Modular genetic control of social status in a cichlid fish.

Social hierarchies are ubiquitous in social species and profoundly influence physiology and behavior. Androgens like testosterone have been strongly linked to social status, yet the molecular mechanisms regulating social status are not known. The African cichlid fish Astatotilapia burtoni is a powerful model species for elucidating the role of androgens in social status given their rich social hierarchy and genetic tractability. Dominant A. burtoni males possess large testes and bright coloration and perform aggressive and reproductive behaviors while nondominant males do not. Social status in A. burtoni is in flux, however, as males alter their status depending on the social environment. Due to a teleost-specific whole-genome duplication, A. burtoni possess two androgen receptor (AR) paralogs, ARα and ARß, providing a unique opportunity to disentangle the role of gene duplication in the evolution of social systems. Here, we used CRISPR/Cas9 gene editing to generate AR mutant A. burtoni and performed a suite of experiments to interrogate the mechanistic basis of social dominance. We find that ARß, but not ARα, is required for testes growth and bright coloration, while ARα, but not ARß, is required for the performance of reproductive behavior and aggressive displays. Both receptors are required to reduce flees from females and either AR is sufficient for attacking males. Thus, social status in A. burtoni is inordinately dissociable and under the modular control of two AR paralogs. This type of nonredundancy may be important in facilitating social plasticity in A. burtoni and other species whose social status relies on social experience.

Behavior-dependent cis regulation reveals genes and pathways associated with bower building in cichlid fishes.

Many behaviors are associated with heritable genetic variation [Kendler and Greenspan (2006) Am J Psychiatry 163:1683-1694]. Genetic mapping has revealed genomic regions or, in a few cases, specific genes explaining part of this variation [Bendesky and Bargmann (2011) Nat Rev Gen 12:809-820]. However, the genetic basis of behavioral evolution remains unclear. Here we investigate the evolution of an innate extended phenotype, bower building, among cichlid fishes of Lake Malawi. Males build bowers of two types, pits or castles, to attract females for mating. We performed comparative genome-wide analyses of 20 bower-building species and found that these phenotypes have evolved multiple times with thousands of genetic variants strongly associated with this behavior, suggesting a polygenic architecture. Remarkably, F1 hybrids of a pit-digging and a castle-building species perform sequential construction of first a pit and then a castle bower. Analysis of brain gene expression in these hybrids showed that genes near behavior-associated variants display behavior-dependent allele-specific expression with preferential expression of the pit-digging species allele during pit digging and of the castle-building species allele during castle building. These genes are highly enriched for functions related to neurodevelopment and neural plasticity. Our results suggest that natural behaviors are associated with complex genetic architectures that alter behavior via cis-regulatory differences whose effects on gene expression are specific to the behavior itself.

Social control of the brain.

In the course of evolution, social behavior has been a strikingly potent selective force in shaping brains to control action. Physiological, cellular, and molecular processes reflect this evolutionary force, particularly in the regulation of reproductive behavior and its neural circuitry. Typically, experimental analysis is directed at how the brain controls behavior, but the brain is also changed by behavior over evolution, during development, and through its ongoing function. Understanding how the brain is influenced by behavior offers unusual experimental challenges. General principles governing the social regulation of the brain are most evident in the control of reproductive behavior. This is most likely because reproduction is arguably the most important event in an animal's life and has been a powerful and essential selective force over evolution. Here I describe the mechanisms through which behavior changes the brain in the service of reproduction using a teleost fish model system.

Genome-wide effects of social status on DNA methylation in the brain of a cichlid fish, Astatotilapia burtoni.

BACKGROUND: Successful social behavior requires real-time integration of information about the environment, internal physiology, and past experience. The molecular substrates of this integration are poorly understood, but likely modulate neural plasticity and gene regulation. In the cichlid fish species Astatotilapia burtoni, male social status can shift rapidly depending on the environment, causing fast behavioral modifications and a cascade of changes in gene transcription, the brain, and the reproductive system. These changes can be permanent but are also reversible, implying the involvement of a robust but flexible mechanism that regulates plasticity based on internal and external conditions. One candidate mechanism is DNA methylation, which has been linked to social behavior in many species, including A. burtoni. But, the extent of its effects after A. burtoni social change were previously unknown. RESULTS: We performed the first genome-wide search for DNA methylation patterns associated with social status in the brains of male A. burtoni, identifying hundreds of Differentially Methylated genomic Regions (DMRs) in dominant versus non-dominant fish. Most DMRs were inside genes supporting neural development, synapse function, and other processes relevant to neural plasticity, and DMRs could affect gene expression in multiple ways. DMR genes were more likely to be transcription factors, have a duplicate elsewhere in the genome, have an anti-sense lncRNA, and have more splice variants than other genes. Dozens of genes had multiple DMRs that were often seemingly positioned to regulate specific splice variants. CONCLUSIONS: Our results revealed genome-wide effects of A. burtoni social status on DNA methylation in the brain and strongly suggest a role for methylation in modulating plasticity across multiple biological levels. They also suggest many novel hypotheses to address in mechanistic follow-up studies, and will be a rich resource for identifying the relationships between behavioral, neural, and transcriptional plasticity in the context of social status.

Hormonal regulation of social ascent and temporal patterns of behavior in an African cichlid.

For many species, social rank determines which individuals perform certain social behaviors and when. Higher ranking or dominant (DOM) individuals maintain status through aggressive interactions and perform courtship behaviors while non-dominant (ND) individuals do not. In some species ND individuals ascend (ASC) in social rank when the opportunity arises. Many important questions related to the mechanistic basis of social ascent remain to be answered. We probed whether androgen signaling regulates social ascent in male Astatotilapia burtoni, an African cichlid whose social hierarchy can be readily controlled in the laboratory. As expected, androgen receptor (AR) antagonism abolished reproductive behavior during social ascent. However, we discovered multiple AR- and status-dependent temporal behavioral patterns that typify social ascent and dominance. AR antagonism in ASC males increased the time between successive behaviors compared to DOM males. Socially ascending males, independent of AR activation, were more likely than DOM males to follow aggressive displays with another aggressive display. Further analyses revealed differences in the sequencing of aggressive and courtship behaviors, wherein DOM males were more likely than ASC males to follow male-directed aggression with courtship displays. Strikingly, this difference was driven mostly by ASC males taking longer to transition from aggression to courtship, suggesting ASC males can perform certain DOM-typical temporal behavioral patterns. Our results indicate androgen signaling is necessary for social ascent and hormonal signaling and social experience may shape the full suite of DOM-typical behavioral patterns.

Mechanistic target of rapamycin (mTOR) implicated in plasticity of the reproductive axis during social status transitions.

The highly conserved brain-pituitary-gonadal (BPG) axis controls reproduction in all vertebrates, so analyzing the regulation of this signaling cascade is important for understanding reproductive competence. The protein kinase mechanistic target of rapamycin (mTOR) functions as a conserved regulator of cellular growth and metabolism in all eukaryotes, and also regulates the reproductive axis in mammals. However, whether mTOR might also regulate the BPG axis in non-mammalian vertebrates remains unexplored. We used complementary experimental approaches in an African cichlid fish, Astatotilapia burtoni, to demonstrate that mTOR is involved in regulation of the brain, pituitary, and testes when males rise in rank to social dominance. mTOR or downstream components of its signaling pathway (p-p70S6K) were detected in gonadotropin-releasing hormone (GnRH1) neurons, the pituitary, and testes. Transcript levels of mtor in the pituitary and testes also varied when reproductively-suppressed subordinate males rose in social rank to become dominant reproductively-active males, a transition similar to puberty in mammals. Intracerebroventricular injection of the mTORC1 inhibitor, rapamycin, revealed a role for mTOR in the socially-induced hypertrophy of GnRH1 neurons. Rapamycin treatment also had effects at the pituitary and testes, suggesting involvement of the mTORC1 complex at multiple levels of the reproductive axis. Thus, we show that mTOR regulation of BPG function is conserved to fishes, likely playing important roles in regulating reproduction and fertility across all male vertebrates.

Electrical synapses connect a network of gonadotropin releasing hormone neurons in a cichlid fish.

Initiating and regulating vertebrate reproduction requires pulsatile release of gonadotropin-releasing hormone (GnRH1) from the hypothalamus. Coordinated GnRH1 release, not simply elevated absolute levels, effects the release of pituitary gonadotropins that drive steroid production in the gonads. However, the mechanisms underlying synchronization of GnRH1 neurons are unknown. Control of synchronicity by gap junctions between GnRH1 neurons has been proposed but not previously found. We recorded simultaneously from pairs of transgenically labeled GnRH1 neurons in adult male Astatotilapia burtoni cichlid fish. We report that GnRH1 neurons are strongly and uniformly interconnected by electrical synapses that can drive spiking in connected cells and can be reversibly blocked by meclofenamic acid. Our results suggest that electrical synapses could promote coordinated spike firing in a cellular assemblage of GnRH1 neurons to produce the pulsatile output necessary for activation of the pituitary and reproduction.

Rhythmic expressed clock regulates the transcription of proliferating cellular nuclear antigen in teleost retina.

Teleost fish continues to grow their eyes throughout life with the body size. In Astatotilapia burtoni, the fish retina increases by adding new retinal cells at the ciliary marginal zone (CMZ) and in the outer nuclear layer (ONL). Cell proliferation at both sites exhibits a daily rhythm in number of dividing cells. To understand how this diurnal rhythm of new cell production is controlled in retinal progenitor cells, we studied the transcription pattern of clock genes in retina, including clock1a, clock1b, bmal1a (brain and muscle ARNT-Like), and per1b (period1b). We found that these genes have a strong diurnal rhythmic transcription during light-dark cycles but not in constant darkness. An oscillation in pcna transcription was also observed during light-dark cycles, but again not in constant darkness. Our results also indicate an association between Clock proteins and the upstream region of pcna (proliferating cellular nuclear antigen) gene. A luciferase reporter assay conducted in an inducible clock knockdown cell line further demonstrated that the mutation on predicted E-Boxes in pcna promoter region significantly attenuated the transcriptional activation induced by Clock protein. These results suggested that the diurnal rhythmic expression of clock genes in A. burtoni retina could be light dependent and might contribute to the daily regulation of the proliferation of the retina progenitors through key components of cell cycle machinery, for instance, pcna.

Cognitive skills and the evolution of social systems.

How do animal social skills influence evolution? Complex animal social behaviors require many cognitive skills including individual recognition and observational learning. For social systems to evolve, these abilities need to be transmitted genetically or culturally and supported by the evolution of underlying neural systems. Because animal skill sets are so varied, it seems best to describe animal cognitive behaviors as being a social calculus that can change with experience, which has evolved to match and facilitate the complexity of the social system where it arose. That is, acquiring and using social information in response to a rapidly changing complex world leads to social competence enabling success in essential behavioral interactions. Here, we describe the remarkable suite of social skills discovered in the African cichlid fish Astatotilapia burtoni, including an attention hierarchy, male deception, transitive inference, the mechanistic bases of social dominance, female mate choice and the neural control of female reproductive behavior. The social calculus of this species is presented as an example of a potential causal factor in the evolution of sophisticated social behavior necessary for the evolutionary success of their social system.

Identification of prohormones and pituitary neuropeptides in the African cichlid, Astatotilapia burtoni.

BACKGROUND: Cichlid fishes have evolved remarkably diverse reproductive, social, and feeding behaviors. Cell-to-cell signaling molecules, notably neuropeptides and peptide hormones, are known to regulate these behaviors across vertebrates. This class of signaling molecules derives from prohormone genes that have undergone multiple duplications and losses in fishes. Whether and how subfunctionalization, neofunctionalization, or losses of neuropeptides and peptide hormones have contributed to fish behavioral diversity is largely unknown. Information on fish prohormones has been limited and is complicated by the whole genome duplication of the teleost ancestor. We combined bioinformatics, mass spectrometry-enabled peptidomics, and molecular techniques to identify the suite of neuropeptide prohormones and pituitary peptide products in Astatotilapia burtoni, a well-studied member of the diverse African cichlid clade. RESULTS: Utilizing the A. burtoni genome, we identified 148 prohormone genes, with 21 identified as a single copy and 39 with at least 2 duplicated copies. Retention of prohormone duplicates was therefore 41 %, which is markedly above previous reports for the genome-wide average in teleosts. Beyond the expected whole genome duplication, differences between cichlids and mammals can be attributed to gene loss in tetrapods and additional duplication after divergence. Mass spectrometric analysis of the pituitary identified 620 unique peptide sequences that were matched to 120 unique proteins. Finally, we used in situ hybridization to localize the expression of galanin, a prohormone with exceptional sequence divergence in cichlids, as well as the expression of a proopiomelanocortin, prohormone that has undergone an additional duplication in some bony fish lineages. CONCLUSION: We characterized the A. burtoni prohormone complement. Two thirds of prohormone families contain duplications either from the teleost whole genome duplication or a more recent duplication. Our bioinformatic and mass spectrometric findings provide information on a major vertebrate clade that will further our understanding of the functional ramifications of these prohormone losses, duplications, and sequence changes across vertebrate evolution. In the context of the cichlid radiation, these findings will also facilitate the exploration of neuropeptide and peptide hormone function in behavioral diversity both within A. burtoni and across cichlid and other fish species.

