期刊
BIOLOGICAL PSYCHIATRY
卷 85, 期 3, 页码 248-256出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2018.07.028
关键词
Behavioral sensitivity; Extinction training; Glomeruli; Olfaction; Olfactory sensory neurons; Sperm
资金
- National Institute of Health (NIH) [R01-MH108665, R01-HD071982, R21-HD088931]
- Ruth L. Kirschtein National Research Service Award Predoctoral Fellowship [F31 MH105237-01]
- Emory University Department of Psychiatry and Behavioral Sciences
- Emory Brain Health Institute
- Yerkes National Primate Research Center (YNPRC)
- Canadian Institute for Advanced Research Azrieli Global Scholar Award
- NIH Director's Office of Research Infrastructure Programs [P51OD11132]
- Catherine Shopshire Hardman Fund
BACKGROUND: Stressors affect populations exposed to them as well as offspring. Strategies preventing the intergenerational propagation of effects of stress would benefit public health. Olfactory cue-based fear conditioning provides a framework to address this issue. METHODS: We 1) exposed adult male mice to an odor, acetophenone (Ace) or Lyral (parental generation [F0]-Exposed), 2) trained mice to associate these odors with mild foot shocks (F0-Trained), and 3) trained mice to associate these odors with mild foot shocks and then extinguished their fear toward these odors with odor-only presentations (F0-Extinguished). We then examined sensitivity of future generation (F1) offspring to these odors, expression of M71 odorant (Ace-responsive) and MOR23 odorant (Lyral-responsive) receptor-expressing cell populations in F1 offspring, and DNA methylation at genes encoding the Ace- (Olfr151, Olfr160) and Lyral- (Olfr16) responsive receptors in F0 sperm. RESULTS: Extinguishing fear toward Ace or Lyral of F0 male mice (F0-Extinguished) that had been fear conditioned with Ace or Lyral, respectively, results in F1-Extinguished offspring that do not demonstrate behavioral sensitivity to Ace or Lyral, respectively, and do not have enhanced representation for M71 or MOR23 odorant receptors in the olfactory system, as is observed in F1-Trained-Ace or F1-Trained-Lyral cohorts, respectively. The promoters of genes encoding Olfr151 and Olfr160 receptors are less methylated in F0-Trained-Ace sperm compared with F0-Exposed-Ace sperm. The Olfr16 promoter is less methylated in F0-Trained-Lyral sperm compared with F0-Exposed-Lyral sperm, and F0-Extinguished-Lyral sperm have methylation levels comparable to F0-Exposed-Lyral sperm. CONCLUSIONS: Our study demonstrates the potential of using extinction-based behavioral strategies to reverse influences of parental stress in offspring and in the parental germline.
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