Ongoing Research
Our goal is to understand how the brain, seemingly indistinguishable between men and women, generates sex differences in behaviors. For our studies, we focus on sex differences in social behaviors such as mating, aggression, and parenting that are easily elicited in laboratory conditions using ethological meaningful stimuli. In addition, these behaviors require no prior training or experience and are reproducible, stereotyped, and quantifiable, thereby making them amenable to rigorous experimental analysis. We use a variety of approaches, including behavioral analysis, biochemistry and chemical biology, electrophysiology, in vivo calcium imaging, genetics, molecular biology, and opto and chemo-genetics, to discover the genetic and neural circuit underpinnings of these sexually dimorphic social interactions. Most of our studies use mice as a model organism although we have exciting projects using the prairie vole as a model for social attachments as discussed below.
A. The role of nature: How our genome regulates sex differences in behaviors
Molecular and neural control of sexually dimorphic behaviors
Behaviors such as mating, aggression, and nursing are innate in the sense that they can be displayed without prior training or experience, suggesting that the circuits underlying these behaviors are developmentally hard-wired.
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Behaviors such as mating, aggression, and nursing are innate in the sense that they can be displayed without prior training or experience, suggesting that the circuits underlying these behaviors are developmentally hard-wired. In mice and other vertebrates, this hard-wiring is controlled by sex hormones produced by the gonads. We and others have elucidated the over-arching logic whereby these hormones exert global control over sexually dimorphic behaviors, with estrogens acting neonatally to masculinize neural substrates for behavior and testosterone acting later to amplify the intensity of male behavioral displays (Wu et al, Cell 2009; Juntti et al, Neuron 2010; Yang et al, Neuron 2014).
We are studying the genetic and epigenetic mechanisms whereby sex hormones control development and adult function of neural circuits underlying sexually dimorphic behaviors. We recently discovered that sex hormones regulate sexually dimorphic expression of many genes in different hypothalamic and amygdalar regions, and these genes control very specific subroutines of mating or aggression or parenting rather than an entire behavioral program (Xu et al, Cell 2012). Our findings provide evidence for a modular control of social interactions such that there are genetically separable pathways that regulate some but not other components of these behaviors. In other words, it is possible to disassemble particular sexually dimorphic behaviors without disrupting the entire behavioral program related to gender.
We are also identifying and functionally characterizing sex hormone responsive neural circuits in an effort to understand how these pathways regulate sexually dimorphic behaviors. Our findings show that molecularly defined neuronal populations influence specific components of sexually dimorphic behaviors without altering other related behaviors. In recent studies, we have identified long-sought neurons in the ventromedial hypothalamus that regulate aggression and sexual behavior (Yang et al, Cell 2013) and neurons in the medial amygdala that regulate territorial aggression in males and maternal defense of pups in females (Unger et al, Cell Reports 2015). Thus, the neural circuit control, similar to findings with gene manipulations mentioned in the preceding paragraph, of social interactions is also modular, with different neural pathways regulating particular components of a behavioral program.
In mice and many other animals, social interactions are triggered in response to particular pheromones, chemicals secreted by an animal to communicate social, sexual or other information to members of its own species. We have made important contributions in understanding the particular pheromone-sensing pathways that regulate sexually dimorphic behaviors in males (Mandiyan et al, Nature Neurosci 2005) and females (Fraser et al, Plos One 2014). In a parallel project in fruit flies, we discovered key molecular and neural circuit mechanisms whereby such chemosensory cues regulate social interactions not only within a members of a species, but also between closely related species (Fan et al, Cell 2013). Ongoing projects focus on understanding how such pheromone-sensing pathways intersect with sex hormone responsive neural circuits to govern sexually dimorphic social interactions.
B. How context and experience regulate sex differences in social behaviors
Social context-dependent control of aggression in male mice
i. Mice: Although mating, aggression, and nursing are innate behaviors, animals only engage in these interactions in the appropriate social context.
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i. Mice: Although mating, aggression, and nursing are innate behaviors, animals only engage in these interactions in the appropriate social context. For example, male mice are territorial and attack other males intruding in their home range whereas male mice that venture into another male’s territory do not initiate attacks upon the resident male. We recently showed that progesterone and estrogen receptor co-expressing neurons in the ventromedial hypothalamus are necessary and sufficient for male resident aggression (Yang et al, Cell 2013; Yang et al, Neuron 2017). These neurons represent the long sought center for attack in the caudal hypothalamus. Nevertheless, we demonstrated that these neurons cannot elicit aggression in intruder males. This contextual inhibition of aggression in males that would be aggressive in their own territory is dependent on pheromonal cues emanating from resident males (Yang et al, Neuron 2017). These studies provide an important example of the profound influence of the environment (nurture) in modulating developmentally-wired (nature) behavioral programs.
Ongoing studies are focused on uncovering the molecular and neural mechanisms that enable nurture to override nature in the display of aggression and related social behaviors. These studies also have important translational implications. For instance, common conditions such as Alzheimer’s disease and Intermittent Explosive Disorder often lead to extreme agitation and even aggression in situations that do not warrant or typically trigger such behavior. Findings from our studies that aim to understand the interactions between nature and nurture may inform our understanding of inappropriate behavioral displays in humans.
A mating pair of prairie voles shows huddling behavior
ii. Voles: Unlike mice and most other mammals that exhibit promiscuous mating, prairie voles form long term attachments, or pair bonds, with their mating partner.
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ii. Voles: Unlike mice and most other mammals that exhibit promiscuous mating, prairie voles form long term attachments, or pair bonds, with their mating partner. Pair bonded voles reject other potential mating partners and also guard their mate from other suitors. Such pair bonds can endure for life, and experimental separation of pair bonded voles elicits separation anxiety-type behaviors. Initially funded by a Pioneer grant, we have developed gene targeting tools, including iPS cells (Manoli et al, Plos One 2013), ES cells, and CRISPR-targeting, in prairie voles to dissect mechanisms underlying this pair bonding behavior. Our studies in prairie voles should provide insights into how the brain encodes plasticity in behaviors such as mating and aggression that are otherwise developmentally hard-wired.
Our studies in voles have important biomedical implications. We form many long term attachments in our lives, with spouses, children, parents, friends, colleagues from work, and through other affiliations. Diseases like autism, which disrupt the ability to form such bonds, are devastating conditions that highlight the critical role of social ties in our daily lives. In fact, fractured social attachments are often an early indicator of mental illness and one of the most difficult to heal. Social attachments have largely resisted experimental study because traditional models such as mice, rats, most primates, flies, and worms do not form bonds. Critical to the translational relevance of our work, oxytocin, also referred to as the “trust” hormone in popular media, which is undergoing testing for its role in improving social performance in autism, is also vital for pair bonding in prairie voles. Given this shared mechanism between voles and humans in social attachments, we are confident that our work on voles will provide a genetically tractable model to study this elusive but important behavior that is so central to our lives.