Polygenic sex determination in the cichlid fish Astatotilapia burtoni.

BACKGROUND: The East African riverine cichlid species Astatotilapia burtoni serves as an important laboratory model for sexually dimorphic physiology and behavior, and also serves as an outgroup species for the explosive adaptive radiations of cichlid species in Lake Malawi and Lake Victoria. An astounding diversity of genetic sex determination systems have been revealed within the adaptive radiation of East African cichlids thus far, including polygenic sex determination systems involving the epistatic interaction of multiple, independently segregating sex determination alleles. However, sex determination has remained unmapped in A. burtoni. Here we present mapping results supporting the presence of multiple, novel sex determination alleles, and thus the presence of polygenic sex determination in A. burtoni. RESULTS: Using mapping in small families in conjunction with restriction-site associated DNA sequencing strategies, we identify associations with sex at loci on linkage group 13 and linkage group 5-14. Inheritance patterns support an XY sex determination system on linkage group 5-14 (a chromosome fusion relative to other cichlids studied), and an XYW system on linkage group 13, and these associations are replicated in multiple families. Additionally, combining our genetic data with comparative genomic analysis identifies another fusion that is unassociated with sex, with linkage group 8-24 and linkage group 16-21 fused in A. burtoni relative to other East African cichlid species. CONCLUSIONS: We identify genetic signals supporting the presence of three previously unidentified sex determination alleles at two loci in the species A. burtoni, strongly supporting the presence of polygenic sex determination system in the species. These results provide a foundation for future mapping of multiple sex determination genes and their interactions. A better understanding of sex determination in A. burtoni provides important context for their use in behavioral studies, as well as studies of the evolution of genetic sex determination and sexual conflicts in East African cichlids.

Dopaminergic inhibition of gonadotropin-releasing hormone neurons in the cichlid fish Astatotilapia burtoni.

Dopamine regulates reproduction in part by modulating neuronal activity within the hypothalamic-pituitary-gonadal (HPG) axis. Previous studies suggested numerous mechanisms by which dopamine exerts inhibitory control over the HPG axis, ultimately changing the levels of sex steroids that regulate reproductive behaviors. However, it is not known whether these mechanisms are conserved across vertebrate species. In particular, it is unknown whether mechanisms underlying dopaminergic control of reproduction are shared between mammals and teleost fish. In mammals, dopamine directly inhibits gonadotropin-releasing hormone (GnRH1) hypothalamic neurons, the gatekeepers for activation of the HPG axis. Here, we demonstrate, for the first time in teleost fish, dopaminergic control of GnRH1 neurons via direct dopamine type-2-like receptor (D2R)-mediated inhibition within the hypothalamus. These results suggest that direct dopaminergic control of GnRH1 neurons via interactions in the hypothalamus is not exclusive to tetrapod reproductive control, but is likely conserved across vertebrate species.

Social information changes the brain.

Social animals live in complex physical and social environments requiring them to attend and rapidly respond to social and environmental information by changing their behavior. A key social influence is rank or status, a ubiquitous element in animal societies. Rank typically regulates access to reproduction and other resources, among other consequences for individuals. Because reproduction is arguably the most important event in any animals' life, understanding how reproduction is regulated by social status and related physiological factors can instruct our understanding of evolutionary change. This article reviews evidence from a model social system in which reproduction is tightly controlled by social status. Surprisingly, changes in social status have rapid and profound effects over very short time scales and radically alter overt behavior, as well as physiological, cellular, and molecular factors that regulate reproductive capacity.

Social regulation of cortisol receptor gene expression.

