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The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague–Dawley rats

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Abstract

Rationale

Social stress has been linked to several neuropsychiatric diseases, including depression, which is a debilitating disease that has genetic, environmental, and epigenetic underpinnings.

Objectives

This study examined the effects of repeated social defeat on both depressive-like behaviors and histone acetylation in the hippocampus, amygdala, and dorsal prefrontal cortex of male Sprague-Dawley rats.

Materials and methods

Subjects were exposed to four consecutive social defeats. Depressive-like behaviors were assayed in the sucrose preference, forced swim, contextual fear, and social approach and avoidance tests. Histone H3 and H4 acetylation in the hippocampus, amygdala, and prefrontal cortex were examined by Western blots under basal conditions and at several time points. We also investigated the potential involvement of N-methyl-d-aspartic acid (NMDA) receptors and glucocorticoid receptors (GR) by injecting respective antagonists prior to each social defeat and examining their effect on histone acetylation in the hippocampus.

Results

Social defeat resulted in behavioral changes in the forced swim, social avoidance, and contextual fear tests nearly 6 weeks after defeat, with no change in sucrose preference. Additionally, histone H3 acetylation was increased in the hippocampus 30 min following the last defeat and was not blocked by antagonism of either NMDA or GR receptors. There were no changes in histone H4 acetylation.

Conclusions

These results indicate that social defeat induces several long-lasting depressive-like behaviors in rats and induces a significant, short-lived increase in H3 acetylation in the hippocampus, although the underlying mechanism behind this change warrants further investigation.

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Acknowledgments

This work was supported by two National Institute of Drug Abuse (NIDA) grants (R01 DA019627-01 and R03 DA021554-01-A1) and National Institute of Mental Health (NIMH) grant (R21 MH081046-0182). F. Hollis is supported by the Florida State University Department of Biomedical Sciences Graduate program.

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Authors and Affiliations

  1. Department of Biomedical Sciences, Florida State University College of Medicine, 1115 W. Call St., Tallahassee, FL, 32306, USA

    Fiona Hollis, Hui Wang, David Dietz, Akash Gunjan & Mohamed Kabbaj

  2. Program in Neuroscience, Florida State University, Tallahassee, FL, USA

    David Dietz & Mohamed Kabbaj

Authors
  1. Fiona Hollis
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  2. Hui Wang
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  3. David Dietz
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  4. Akash Gunjan
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Corresponding author

Correspondence to Mohamed Kabbaj.

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Supplemental Figure 1

The effect of repeated defeat on histone H3 acetylation in the hippocampus 72 h following the last social defeat exposure. An additional group of 12 rats were used to compare histone acetylation 72 h following the last exposure to repeated defeat (72 h group) with basal, nondefeated controls (n = 6 per group). Hippocampi were tissue-punched at 2.0 mm and proteins were isolated as previously described. Western blots were probed with antibodies for H3 hyperacetylation and total H3, and then the ratio of acetylated histone H3 (H3hypAc) to total H3 (TH3) in each sample was calculated. At this time point, histone H3 acetylation has returned to baseline (p = 0.45) (DOCX 18 kb)

Supplementary Table S1

Timeline for experiment 1, investigating the effects of repeated social defeat on depressive-like behavior in rats (DOCX 14 kb)

Supplementary Table S2

The effect of repeated defeat on the ratio of histone H4 hyperacetylation to total H4. Repeated defeat had no significant effect on histone H4 acetylation in the hippocampus (HPC), the amygdala (AMG), or the prefrontal cortex (PFC). Data shown are mean values ± standard error (DOCX 45 kb)

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Hollis, F., Wang, H., Dietz, D. et al. The effects of repeated social defeat on long-term depressive-like behavior and short-term histone modifications in the hippocampus in male Sprague–Dawley rats. Psychopharmacology 211, 69–77 (2010). https://doi.org/10.1007/s00213-010-1869-9

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  • DOI: https://doi.org/10.1007/s00213-010-1869-9

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