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Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice

Kristyn N. Borrelli, Emily J. Yao, Will W. Yen, Qiu T. Ruan, Melanie M. Chen, Julia C. Kelliher, Carly R. Langan, Julia L. Scotellaro, Richard K. Babbs, Jacob C. Beierle, Ryan W. Logan, William Evan Johnson, Elisha M. Wachman, Alberto Cruz-Martín, Camron D. Bryant
doi: https://doi.org/10.1101/2021.04.02.438265
Kristyn N. Borrelli
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
2Graduate Program in Neuroscience, Boston University, Boston, MA, USA 02118
3Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA 02118
4NIGMS Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA 02118
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Emily J. Yao
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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Will W. Yen
5Department of Biology, Boston University, Boston, MA, USA 02118
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Qiu T. Ruan
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
3Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA 02118
4NIGMS Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA 02118
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Melanie M. Chen
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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Julia C. Kelliher
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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Carly R. Langan
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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Julia L. Scotellaro
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
6Undergraduate Research Opportunity Program, Boston University, Boston, MA, USA 02118
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Richard K. Babbs
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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Jacob C. Beierle
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
3Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA 02118
4NIGMS Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, USA 02118
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Ryan W. Logan
7Laboratory of Sleep, Rhythms, and Addiction, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA 02118
8Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME, USA 04609
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William Evan Johnson
9Department of Medicine, Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA 02118
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Elisha M. Wachman
10Department of Pediatrics, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA 02118
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Alberto Cruz-Martín
5Department of Biology, Boston University, Boston, MA, USA 02118
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Camron D. Bryant
1Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118
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  • For correspondence: camron@bu.edu
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ABSTRACT

The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third trimester of human gestation. Male and female mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine exposed female and male mice displayed hyperalgesia on the hot plate and tail flick assays, with females having greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena at P21. Transcriptome analysis of the brainstem (medulla plus pons), an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors.

SIGNIFICANCE STATEMENT Neonatal opioid withdrawal syndrome (NOWS) is a poorly understood condition that has both a genetic and environmental component and is thought to be mechanistically distinct from opioid withdrawal in adults. The development of murine models for measuring neurobehavioral responses is critical for informing the neurobiological adaptations underlying NOWS. Using outbred mice that more closely model human genetic variation, we discovered a surprising degree of sexual dimorphism in behavioral timing and severity of NOWS-model behaviors as well as transcriptomic adaptations in brain tissue that together suggest distinct mechanisms and sex-specific therapeutics for reversing withdrawal symptoms and restoring brain function.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Conflicts of Interest: None

  • Funding Sources: Spivack Center for Clinical and Translational Neuroscience, NIDA U01DA050243 and NIDA R01DA039168 (C.D.B.); NHLBI R01150432 (R.W.L); NICHD R01HD096798 (E.W.); NARSAD Young Investigator Grant (A.C-M., #27202), Boston University’s Undergraduate Research Opportunities Program (J.L.S.)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice
Kristyn N. Borrelli, Emily J. Yao, Will W. Yen, Qiu T. Ruan, Melanie M. Chen, Julia C. Kelliher, Carly R. Langan, Julia L. Scotellaro, Richard K. Babbs, Jacob C. Beierle, Ryan W. Logan, William Evan Johnson, Elisha M. Wachman, Alberto Cruz-Martín, Camron D. Bryant
bioRxiv 2021.04.02.438265; doi: https://doi.org/10.1101/2021.04.02.438265
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Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice
Kristyn N. Borrelli, Emily J. Yao, Will W. Yen, Qiu T. Ruan, Melanie M. Chen, Julia C. Kelliher, Carly R. Langan, Julia L. Scotellaro, Richard K. Babbs, Jacob C. Beierle, Ryan W. Logan, William Evan Johnson, Elisha M. Wachman, Alberto Cruz-Martín, Camron D. Bryant
bioRxiv 2021.04.02.438265; doi: https://doi.org/10.1101/2021.04.02.438265

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