Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles

Abstract

In the socially monogamous prairie vole (Microtus ochrogaster), mating induces enduring pair-bonds that are initiated by partner preference formation and regulated by a variety of neurotransmitters, including oxytocin, vasopressin and dopamine. We examined potential epigenetic mechanisms mediating pair-bond regulation and found that the histone deacetylase inhibitors sodium butyrate and trichostatin A (TSA) facilitated partner preference formation in female prairie voles in the absence of mating. This was associated with a specific upregulation of oxytocin receptor (OTR, oxtr) and vasopressin V1a receptor (V1aR, avpr1a) in the nucleus accumbens (NAcc), through an increase in histone acetylation at their respective promoters. Furthermore, TSA-facilitated partner preference was prevented by OTR or V1aR blockade in the NAcc. Notably, mating-induced partner preference triggered the same epigenetic regulation of oxtr and avpr1a gene promoters as TSA. These observations indicate that TSA and mating facilitate partner preference through epigenetic events, providing, to the best of our knowledge, the first direct evidence for epigenetic regulation of pair-bonding.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: An acute injection of TSA facilitates partner preference formation in female prairie voles in the absence of mating.
Figure 2: TSA treatment (0.4 ng) upregulates OTR and V1aR in female prairie voles during cohabitation with a male in the absence of mating.
Figure 3: TSA treatment enhances histone acetylation of oxtr and avpr1a promoters during cohabitation with a male in the absence of mating.
Figure 4: TSA-facilitated partner preference requires OTR- and V1aR-mediated neurotransmission in the female NAcc.
Figure 5: Cohabitation with mating induces an upregulation of OTR and V1aR in the NAcc of female prairie voles.

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Bora, E., Yucel, M. & Allen, N.B. Neurobiology of human affiliative behavior: implications for psychiatric disorders. Curr. Opin. Psychiatry 22, 320–325 (2009).

    Article  Google Scholar 

  2. Thomas, J.A. & Birney, E.C. Parental care and mating system of the prairie vole (Microtus ochrogaster). Behav. Ecol. Sociobiol. 5, 171–186 (1979).

    Article  Google Scholar 

  3. Getz, L.L. & Hofmann, J.E. Social organization in free-living prairie voles (Microtus ochrogaster). Behav. Ecol. Sociobiol. 18, 275–282 (1986).

    Article  Google Scholar 

  4. Williams, J.R., Catania, K.C. & Carter, C.S. Development of partner preferences in female prairie voles (Microtus ochrogaster): the role of social and sexual experience. Horm. Behav. 26, 339–349 (1992).

    CAS  Article  Google Scholar 

  5. Young, K.A., Gobrogge, K.L., Liu, Y. & Wang, Z. The neurobiology of pair bonding: insights from a socially monogamous rodent. Front. Neuroendocrinol. 32, 53–69 (2011).

    Article  Google Scholar 

  6. Liu, Y., Curtis, J.T. & Wang, Z. Vasopressin in the lateral septum regulates pair bond formation in male prairie voles (Microtus ochrogaster). Behav. Neurosci. 115, 910–919 (2001).

    CAS  Article  Google Scholar 

  7. Lim, M.M. & Young, L.J. Vasopressin-dependent neural circuits underlying pair bond formation in the monogamous prairie vole. Neuroscience 125, 35–45 (2004).

    CAS  Article  Google Scholar 

  8. Liu, Y. & Wang, Z.X. Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles. Neuroscience 121, 537–544 (2003).

    CAS  Article  Google Scholar 

  9. Gingrich, B., Liu, Y., Cascio, C., Wang, Z. & Insel, T.R. Dopamine D2 receptors in the nucleus accumbens are important for social attachment in female prairie voles (Microtus ochrogaster). Behav. Neurosci. 114, 173–183 (2000).

    CAS  Article  Google Scholar 

  10. Aragona, B.J. et al. Nucleus accumbens dopamine differentially mediates the formation and maintenance of monogamous pair bonds. Nat. Neurosci. 9, 133–139 (2006).

    CAS  Article  Google Scholar 

  11. Liu, Y. et al. Nucleus accumbens dopamine mediates amphetamine-induced impairment of social bonding in a monogamous rodent species. Proc. Natl. Acad. Sci. USA 107, 1217–1222 (2010).

    CAS  Article  Google Scholar 

  12. Keebaugh, A.C. & Young, L.J. Increasing oxytocin receptor expression in the nucleus accumbens of pre-pubertal female prairie voles enhances alloparental responsiveness and partner preference formation as adults. Horm. Behav. 60, 498–504 (2011).

