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Peer-reviewedCC BYJournal of Neuroscience

Altered Postnatal Chromatin Development in the Nucleus Accumbens Primes Enduring Stress Sensitivity

  • Rebekah L. Rashford1
  • Lisa Z. Fang2
  • Michael DeBerardine1
  • Hye Ji J. Kim1
  • Laura W. Hirschfield1
  • Ella Cervi1
  • Mason R. Barrett2,3
  • Jeremy M. Thompson2
  • Meaghan C. Creed2,3
  • Catherine J. Peña1
  1. 1Princeton Neuroscience Institute, Princeton University, Princeton, NJ 08544, USA
  2. 2Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63110, USA
  3. 3Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, USA
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Abstract

Early life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc)—a key limbic and reward-associated brain region—ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase Setd7 in juvenile NAc of male and female mice induced persistent chromatin changes and predominately opened chromatin at long-range cis-regulatory elements predicted to enhance immediate early genes and transcriptional regulators of mesolimbic development and synaptic activity. These epigenetic changes altered physiological properties of D2-type medium spiny neurons in NAc to resemble neurons of stressed mice, without significantly altering D1-type neurons. Finally, juvenile—but not adult— Setd7 overexpression and H3K4me1 enrichment in NAc enhanced behavioral sensitivity to future stress. Together, these data indicate that altered postnatal chromatin development in NAc by H3K4me1 enrichment is sufficient to prime long-lasting transcriptional, physiological, and behavioral stress sensitivity.

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Cite

BibTeXRIS
BibTeX
@article{rashford2026altered,
  title = {{Altered Postnatal Chromatin Development in the Nucleus Accumbens Primes Enduring Stress Sensitivity}},
  author = {Rebekah L. Rashford and Lisa Z. Fang and Michael DeBerardine and Hye Ji J. Kim and Laura W. Hirschfield and Ella Cervi and Mason R. Barrett and Jeremy M. Thompson and Meaghan C. Creed and Catherine J. Peña},
  journal = {Journal of Neuroscience},
  year = {2026},
  month = jul,
  doi = {10.1523/jneurosci.2217-25.2026},
  url = {https://doi.org/10.1523/jneurosci.2217-25.2026},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Altered Postnatal Chromatin Development in the Nucleus Accumbens Primes Enduring Stress Sensitivity
AU  - Rebekah L. Rashford
AU  - Lisa Z. Fang
AU  - Michael DeBerardine
AU  - Hye Ji J. Kim
AU  - Laura W. Hirschfield
AU  - Ella Cervi
AU  - Mason R. Barrett
AU  - Jeremy M. Thompson
AU  - Meaghan C. Creed
AU  - Catherine J. Peña
PY  - 2026
DA  - 2026/07/23
JO  - Journal of Neuroscience
DO  - 10.1523/jneurosci.2217-25.2026
UR  - https://doi.org/10.1523/jneurosci.2217-25.2026
AB  - Early life stress (ELS) sensitizes individuals to subsequent stressors to increase lifetime risk for psychiatric disorders. Within the nucleus accumbens (NAc)—a key limbic and reward-associated brain region—ELS sensitizes both cellular and transcriptional response to later stress, which are programmed by enduring epigenetic changes. Among the histone modifications persistently enriched by ELS in NAc is H3K4me1, which is associated with open chromatin and epigenetic priming of genomic enhancers. Here, we sought to determine whether H3K4me1 enrichment in NAc was sufficient to prime cellular and behavioral responses to adult stress. Viral-mediated overexpression of the histone H3 monomethyltransferase Setd7 in juvenile NAc of male and female mice induced persistent chromatin changes and predominately opened chromatin at long-range cis-regulatory elements predicted to enhance immediate early genes and transcriptional regulators of mesolimbic development and synaptic activity. These epigenetic changes altered physiological properties of D2-type medium spiny neurons in NAc to resemble neurons of stressed mice, without significantly altering D1-type neurons. Finally, juvenile—but not adult— Setd7 overexpression and H3K4me1 enrichment in NAc enhanced behavioral sensitivity to future stress. Together, these data indicate that altered postnatal chromatin development in NAc by H3K4me1 enrichment is sufficient to prime long-lasting transcriptional, physiological, and behavioral stress sensitivity.
SN  - 0270-6474
SN  - 1529-2401
ER  -