those in which the study of mechanism is placed within natural and/or evolutionary contexts, whether they directly compare different species or not. Studies are discussed in relation to how they have either extended or challenged generalities associated with the frameworks, how they have shaped subsequent work in model organisms to further elucidate neuroendocrine behavioral regulatory mechanisms, and how they have stimulated work to determine if and when similar mechanisms influence behavior in our own species.

Rapid sex steroid effects on reproductive responses in male goldfish: Sensory and motor mechanisms.

Contribution to Special Issue on Fast effects of steroids. Although we have learned a great deal about the molecular mechanisms through which sex steroids rapidly affect cellular physiology, we still know little about the links between those mechanisms and behavioral output, nor about their functional consequences in natural contexts. In this review, we first briefly discuss the contexts associated with rapid effects of sex steroids on reproductive behaviors and their likely functional outcomes, as well the sensory, motor, and motivational mechanisms associated with those effects. We then discuss our recent studies on the rapid effects of testosterone in goldfish. Those studies indicate that testosterone, through its aromatization and the subsequent activation of estrogen receptors, rapidly stimulates physiological processes related to the release of milt/sperm through likely influences on motor pathways, as well as behavioral responses to female visual stimuli that may reflect, in part, influences on early stages of sensory processing. Such motor and sensory mechanism are likely important for sperm competition and mate detection / tracking, respectively, in competitive mating contexts. We also present preliminary data on rapid effects of testosterone on responses to pheromones that may not involve estrogen receptors, suggesting a dissociation in the receptor mechanisms that mediate behavioral responses in different sensory modalities. Lastly, we briefly discuss the implications of our work on unresolved questions about rapid sex steroid neuromodulation in fish.

Maternal and fetal genetic contribution to gestational weight gain.

BACKGROUND: Clinical recommendations to limit gestational weight gain (GWG) imply high GWG is causally related to adverse outcomes in mother or offspring, but GWG is the sum of several inter-related complex phenotypes (maternal fat deposition and vascular expansion, placenta, amniotic fluid and fetal growth). Understanding the genetic contribution to GWG could help clarify the potential effect of its different components on maternal and offspring health. Here we explore the genetic contribution to total, early and late GWG. PARTICIPANTS AND METHODS: A genome-wide association study was used to identify maternal and fetal variants contributing to GWG in up to 10 543 mothers and 16 317 offspring of European origin, with replication in 10 660 mothers and 7561 offspring. Additional analyses determined the proportion of variability in GWG from maternal and fetal common genetic variants and the overlap of established genome-wide significant variants for phenotypes relevant to GWG (for example, maternal body mass index (BMI) and glucose, birth weight). RESULTS: Approximately 20% of the variability in GWG was tagged by common maternal genetic variants, and the fetal genome made a surprisingly minor contribution to explain variation in GWG. Variants near the pregnancy-specific beta-1 glycoprotein 5 (PSG5) gene reached genome-wide significance (P=1.71 × 10-8) for total GWG in the offspring genome, but did not replicate. Some established variants associated with increased BMI, fasting glucose and type 2 diabetes were associated with lower early, and higher later GWG. Maternal variants related to higher systolic blood pressure were related to lower late GWG. Established maternal and fetal birth weight variants were largely unrelated to GWG. CONCLUSIONS: We found a modest contribution of maternal common variants to GWG and some overlap of maternal BMI, glucose and type 2 diabetes variants with GWG. These findings suggest that associations between GWG and later offspring/maternal outcomes may be due to the relationship of maternal BMI and diabetes with GWG.

Corrigendum: Dose-Dependent and Lasting Influences of Intranasal Vasopressin on Face Processing in Men.

[This corrects the article on p. 220 in vol. 8, PMID: 29018407.].

Dose-Dependent and Lasting Influences of Intranasal Vasopressin on Face Processing in Men.

Arginine vasopressin (AVP) and related peptides have diverse effects on social behaviors in vertebrates, sometimes promoting affiliative interactions and sometimes aggressive or antisocial responses. The type of influence, in at least some species, depends on social contexts, including the sex of the individuals in the interaction and/or on the levels of peptide within brain circuits that control the behaviors. To determine if AVP promotes different responses to same- and other-sex faces in men, and if those effects are dose dependent, we measured the effects of two doses of AVP on subjective ratings of male and female faces. We also tested if any influences persist beyond the time of drug delivery. When AVP was administered intranasally on an initial test day, 20 IU was associated with decreased social assessments relative to placebo and 40 IU, and some of the effects persisted beyond the initial drug delivery and appeared to generalize to novel faces on subsequent test days. In single men, those influences were most pronounced, but not exclusive, for male faces, whereas in coupled men they were primarily associated with responses to female faces. Similar influences were not observed if AVP was delivered after placebo on a second test day. In a preliminary analysis, the differences in social assessments observed between men who received 20 and 40 IU, which we suggest primarily reflect lowered social assessments induced by the lower dose, appeared most pronounced in subjects who carry what has been identified as a risk allele for the V1a receptor gene. Together, these results suggest that AVP's effects on face processing, and possibly other social responses, differ according to dose, depend on relationship status, and may be more prolonged than previously recognized.

Arginine Vasopressin Effects on Subjective Judgments and Neural Responses to Same and Other-Sex Faces in Men and Women.

Arginine vasopressin (AVP) influences social and emotional behaviors across a wide range of species. In humans, intranasal AVP has been previously shown to alter physiological responses to and subjective judgments of same-sex faces in both men and women. The present study attempted to elucidate the neural mechanism for these effects by randomizing 40 healthy men and 40 healthy women to treatment with either 40 IU intranasal AVP or a saline placebo approximately 30 min before imaging their brain function with fMRI as they viewed same and other-sex faces. All subjects were also scanned a second time several days later with no treatment to evaluate the persistence of AVP effects over time. AVP acutely increased positive ratings of same-sex faces in women, with some evidence that these effects persisted until the second scan. While AVP had no acute effects on same-sex ratings in men, AVP increased positive ratings of same-sex faces several days later. On the other hand, AVP had no effect on other-sex face judgments in either sex. AVP modulation of brain function was focused on the nucleus accumbens (NAc) and the lateral septum, two reward processing areas involved in the formation of social bonds. AVP provoked acute increases in right NAc and bilateral lateral septum responses to female faces among men, with left lateral septum responses persisting over time while right NAc responses reversed over time. Finally, AVP modulated hypothalamic activation to faces in both men and women. The present study therefore indicates that intranasal AVP affects subjective ratings and neural responses to same and other-sex faces in men and women, with some effects persisting and others emerging over time. Future studies should investigate whether AVP effects are modulated by individual variables such as genotype, personality, or attachment style as previously reported for other nonapeptides.

Deterrence and Risk Preferences in Sequential Attacker-Defender Games with Continuous Efforts.

Most attacker-defender games consider players as risk neutral, whereas in reality attackers and defenders may be risk seeking or risk averse. This article studies the impact of players' risk preferences on their equilibrium behavior and its effect on the notion of deterrence. In particular, we study the effects of risk preferences in a single-period, sequential game where a defender has a continuous range of investment levels that could be strategically chosen to potentially deter an attack. This article presents analytic results related to the effect of attacker and defender risk preferences on the optimal defense effort level and their impact on the deterrence level. Numerical illustrations and some discussion of the effect of risk preferences on deterrence and the utility of using such a model are provided, as well as sensitivity analysis of continuous attack investment levels and uncertainty in the defender's beliefs about the attacker's risk preference. A key contribution of this article is the identification of specific scenarios in which the defender using a model that takes into account risk preferences would be better off than a defender using a traditional risk-neutral model. This study provides insights that could be used by policy analysts and decisionmakers involved in investment decisions in security and safety.

GPER/GPR30, a membrane estrogen receptor, is expressed in the brain and retina of a social fish (Carassius auratus) and colocalizes with isotocin.

Estradiol rapidly (within 30 minutes) influences a variety of sociosexual behaviors in both mammalian and nonmammalian vertebrates, including goldfish, in which it rapidly stimulates approach responses to the visual cues of females. Such rapid neuromodulatory effects are likely mediated via membrane-associated estrogen receptors; however, the localization and distribution of such receptors within the nervous system is not well described. To begin to address this gap, we identified GPER/GPR30, a G-protein-coupled estrogen receptor, in goldfish (Carassius auratus) neural tissue and used reverse-transcription polymerase chain reaction (RT-PCR) and in situ hybridization to test if GPR30 is expressed in the brain regions that might mediate visually guided social behaviors in males. We then used immunohistochemistry to determine whether GPR30 colocalizes with isotocin-producing cells in the preoptic area, a critical node in the highly conserved vertebrate social behavior network. We used quantitative (q)PCR to test whether GPR30 mRNA levels differ in males in breeding vs. nonbreeding condition and in males that were socially interacting with a female vs. a rival male. Our results show that GPR30 is expressed in the retina and in many brain regions that receive input from the retina and/or optic tectum, as well as in a few nodes in the social behavior network, including cell populations that produce isotocin. J. Comp. Neurol. 525:252-270, 2017. © 2016 Wiley Periodicals, Inc.

Challenges and novel approaches for investigating molecular mediation.

Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.

Prospective associations of parental smoking, alcohol use, marital status, maternal satisfaction, and parental and childhood body mass index at 6.5 years with later problematic eating attitudes.

BACKGROUND: Few studies have prospectively investigated whether early-life exposures are associated with pre-adolescent eating attitudes. OBJECTIVE: The objective of this study is to prospectively investigate associations of parental smoking, alcohol use, marital status, measures of maternal satisfaction, self-reported parental body mass index (BMI) and clinically measured childhood BMI, assessed between birth and 6.5 years, with problematic eating attitudes at 11.5 years. METHODS: Observational cohort analysis nested within the Promotion of Breastfeeding Intervention Trial, a cluster-randomised trial conducted in 31 maternity hospitals and affiliated polyclinics in Belarus. Our primary outcome was a Children's Eating Attitudes Test (ChEAT) score 22.5 (85th percentile), an indicator of problematic eating attitudes. We employed multivariable mixed logistic regression models, which allow inference at the individual level. We also performed instrumental variable (IV) analysis using parents' BMIs as instruments for the child's BMI, to assess whether associations could be explained by residual confounding or reverse causation. SUBJECTS: Of the 17 046 infants enrolled between 1996 and 1997 across Belarus, 13 751 (80.7%) completed the ChEAT test at 11.5 years. RESULTS: In fully adjusted models, overweight children at age 6.5 years had a 2.14-fold (95% confidence interval (CI): 1.82, 2.52) increased odds of having ChEAT scores 85th percentile at age 11.5 years, and those who were obese had a 3.89-fold (95% CI: 2.95, 5.14) increased odds compared with normal-weight children. Children of mothers or fathers who were themselves overweight or obese were more likely to score 85th percentile (P for trend 0.001). IV analysis was consistent with a child's BMI causally affecting future eating attitudes. There was little evidence that parental smoking, alcohol use, or marital status or maternal satisfaction were associated with eating attitudes. CONCLUSION: In our large, prospective cohort in Belarus, both parental and childhood overweight and obesity at 6.5 years were associated with pre-adolescent problematic eating attitudes 5 years later.

Pheromone exposure influences preoptic arginine vasotocin gene expression and inhibits social approach behavior in response to rivals but not potential mates.

The nonapeptides arginine vasotocin (AVT) and vasopressin mediate a variety of social behaviors in vertebrates. However, the effects of these peptides on behavior can vary considerably both between and within species. AVT, in particular, stimulates aggressive and courtship responses typical of dominant males in several species, although it can also inhibit social interactions in some cases. Such differential effects may depend upon AVT influences within brain circuits that differ among species or between males that adopt alternative reproductive phenotypes and/or upon the differential activation of those circuits in different social contexts. However, to date, very little is known about how social stimuli that promote alternative behavioral responses influence AVT circuits within the brain. To address this issue, we exposed adult male goldfish to androstenedione (AD), a pheromonal signal that is released by both males and females during the breeding season, and measured social approach responses of males towards same- and other-sex individuals before and after AD exposure. In a second experiment, we measured AD-induced AVT gene expression using in situ hybridization. We found that brief exposure to AD induces social avoidance in response to rival males, but does not affect the level of sociality exhibited in response to sexually receptive females. Exposure to AD also increases AVT gene expression in the preoptic area of male goldfish, particularly in the parvocellular population of the preoptic nucleus. Together, these data suggest that AD is part of a social signaling system that induces social withdrawal specifically during male-male interactions by activating AVT neurons.