    CAS  Article  Google Scholar 

  13. Ross, H.E. et al. Variation in oxytocin receptor density in the nucleus accumbens has differential effects on affiliative behaviors in monogamous and polygamous voles. J. Neurosci. 29, 1312–1318 (2009).

    CAS  Article  Google Scholar 

  14. Pitkow, L.J. et al. Facilitation of affiliation and pair-bond formation by vasopressin receptor gene transfer into the ventral forebrain of a monogamous vole. J. Neurosci. 21, 7392–7396 (2001).

    CAS  Article  Google Scholar 

  15. Veenema, A.H. Toward understanding how early-life social experiences alter oxytocin- and vasopressin-regulated social behaviors. Horm. Behav. 61, 304–312 (2012).

    CAS  Article  Google Scholar 

  16. Francis, D.D., Young, L.J., Meaney, M.J. & Insel, T.R. Naturally occurring differences in maternal care are associated with the expression of pxytocin and vasopressin (V1a) receptors: gender differences. J. Neuroendocrinol. 14, 349–353 (2002).

    CAS  Article  Google Scholar 

  17. Champagne, F.A. et al. Maternal care associated with methylation of the estrogen receptor-α1b promoter and estrogen receptor-α expression in the medial preoptic area of female offspring. Endocrinology 147, 2909–2915 (2006).

    CAS  Article  Google Scholar 

  18. Murgatroyd, C. et al. Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat. Neurosci. 12, 1559–1566 (2009).

    CAS  Article  Google Scholar 

  19. Weaver, I.C.G. et al. Epigenetic programming by maternal behavior. Nat. Neurosci. 7, 847–854 (2004).

    CAS  Article  Google Scholar 

  20. Weaver, I.C.G., Meaney, M.J. & Szyf, M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc. Natl. Acad. Sci. USA 103, 3480–3485 (2006).

    CAS  Article  Google Scholar 

  21. Bonthuis, P.J., Patteson, J.K. & Rissman, E.F. Acquisition of sexual receptivity: roles of chromatin acetylation, estrogen receptor-α, and ovarian hormones. Endocrinology 152, 3172–3181 (2011).

    CAS  Article  Google Scholar 

  22. Zhong, S., Fields, C.R., Su, N., Pan, Y.X. & Robertson, K.D. Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer. Oncogene 26, 2621–2634 (2007).

    CAS  Article  Google Scholar 

  23. Yoshida, M., Horinouchi, S. & Beppu, T. Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function. Bioessays 17, 423–430 (1995).

    CAS  Article  Google Scholar 

  24. Monneret, C. Histone deacetylase inhibitors. Eur. J. Med. Chem. 40, 1–13 (2005).

    CAS  Article  Google Scholar 

  25. Ross, H.E. et al. Characterization of the oxytocin system regulating affiliative behavior in female prairie voles. Neuroscience 162, 892–903 (2009).

    CAS  Article  Google Scholar 

  26. Young, L.J., Huot, B., Nilsen, R., Wang, Z. & Insel, T.R. Species differences in central oxytocin receptor gene expression: comparative analysis of promoter sequences. J. Neuroendocrinol. 8, 777–783 (1996).

    CAS  Article  Google Scholar 

  27. Witt, O., Deubzer, H.E., Milde, T. & Oehme, I. HDAC family: What are the cancer relevant targets? Cancer Lett. 277, 8–21 (2009).

    CAS  Article  Google Scholar 

  28. Vecsey, C.G. et al. Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB: CBP-dependent transcriptional activation. J. Neurosci. 27, 6128–6140 (2007).

    CAS  Article  Google Scholar 

  29. Monsey, M.S., Ota, K.T., Akingbade, I.F., Hong, E.S. & Schafe, G.E. Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala. PLoS ONE 6, e19958 (2011).

    CAS  Article  Google Scholar 

  30. Van Lint, C., Emiliani, S. & Verdin, E. The expression of a small fraction of cellular genes is changed in response to histone hyperacetylation. Gene Expr. 5, 245–253 (1996).

    CAS  PubMed  Google Scholar 

  31. Mariadason, J.M., Corner, G.A. & Augenlicht, L.H. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with Trichostatin A, sulindac, and curcumin and implications for chemoprevention of colon cancer. Cancer Res. 60, 4561–4572 (2000).

    CAS  PubMed  Google Scholar 

  32. Halsall, J., Gupta, V., O'Neill, L.P., Turner, B.M. & Nightingale, K.P. Genes are often sheltered from the global histone hyperacetylation induced by HDAC inhibitors. PLoS ONE 7, e33453 (2012).

