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Transcriptomic profiling of reward and sensory brain areas in perinatal fentanyl exposed juvenile mice

Neuropsychopharmacology volume 48, pages 1724–1734 (2023)Cite this article

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Abstract

Use of the synthetic opioid fentanyl increased ~300% in the last decade, including among women of reproductive ages. Adverse neonatal outcomes and long-term behavioral disruptions are associated with perinatal opioid exposure. Our previous work demonstrated that perinatal fentanyl exposed mice displayed enhanced negative affect and somatosensory circuit and behavioral disruptions during adolescence. However, little is known about molecular adaptations across brain regions that underlie these outcomes. We performed RNA sequencing across three reward and two sensory brain areas to study transcriptional programs in perinatal fentanyl exposed juvenile mice. Pregnant dams received 10 μg/ml fentanyl in the drinking water from embryonic day 0 (E0) through gestational periods until weaning at postnatal day 21 (P21). RNA was extracted from nucleus accumbens (NAc), prelimbic cortex (PrL), ventral tegmental area (VTA), somatosensory cortex (S1) and ventrobasal thalamus (VBT) from perinatal fentanyl exposed mice of both sexes at P35. RNA sequencing was performed, followed by analysis of differentially expressed genes (DEGs) and gene co-expression networks. Transcriptome analysis revealed DEGs and gene modules significantly associated with exposure to perinatal fentanyl in a sex-wise manner. The VTA had the most DEGs, while robust gene enrichment occurred in NAc. Genes enriched in mitochondrial respiration were pronounced in NAc and VTA of perinatal fentanyl exposed males, extracellular matrix (ECM) and neuronal migration enrichment were pronounced in NAc and VTA of perinatal fentanyl exposed males, while genes associated with vesicular cycling and synaptic signaling were markedly altered in NAc of perinatal fentanyl exposed female mice. In sensory areas from perinatal fentanyl exposed females, we found alterations in mitochondrial respiration, synaptic and ciliary organization processes. Our findings demonstrate distinct transcriptomes across reward and sensory brain regions, with some showing discordance between sexes. These transcriptome adaptations may underlie structural, functional, and behavioral changes observed in perinatal fentanyl exposed mice.

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Fig. 1: Transcriptomic profiling of reward and sensory brain areas of perinatal fentanyl exposed juvenile mice.
Fig. 2: Threshold-free analysis of concordant and discordant gene overlap between sexes across brain areas in perinatal fentanyl exposed mice.
Fig. 3: Weighted gene co-expression network analyses (WGCNA) showing significant modules associated with fentanyl in a sex-wise manner in reward brain areas.
Fig. 4: WGCNA showing significant modules associated with fentanyl in a sex-wise manner in sensory brain areas.
Fig. 5: In silico predictions of top transcription factors regulating fentanyl associated developmental processes.

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Acknowledgements

The authors thank the UMSOM Institute for Genome Sciences for RNAseq services.

Funding

This work was supported by NIH R01DA054905 (to MKL, SAA, and AK), R01DA038613 (to MKL), University of Maryland Strategic Partnership Empowering the State, and University of Maryland School of Medicine (UMSOM) Center for Substance Use in Pregnancy.

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Authors and Affiliations

  1. Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Jimmy Olusakin, Gautam Kumar, Cali A. Calarco, Jason B. Alipio, Catherine Haga, Makeda D. Turner, Asaf Keller & Mary Kay Lobo

  2. Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA

    Jimmy Olusakin, Gautam Kumar, Cali A. Calarco, Jason B. Alipio, Catherine Haga, Asaf Keller, Seth A. Ament & Mary Kay Lobo

  3. Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Mahashweta Basu & Seth A. Ament

  4. Department of Anesthesiology, Penn State College of Medicine, Hershey, PA, USA

    Megan E. Fox

  5. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA

    Asaf Keller, Seth A. Ament & Mary Kay Lobo

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  1. Jimmy Olusakin
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Contributions

CAC, MEF, JBA, CH and MDT assisted with experiments and tissue collection. SAA, MB, JO and GK analyzed data. JO, MEF, MKL, AK and SAA oversaw experimental design. JO and MKL oversaw data interpretation and writing the manuscript. MKL conceived and directed the project. All authors reviewed and edited the manuscript.

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Correspondence to Mary Kay Lobo.

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Olusakin, J., Kumar, G., Basu, M. et al. Transcriptomic profiling of reward and sensory brain areas in perinatal fentanyl exposed juvenile mice. Neuropsychopharmacol. 48, 1724–1734 (2023). https://doi.org/10.1038/s41386-023-01639-8

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