An aggression-specific cell type in the anterior hypothalamus of finches.

The anterior hypothalamus (AH) is a major integrator of neural processes related to aggression and defense, but cell types in the AH that selectively promote aggression are unknown. We here show that aggression is promoted in a very selective and potent manner by dorsal AH neurons that produce vasoactive intestinal polypeptide (VIP). Fos activity in a territorial finch, the violet-eared waxbill (Estrildidae: Uraeginthus granatina) is positively related to aggression in the dorsal AH, overlapping a population of VIP-producing neurons. VIP is known to promote territorial aggression in songbirds, and thus we used antisense oligonucleotides to selectively block AH VIP production in male and female waxbills. This manipulation virtually abolishes aggression, reducing the median number of displacements in a 3-min resident-intruder test from 38 in control subjects to 0 in antisense subjects. Notably, most antisense and control waxbills exhibit an agonistic response such as a threat or agonistic call within 2 s of intrusion. Thus, antisense subjects clearly classify intruders as offensive, but fail to attack. Other social and anxiety-like behaviors are not affected and VIP cell numbers correlate positively with aggression, suggesting that these cells selectively titrate aggression. Additional experiments in the gregarious zebra finch (Estrildidae: Taeniopygia guttata) underscore this functional specificity. Colony-housed finches exhibit significant reductions in aggression (primarily nest defense) following AH VIP knockdown, but no effects are observed for social preferences, pair bonding, courtship, maintenance behaviors, or anxiety-like behaviors. To our knowledge, these findings represent a unique identification of an aggression-specific cell type in the brain.

Adaptive toothbrush handle: case report of a Thalidomide patient.

Thalidomide poisoning can result in malformation of limbs, specifically upper limbs, compromising manual dexterity. Although Thalidomide has long since been withdrawn for use in pregnant patients, its affects on those exposed pose significant challenges for patients' oral hygiene maintenance. This case reports a novel technique of adaptation to facilitate a Thalidomide poisoned patient in maintenance of oral hygiene via an adaptive toothbrush handle.

Testosterone rapidly increases ejaculate volume and sperm density in competitively breeding goldfish through an estrogenic membrane receptor mechanism.

The social environment can have dramatic influences on reproductive behavior and physiology in many vertebrate species. In males, interactions with conspecifics affect physiological processes that increase an individual's ability to compete for mates. For example, in some species, males rapidly adjust the number of sperm they ejaculate in response to sociosexual cues from male and female conspecifics, however, little is known about the physiological mechanisms mediating this behavior. In goldfish, as in many vertebrates, social cues also drive transient surges of the gonadal hormone testosterone (T), which induces rapid effects on cellular processes via its conversion to estradiol (E2). We asked whether such surges rapidly influence ejaculate quantity and quality by experimentally manipulating peripheral levels of T and E2. We show that male goldfish injected with T increased ejaculate (milt) volume and sperm density within just 1 hr. Furthermore, increases in expressible milt were dependent on the conversion of T to E2 by the enzyme aromatase, required activation of estrogen receptors α and ß, and were also elicited by BSA-conjugated E2, which acts on cell membrane-bound estrogen receptors. Together, these findings represent a novel steroid mechanism for the social modulation of sperm output over the short time scales that characterize reproductive encounters, and thus demonstrate a previously undescribed functional consequence of rapid estrogen signaling mechanisms. We suggest that such mechanisms may play a critical role in the enhancement of physiological and behavioral processes that increase reproductive success in competitive mating contexts.