    CAS  Article  Google Scholar 

  33. Ito, K. & Adcock, I. Histone acetylation and histone deacetylation. Mol. Biotechnol. 20, 99–106 (2002).

    CAS  Article  Google Scholar 

  34. Molfese, D.L. Advancing neuroscience through epigenetics: molecular mechanisms of learning and memory. Dev. Neuropsychol. 36, 810–827 (2011).

    Article  Google Scholar 

  35. Young, L.J., Lim, M.M., Gingrich, B. & Insel, T.R. Cellular mechanisms of social attachment. Horm. Behav. 40, 133–138 (2001).

    CAS  Article  Google Scholar 

  36. Hawk, J.D., Florian, C. & Abel, T. Post-training intrahippocampal inhibition of class I histone deacetylases enhances long-term object-location memory. Learn. Mem. 18, 367–370 (2011).

    CAS  Article  Google Scholar 

  37. Stefanko, D.P., Barrett, R.M., Ly, A.R., Reolon, G.K. & Wood, M.A. Modulation of long-term memory for object recognition via HDAC inhibition. Proc. Natl. Acad. Sci. USA 106, 9447–9452 (2009).

    CAS  Article  Google Scholar 

  38. Yang, X.-J. & Seto, E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31, 449–461 (2008).

    CAS  Article  Google Scholar 

  39. Cho, M.M., DeVries, A.C., Williams, J.R. & Carter, C.S. The effects of oxytocin and vasopressin on partner preferences in male and female prairie voles (Microtus ochrogaster). Behav. Neurosci. 113, 1071–1079 (1999).

    CAS  Article  Google Scholar 

  40. Insel, T.R. & Hulihan, T.J. A gender-specific mechanism for pair bonding: oxytocin and partner preference formation in monogamous voles. Behav. Neurosci. 109, 782–789 (1995).

    CAS  Article  Google Scholar 

  41. Stimson, L. & La Thangue, N.B. Biomarkers for predicting clinical responses to HDAC inhibitors. Cancer Lett. 280, 177–183 (2009).

    CAS  Article  Google Scholar 

  42. Iannitti, T. & Palmieri, B. Clinical and experimental applications of sodium phenylbutyrate. Drugs R D. 11, 227–249 (2011).

    Article  Google Scholar 

  43. Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005).

    CAS  Article  Google Scholar 

  44. Schroeder, F.A., Lin, C.L., Crusio, W.E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).

    CAS  Article  Google Scholar 

  45. Manning, M. et al. Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. in Progress in Brain Research (eds. D.N. Inga & L. Rainer) 473–512 (Elsevier, 2008).

  46. Witt, D.M. & Insel, T.R. A selective oxytocin antagonist attenuates progesterone facilitation of female sexual behavior. Endocrinology 128, 3269–3276 (1991).

    CAS  Article  Google Scholar 

  47. Winslow, J.T., Hastings, N., Carter, C.S., Harbaugh, C.R. & Insel, T.R. A role for central vasopressin in pair bonding in monogamous prairie voles. Nature 365, 545–548 (1993).

    CAS  Article  Google Scholar 

  48. Insel, T.R. Oxytocin–a neuropeptide for affiliation: evidence from behavioral, receptor autoradiographic, and comparative studies. Psychoneuroendocrinology 17, 3–35 (1992).

    CAS  Article  Google Scholar 

  49. Insel, T.R., Wang, Z. & Ferris, C. Patterns of brain vasopressin receptor distribution associated with social organization in microtine rodents. J. Neurosci. 14, 5381–5392 (1994).

    CAS  Article  Google Scholar 

  50. Hollis, F., Duclot, F., Gunjan, A. & Kabbaj, M. Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus. Horm. Behav. 59, 331–337 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We also thank M. Manning for the generous gift of the OTR antagonist OTA(T) (University of Toledo). This work was supported by grants from the National Institute of Mental Health (MHR21-083128 to M.K. and Z.W., and MHR01-058616 to Z.W.).

Author information

Authors and Affiliations

Authors

Contributions

H.W., F.D. and Y.L. performed the experiments. H.W. and F.D. analyzed the data. H.W., F.D., Z.W. and M.K. designed the study. F.D., Z.W. and M.K. wrote the paper. All of the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Zuoxin Wang or Mohamed Kabbaj.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 1011 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, H., Duclot, F., Liu, Y. et al. Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles. Nat Neurosci 16, 919–924 (2013). https://doi.org/10.1038/nn.3420

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3420

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing