Annaliese K. Beery

Sex bias in neuroscience and biomedical research

Female mammals have long been neglected in biomedical research. The NIH mandated enrollment of women in human clinical trials in 1993, but no similar initiatives exist to foster research on female animals. We reviewed sex bias in research on mammals in 10 biological fields for 2009 and their historical precedents. Male bias was evident in 8 disciplines and most prominent in neuroscience, with single-sex studies of male animals outnumbering those of females 5.5 to 1. In the past half-century, male bias in non-human studies has increased while declining in human studies. Studies of both sexes frequently fail to analyze results by sex. Underrepresentation of females in animal models of disease is also commonplace, and our understanding of female biology is compromised by these deficiencies. The majority of articles in several journals are conducted on rats and mice to the exclusion of other useful animal models. The belief that non-human female mammals are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation. We recommend that when only one sex is studied, this should be indicated in article titles, and that funding agencies favor proposals that investigate both sexes and analyze data by sex.

Males still dominate animal studies.

Many researchers avoid using female animals. Stringent measures should consign this prejudice to the past, argue Irving Zucker and Annaliese Beery, in the third piece of three on gender bias in biomedicine.

Oxytocin and vasopressin receptor distributions in a solitary and a social species of tuco‐tuco (Ctenomys haigi and Ctenomys sociabilis)

The neuropeptides oxytocin and vasopressin and their receptors have been implicated in elements of mammalian social behavior such as attachment to mates and offspring, but their potential role in mediating other types of social relationships remains largely unknown. We performed receptor autoradiography to assess whether forebrain oxytocin receptor (OTR) or vasopressin V1a receptor (V1aR) distributions differed with social structure in two closely related and ecologically similar species of South American rodents, the colonial tuco‐tuco (Ctenomys sociabilis) and the Patagonian tuco‐tuco (Ctenomys haigi). Long‐term field studies have revealed that C. haigi is solitary, whereas C. sociabilis is social and provides a model of female‐based group living. Our analyses revealed marked differences in OTR and V1aR distributions between these species. For example, only C. sociabilis had OTR binding in the piriform cortex and thalamus and V1aR binding in the olfactory bulbs. In contrast, C. haigi exhibited dramatically higher levels of OTR binding throughout the lateral septum and hippocampus. More generally, the group‐living C. sociabilis exhibited a pattern of nucleus accumbens OTR and ventral pallidum V1aR binding different from that associated with the formation of opposite‐sex pair bonds in microtine rodents. Higher binding in the central nucleus of the amygdala of C. sociabilis was consistent with the hypothesis that formation of social groups in C. sociabilis may be facilitated by reduced social anxiety. Low OTR binding in the lateral septum might also be a permissive factor for group living in C. sociabilis. Future studies will expand on these analyses to explore interspecific differences in ctenomyid receptor binding patterns in a phylogenetic context. J. Comp. Neurol. 507:1847–1859, 2008.

Stress, social behavior, and resilience: Insights from rodents

The neurobiology of stress and the neurobiology of social behavior are deeply intertwined. The social environment interacts with stress on almost every front: social interactions can be potent stressors; they can buffer the response to an external stressor; and social behavior often changes in response to stressful life experience. This review explores mechanistic and behavioral links between stress, anxiety, resilience, and social behavior in rodents, with particular attention to different social contexts. We consider variation between several different rodent species and make connections to research on humans and non-human primates.

An evolutionary framework for studying mechanisms of social behavior

Social interactions are central to most animals and have a fundamental impact upon the phenotype of an individual. Social behavior (social interactions among conspecifics) represents a central challenge to the integration of the functional and mechanistic bases of complex behavior. Traditionally, studies of proximate and ultimate elements of social behavior have been conducted by distinct groups of researchers, with little communication across perceived disciplinary boundaries. However, recent technological advances, coupled with increased recognition of the substantial variation in mechanisms underlying social interactions, should compel investigators from divergent disciplines to pursue more integrative analyses of social behavior. We propose an integrative conceptual framework intended to guide researchers towards a comprehensive understanding of the evolution and maintenance of mechanisms governing variation in sociality.

Life in groups: the roles of oxytocin in mammalian sociality.