In many social species, individuals influence the reproductive capacity of conspecifics. In a well-studied African cichlid fish species, Astatotilapia burtoni, males are either dominant (D) and reproductively competent or non-dominant (ND) and reproductively suppressed as evidenced by reduced gonadotropin releasing hormone (GnRH1) release, regressed gonads, lower levels of androgens and elevated levels of cortisol. Here, we asked whether androgen and cortisol levels might regulate this reproductive suppression. Astatotilapia burtoni has four glucocorticoid receptors (GR1a, GR1b, GR2 and MR), encoded by three genes, and two androgen receptors (ARα and ARß), encoded by two genes. We previously showed that ARα and ARß are expressed in GnRH1 neurons in the preoptic area (POA), which regulates reproduction, and that the mRNA levels of these receptors are regulated by social status. Here, we show that GR1, GR2 and MR mRNAs are also expressed in GnRH1 neurons in the POA, revealing potential mechanisms for both androgens and cortisol to influence reproductive capacity. We measured AR, MR and GR mRNA expression levels in a microdissected region of the POA containing GnRH1 neurons, comparing D and ND males. Using quantitative PCR (qPCR), we found D males had higher mRNA levels of ARα, MR, total GR1a and GR2 in the POA compared with ND males. In contrast, ND males had significantly higher levels of GR1b mRNA, a receptor subtype with a reduced transcriptional response to cortisol. Through this novel regulation of receptor type, neurons in the POA of an ND male will be less affected by the higher levels of cortisol typical of low status, suggesting GR receptor type change as a potential adaptive mechanism to mediate high cortisol levels during social suppression.

Social status differences regulate the serotonergic system of a cichlid fish, Astatotilapia burtoni.

Serotonin (5-HT) inhibits aggression and modulates aspects of sexual behaviour in many species, but the mechanisms responsible are not well understood. Here, we exploited the social dominance hierarchy of Astatotilapia burtoni to understand the role of the serotonergic system in long-term maintenance of social status. We identified three populations of 5-HT cells in dorsal and ventral periventricular pretectal nuclei (PPd, PPv), the nucleus of the paraventricular organ (PVO) and raphe. Dominant males had more 5-HT cells than subordinates in the raphe, but the size of these cells did not differ between social groups. Subordinates had higher serotonergic turnover in the raphe and preoptic area (POA), a nucleus essential for hypothalamic-pituitary-gonadal (HPG) axis function. The relative abundance of mRNAs for 5-HT receptor (5-HTR) subtypes 1A and 2A (htr1a, htr2a) was higher in subordinates, a difference restricted to the telencephalon. Because social status is tightly linked to reproductive capacity, we asked whether serotonin turnover and the expression of its receptors correlated with testes size and circulating levels of 11-ketotestosterone (11-KT). We found negative correlations between both raphe and POA serotonin turnover and testes size, as well as between htr1a mRNA levels and circulating 11-KT. Thus, increased serotonin turnover in non-aggressive males is restricted to specific brain nuclei and is associated with increased expression of 5-HTR subtypes 1A and 2A exclusively in the telencephalon.

Brains over brawn: experience overcomes a size disadvantage in fish social hierarchies.

Life experiences can alter cognitive abilities and subsequent behavior. Here we asked whether differences in experience could affect social status. In hierarchical animal societies, high-ranking males that typically win aggressive encounters gain territories and hence access to mates. To understand the relative contributions of social experience and physical environment on status, we used a highly territorial African cichlid fish species, Astatotilapia burtoni, that lives in a dynamic lek-like social hierarchy. Astatotilapia burtoni males are either dominant or submissive and can switch status rapidly depending on the local environment. Although dominant males are innately aggressive, we wondered whether they modulated their aggression based on experience. We hypothesized that as males mature they might hone their fighting tactics based on observation of other males fighting. We compared males of different ages and sizes in distinctly different physical environments and subsequently tested their fighting skills. We found that a size difference previously thought negligible (<10% body length) gave a significant advantage to the larger opponent. In contrast, we found no evidence that increasing environmental complexity affected status outcomes. Surprisingly, we found that males only a few days older than their opponents had a significant advantage during territorial disputes so that being older compensated for the disadvantage of being smaller. Moreover, the slightly older winners exploited a consistent fighting strategy, starting with lower levels of aggression on the first day that significantly increased on the second day, a pattern absent in younger winners. These data suggest that experience is an advantage during fights for status, and that social learning provides more relevant experience than the physical complexity of the territory.

Social descent with territory loss causes rapid behavioral, endocrine and transcriptional changes in the brain.

In social species that form hierarchies where only dominant males reproduce, lower-ranking individuals may challenge higher-ranking ones, often resulting in changes in relative social status. How does a losing animal respond to loss of status? Here, using the African cichlid fish Astatotilapia burtoni, we manipulated the social environment, causing males to descend in rank, and then examined changes in behavior, circulating steroids and immediate early gene (IEG) expression (cfos, egr-1) in micro-dissected brain regions as a proxy for neuronal activation. In particular, we examined changes in the conserved 'social behavior network' (SBN), a collection of brain nuclei known to regulate social behaviors across vertebrates. Astatotilapia burtoni has rapidly reversible dominant-subordinate male phenotypes, so that within minutes, descending males lost their bright body coloration, switched to submissive behaviors and expressed higher plasma cortisol levels compared with non-descending and control males. Descending males had higher IEG expression throughout the SBN, but each brain region showed a distinct IEG-specific response in either cfos or egr-1 levels, but not both. Overall, SBN IEG patterns in descending males were distinctly different from the pattern observed in males ascending (subordinate to dominant) in social status. These results reveal that the SBN rapidly coordinates the perception of social cues about status that are of opposite valence, and translates them into appropriate phenotypic changes. This shows for the first time in a non-mammalian vertebrate that dropping in social rank rapidly activates specific socially relevant brain nuclei in a pattern that differs from when males rise to a higher status position.

Fish can infer social rank by observation alone.

Transitive inference (TI) involves using known relationships to deduce unknown ones (for example, using A > B and B > C to infer A > C), and is thus essential to logical reasoning. First described as a developmental milestone in children, TI has since been reported in nonhuman primates, rats and birds. Still, how animals acquire and represent transitive relationships and why such abilities might have evolved remain open problems. Here we show that male fish (Astatotilapia burtoni) can successfully make inferences on a hierarchy implied by pairwise fights between rival males. These fish learned the implied hierarchy vicariously (as 'bystanders'), by watching fights between rivals arranged around them in separate tank units. Our findings show that fish use TI when trained on socially relevant stimuli, and that they can make such inferences by using indirect information alone. Further, these bystanders seem to have both spatial and featural representations related to rival abilities, which they can use to make correct inferences depending on what kind of information is available to them. Beyond extending TI to fish and experimentally demonstrating indirect TI learning in animals, these results indicate that a universal mechanism underlying TI is unlikely. Rather, animals probably use multiple domain-specific representations adapted to different social and ecological pressures that they encounter during the course of their natural lives.

Female genomic response to mate information.

Females should be choosier than males about prospective mates because of the high costs of inappropriate mating decisions. Both theoretical and empirical studies have identified factors likely to influence female mate choices. However, male-male social interactions also can affect mating decisions, because information about a potential mate can trigger changes in female reproductive physiology. We asked how social information about a preferred male influenced neural activity in females, using immediate early gene (IEG) expression as a proxy for brain activity. A gravid female cichlid fish (Astatotilapia burtoni) chose between two socially equivalent males and then saw fights between these two males in which her preferred male either won or lost. We measured IEG expression levels in several brain nuclei including those in the vertebrate social behavior network (SBN), a collection of brain nuclei known to be important in social behavior. When the female saw her preferred male win a fight, SBN nuclei associated with reproduction were activated, but when she saw her preferred male lose a fight, the lateral septum, a nucleus associated with anxiety, was activated instead. Thus social information alone, independent of actual social interactions, activates specific brain regions that differ significantly depending on what the female sees. In female brains, reproductive centers are activated when she chooses a winner, and anxiety-like response centers are activated when she chooses a loser. These experiments assessing the role of mate-choice information on the brain using a paradigm of successive presentations of mate information suggest ways to understand the consequences of social information on animals using IEG expression.

Social regulation of gene expression in the hypothalamic-pituitary-gonadal axis.

Reproduction is a critically important event in every animals' life and in all vertebrates is controlled by the brain via the hypothalamic-pituitary-gonadal (HPG) axis. In many species, this axis, and hence reproductive fitness, can be profoundly influenced by the social environment. Here, we review how the reception of information in a social context causes genomic changes at each level of the HPG axis.