Sperm transcriptional state associated with paternal transmission of stress phenotypes

Ashley M. Cunningham, Deena M. Walker, Aarthi Ramakrishnan, Marie A. Doyle, Rosemary C. Bagot, Hannah M. Cates, Catherine J. Peña, Orna Issler, Casey K. Lardner, Caleb Browne, Scott J. Russo, Li Shen, Eric J. Nestler

Research output: Contribution to journalArticlepeer-review

Abstract

Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend on paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination (AI) reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing (RNA-seq), we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible versus resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes (DEGs) in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience.

Original languageEnglish (US)
Pages (from-to)6202-6216
Number of pages15
JournalJournal of Neuroscience
Volume41
Issue number29
DOIs
StatePublished - Jul 21 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Anxiety
  • Intergenerational stress
  • RNA-sequencing
  • Sperm

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