In recent decades, scientific understanding of the many roles of oxytocin (OT) in social behavior has advanced tremendously. The focus of this research has been on maternal attachments and reproductive pair-bonds, and much less is known about the substrates of sociality outside of reproductive contexts. It is now apparent that OT influences many aspects of social behavior including recognition, trust, empathy, and other components of the behavioral repertoire of social species. This review provides a comparative perspective on the contributions of OT to life in mammalian social groups. We provide background on the functions of OT in maternal attachments and the early social environment, and give an overview of the role of OT circuitry in support of different mating systems. We then introduce peer relationships in group-living rodents as a means for studying the importance of OT in non-reproductive affiliative behaviors. We review species differences in oxytocin receptor (OTR) distributions in solitary and group-living species of South American tuco-tucos and in African mole-rats, as well as singing mice. We discuss variation in OTR levels with seasonal changes in social behavior in female meadow voles, and the effects of OT manipulations on peer huddling behavior. Finally, we discuss avenues of promise for future investigation, and relate current findings to research in humans and non-human primates. There is growing evidence that OT is involved in social selectivity, including increases in aggression toward social outgroups and decreased huddling with unfamiliar individuals, which may support existing social structures or relationships at the expense of others. OT’s effects reach beyond maternal attachment and pair bonds to play a role in affiliative behavior underlying “friendships”, organization of broad social structures, and maintenance of established social relationships with individuals or groups.

Oxytocin and same-sex social behavior in female meadow voles

The neuropeptide oxytocin (OT) has been implicated in a range of mammalian reproductive and social behaviors including parent-offspring bonding and partner preference formation between socially monogamous mates. Its role in mediating non-reproductive social relationships in rodents, however, remains largely unexplored. We examined whether OT facilitates same-sex social preferences between female meadow voles-a species that forms social nesting groups in short, winter-like day lengths. In contrast to results from studies of opposite-sex attachment between prairie vole mates, we found that neither OT nor dopamine neurotransmission was required for baseline levels of social partner preference formation or expression. OT enhanced preference formation beyond baseline levels-an effect that was counteracted by treatment with an oxytocin receptor antagonist (OTA). Oxytocin receptor (OTR) density correlated with social behavior in brain regions not known to be associated with opposite-sex affiliation, including the lateral septum and central amygdala. In addition, voles housed in short day lengths (SD) exhibited higher levels of OTR binding in the central amygdala, and voles exposed to high concentrations of estradiol exhibited less binding in the nucleus accumbens (NAcc) and increased binding in the ventromedial nucleus of the hypothalamus. These results suggest that same-sex social behavior shares common elements with other mammalian social behaviors affected by OT, but that the specific neural pathways through which OT exerts its influence are likely distinct from those known for sexual attachments.

Chronic stress elevates telomerase activity in rats

The enzyme telomerase lengthens telomeres—protective structures containing repetitive DNA sequences at chromosome ends. Telomere shortening is associated with diseases of ageing in mammals. Chronic stress has been related to shorter immune-cell telomeres, but telomerase activity under stress may be low, permitting telomere loss, or high, partially attenuating it. We developed an experimental model to examine the impacts of extended unpredictable stress on telomerase activity in male rats. Telomerase activity was 54 per cent higher in stressed rats than in controls, and associated with stress-related physiological and behavioural outcomes. This significant increase suggests a potential mechanism for resilience to stress-related replicative senescence.

Adaptive significance of natural variations in maternal care in rats: A translational perspective

A wealth of data from the last fifty years documents the potency of early life experiences including maternal care on developing offspring. A majority of this research has focused on the developing stress axis and stress-sensitive behaviors in hopes of identifying factors impacting resilience and risk-sensitivity. The power of early life experience to shape later development is profound and has the potential to increase fitness of individuals for their environments. Current findings in a rat maternal care paradigm highlight the complex and dynamic relation between early experiences and a variety of outcomes. In this review we propose adaptive hypotheses for alternate maternal strategies and resulting offspring phenotypes, and suggest means of distinguishing between these hypotheses. We also provide evidence underscoring the critical role of context in interpreting the adaptive significance of early experiences. If our goal is to identify risk-factors relevant to humans, we must better explore the role of the social and physical environment in our basic animal models.

Taxon matters: promoting integrative studies of social behavior: NESCent Working Group on Integrative Models of Vertebrate Sociality: Evolution, Mechanisms, and Emergent Properties

The neural and molecular mechanisms underlying social behavior - including their functional significance and evolution - can only be fully understood using data obtained under multiple social, environmental, and physiological conditions. Understanding the complexity of social behavior requires integration across levels of analysis in both laboratory and field settings. However, there is currently a disconnect between the systems studied in the laboratory versus the field. We argue that recent conceptual and technical advances provide exciting new opportunities to close this gap by making non-model organisms accessible to modern approaches in both laboratory and nature.