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Parental olfactory experience influences behavior and neural structure in subsequent generations

Nature Neuroscience 17, 89–96 (2014) | Download Citation

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Abstract

Using olfactory molecular specificity, we examined the inheritance of parental traumatic exposure, a phenomenon that has been frequently observed, but not understood. We subjected F0 mice to odor fear conditioning before conception and found that subsequently conceived F1 and F2 generations had an increased behavioral sensitivity to the F0-conditioned odor, but not to other odors. When an odor (acetophenone) that activates a known odorant receptor (Olfr151) was used to condition F0 mice, the behavioral sensitivity of the F1 and F2 generations to acetophenone was complemented by an enhanced neuroanatomical representation of the Olfr151 pathway. Bisulfite sequencing of sperm DNA from conditioned F0 males and F1 naive offspring revealed CpG hypomethylation in the Olfr151 gene. In addition, in vitro fertilization, F2 inheritance and cross-fostering revealed that these transgenerational effects are inherited via parental gametes. Our findings provide a framework for addressing how environmental information may be inherited transgenerationally at behavioral, neuroanatomical and epigenetic levels.

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Change history

  • 09 December 2013

    In the version of this article initially published online, the base grant to the Yerkes National Primate Research Center was omitted from the Acknowledgments. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We would like to thank the animal care staff in the Yerkes Neuroscience Vivarium for assistance with animal husbandry. A. Magklara, S. Lomvardas, B. Carone, O. Rando and A.F.H.M. Peters provided invaluable input on the ChIP experiments. We would like to thank H. Zhang and the staff of the Emory Transgenic Mouse/Gene Targeting Core Facility for assistance with IVF studies. Bisulfite conversion of sperm DNA and sequencing was carried out by Active Motif and we especially thank P. Labhart for addressing our data interpretation queries. Finally, we are grateful to S. Banerjee, R. Andero-Gali, D. Choi, J. Goodman and F. Morrison for help with ensuring double-blindness of data acquisition and analysis, and members of the Ressler laboratory, S. Gourley and M. Davis for helpful feedback on the manuscript. Funding for this study was provided by the Howard Hughes Medical Institute and the Burroughs Wellcome Fund to K.J.R., and a US National Institutes of Health NCRR base grant (P51RR00-0165) to Yerkes National Primate Research Center.

Author information

Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.

    • Brian G Dias
    •  & Kerry J Ressler

  2. Yerkes National Primate Research Center, Atlanta, Georgia, USA.

    • Brian G Dias
    •  & Kerry J Ressler

  3. Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

    • Kerry J Ressler

Authors

  1. Search for Brian G Dias in:

  2. Search for Kerry J Ressler in:

Contributions

B.G.D. conceived of the project, designed and performed experiments, analyzed the data, and wrote the paper. K.J.R. obtained funds, designed experiments, analyzed the data, wrote the paper and supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Brian G Dias or Kerry J Ressler.

Integrated supplementary information

Supplementary figures

  1. 1.

    Experimental design to investigate the effect of cue-specific trauma to an F0 generation on subsequently conceived generations.

  2. 2.

    No differences found in anxiety measures in adult male offspring that had been conceived after the F0 generation males had been subjected to olfactory fear conditioning with acetophenone or propanol.

  3. 3.

    No differences in auditory fear conditioning in adult male offspring that had been conceived after the F0 generation males had been subjected to olfactory fear conditioning with acetophenone or propanol.

  4. 4.

    Cross-fostering study to determine transmission versus inheritance of observed effects.

  5. 5.

    Bisulfite sequencing around the Olfr151 and Olfr6 genes was conducted to query the methylation status of CpG di-nucleotides.

  6. 6.

    Methylation status of CpG di-nucleotides in the Olfr151 (M71) gene in MOE DNA of the odor naive F1 and F2 generations.

  7. 7.

    Validation of Sperm N-ChIP protocol, and histone modifications around the M71 locus in the sperm of F0 males (fathers) that had been subjected to olfactory fear conditioning.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7

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DOI

https://doi.org/10.1038/nn.3594

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