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Paternal nicotine taking elicits heritable sex-specific phenotypes that are mediated by hippocampal Satb2

Molecular Psychiatry volume 27, pages 3864–3874 (2022)Cite this article

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Abstract

Nicotine intake, whether through tobacco smoking or e-cigarettes, remains a global health concern. An emerging preclinical literature indicates that parental nicotine exposure produces behavioral, physiological, and molecular changes in subsequent generations. However, the heritable effects of voluntary parental nicotine taking are unknown. Here, we show increased acquisition of nicotine taking in male and female offspring of sires that self-administered nicotine. In contrast, self-administration of sucrose and cocaine were unaltered in male and female offspring suggesting that the intergenerational effects of paternal nicotine taking may be reinforcer specific. Further characterization revealed memory deficits and increased anxiety-like behaviors in drug-naive male, but not female, offspring of nicotine-experienced sires. Using an unbiased, genome-wide approach, we discovered that these phenotypes were associated with decreased expression of Satb2, a transcription factor known to play important roles in synaptic plasticity and memory formation, in the hippocampus of nicotine-sired male offspring. This effect was sex-specific as no changes in Satb2 expression were found in nicotine-sired female offspring. Finally, increasing Satb2 levels in the hippocampus prevented the escalation of nicotine intake and rescued the memory deficits associated with paternal nicotine taking in male offspring. Collectively, these findings indicate that paternal nicotine taking produces heritable sex-specific molecular changes that promote addiction-like phenotypes and memory impairments in male offspring.

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Fig. 1: Nicotine self-administration by the F0 sires.
Fig. 2: Increased vulnerability to nicotine taking in the offspring of nicotine-experienced sires.
Fig. 3: Paternal nicotine taking is associated with sex-specific spatial memory impairments in the F1 generation.
Fig. 4: Satb2 is downregulated in the hippocampus of nicotine-sired male offspring.
Fig. 5: Increased Satb2 expression in the hippocampus of nicotine-sired male offspring rescues the behavioral deficits associated with paternal nicotine taking.

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Acknowledgements

We thank Adrian Arreola, Duncan Van Nest, Jordan Wolfheimer, and Riley Merkel for their technical contributions, and members of the Center for Interdisciplinary Research on Nicotine Addiction (CIRNA) at Penn for their input and support. We also thank the Next-Generation Sequencing Core (NGSC) at Penn and its Directors Dr. Jonathan Schug (Technical Director) and Dr. John Tobias (Technical Director for Bioinformatics).

Funding

This work was supported by the following grants from the National Institute on Drug Abuse (NIDA): R01 DA037897, R21 DA039393 and R21 DA045792 (HDS), R01 DA033641 (RCP), T32 DA028874 (RJH and MEW), T32 GM008076 (JF), and K01 DA039308 (MEW). This study was also supported by a grant from the Pennsylvania Department of Health (HDS).

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Authors and Affiliations

  1. Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John J. Maurer, Christopher A. Turner, Rae J. Herman, Yafang Zhang, Kael Ragnini, Julia Ferrante, Blake A. Kimmey & Heath D. Schmidt

  2. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    John J. Maurer, Christopher A. Turner, Rae J. Herman, Yafang Zhang, Kael Ragnini, Julia Ferrante, Blake A. Kimmey, Richard C. Crist & Heath D. Schmidt

  3. Department of Psychology, College of Liberal Arts, Temple University, Philadelphia, PA, 19122, USA

    Mathieu E. Wimmer

  4. Brain Health Institute and Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, 08854, USA

    R. Christopher Pierce

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Contributions

JJM, MEW, RCP, and HDS were responsible for the study concept and design. JJM, MEW, CAT, RJH, YZ, KR, JF, BAK, RCC and HDS performed experiments and analyzed the data. JJM, RCC and HDS prepared the figures. JJM, MEW, RCC, RCP and HDS drafted the manuscript. All authors reviewed content and approved the final version for publication.

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Correspondence to Heath D. Schmidt.

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Maurer, J.J., Wimmer, M.E., Turner, C.A. et al. Paternal nicotine taking elicits heritable sex-specific phenotypes that are mediated by hippocampal Satb2. Mol Psychiatry 27, 3864–3874 (2022). https://doi.org/10.1038/s41380-022-01622-7

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