Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
655—Social Behavior: Regulatory Factors
Tuesday, November 12, 2013, 1:00 pm - 5:00 pm
655.01: Epigenetic regulation of pair-bond formation in the monogamous prairie voles
Location: Halls B-H
*F. DUCLOT1,2,3, H. WANG1,4,2, Y. LIU4,2, Z. WANG4,2, M. KABBAJ1,2,3; 1Biomed. Sci., 2Neurosci. Program, 3Ctr. for Brain Repair, 4Psychology, Florida State Univ., Tallahassee, FL
Abstract Body: The formation of a strong and enduring social attachment between two sexually mature adults (a pair-bond) is a core characteristic of human social behaviors. As such, impairments of social affiliation are a common feature in a multitude of neuropsychiatric disorders including schizophrenia and autism spectrum disorders, therefore highlighting the importance of understanding the neurobiology of social attachment. The socially monogamous prairie vole (Microtus ochrogaster) provides an excellent opportunity to study the neurobiology of social behavior. In prairie voles, cohabitation with mating induces enduring pair bonds indicated by the formation of partner preference, and regulated by a variety of neurotransmitters including oxytocin, vasopressin (AVP), and dopamine. Here we tested the hypothesis that an epigenetic basis mediates the neurotransmitter regulation of pair bonding. Adult female prairie voles were treated with two histone deacetylase (HDAC) inhibitors, sodium butyrate (NaB) or Trichostatin A (TSA), and allowed to cohabitate with a male for six hours without mating, which does not induce partner preference in control animals. Remarkably, females treated with either HDAC inhibitor developed a partner preference, while control females did not. Intracerebroventricular infusion of TSA up-regulated oxytocin receptor (OTR) mRNA and proteins levels, as well as AVP V1a receptor (V1aR) protein levels, in the nucleus accumbens (NAcc) but not in the caudate putamen (CP). Dopamine receptors levels remained unaffected by the TSA treatment. Interestingly, chromatin immunoprecipitation analyses revealed that TSA enhanced histone acetylation at the OTR and V1aR gene promoters in the NAcc but not in the CP. Furthermore, the facilitation of partner preference by TSA was blocked by co administration of either OTR or V1aR antagonists in the NAcc. Altogether, this demonstrates that TSA facilitates the formation of partner preference via an epigenetic up-regulation of OTR- and V1aR-mediated neurotransmissions. Importantly, TSA did not affect OTR and V1aR expression in the absence of cohabitation with a male, whereas cohabitation with mating, which reliably leads to partner preference, up-regulated OTR and V1aR genes expression in the NAcc through local increase in histone acetylation, similar to TSA. In addition to suggest that TSA potentiates an endogenous process naturally triggered by cohabitation with a male, our data pave the way for new pharmacological possibilities to influence social behaviors and social attachment in particular.
Lay Language Summary: Social bonding is an intrinsic characteristic of the human nature and amongst the most powerful driving forces of human behaviors. As such, alterations in the ability to form enduring social attachments are common features of severe neuropsychiatric disorders such as schizophrenia and autism. However, we surprisingly know little about the mechanisms directing the formation of a pair bond and its imprint on the brain. Our research indicates that the formation of a pair bond induces in the brain chemical modifications of the DNA structure, called epigenetic modifications, influencing the expression of genes related to social monogamy. Moreover, drugs that regulate such epigenetic modifications can facilitate pair bond formation. Such epigenetic mechanisms have already been identified in the regulation of other social behaviors and social bonds, such as between mothers and their offspring in rats. Previous studies in prairie voles, socially monogamous rodents that form lifelong pair-bonds, have identified oxytocin and vasopressin as major regulators of pair-bond formation following social cohabitation and mating. However, how such experiences induce enduring changes in social behaviors remained to be explained. Our work indicates for the first time that epigenetic modifications regulate the formation of a pair bond in the socially monogamous prairie voles. To test this hypothesis, we measured the acetylation of histones, an epigenetic modification relaxing the DNA structure and promoting gene expression, in the brain of female prairie voles that cohabitated and mated with a male for 24 hours. This protocol, which reliably initiates the formation of a pair bond, increased the expression of genes coding for the receptors to oxytocin and vasopressin in the nucleus accumbens, a brain region closely associated with reinforcement and reward. Notably, this activation of gene expression was mediated through a higher histone acetylation, suggesting that the formation of a pair bond induces an epigenetic reprogramming of gene expression. Under normal conditions, a shorter period of cohabitation without mating is insufficient to initiate the formation of the bond in prairie voles. However, females pre-treated with Trichostatin A (TSA), which promotes high levels of histone acetylation in the brain, displayed a selective preference for the male with which they cohabitated, even if this cohabitation was for a short period of time and without mating. Similar to females who mated, females treated with TSA had higher levels of histone acetylation around the genes coding for the receptors to oxytocin and vasopressin, thereafter promoting their expression in the nucleus accumbens. In this experiment, treatment with TSA played the role of mating and thus facilitated the formation of the pair-bond, even in conditions that normally are insufficient. These results suggest that, in female prairie voles, cohabitation and mating with a male triggers specific neuroadaptations in the brain through an epigenetic reprogramming of gene expression. Notably, our work shows that by promoting the expression of specific gene epigenetically with TSA, it is possible to trigger the formation of pair-bonding. Whether or not similar epigenetic modifications are involved in the maintenance of the bond throughout life, however, still remains to be understood. Social bonding is an intrinsic part of our nature and alterations in the ability to form enduring social attachments are common features of neuropsychiatric disorders. Our results will ultimately lead to a better understanding of the mechanisms of social bonding, and open a new potential approach to influence not only social bonding, but other social behaviors as well.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit