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Sex Differences in Behavioral and Brainstem Transcriptomic Research Article: New Research | Disorders of the Nervous System Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice https://doi.org/10.1523/ENEURO.0143-21.2021 Cite as: eNeuro 2021; 10.1523/ENEURO.0143-21.2021 Received: 31 March 2021 Revised: 2 May 2021 Accepted: 25 August 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.eneuro.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Borrelli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid 2 exposure in outbred mice 3 4 Abbreviated title: Sex-differences in neonatal opioid exposure 5 6 Kristyn N. Borrelli1,2,3,4#, Emily J. Yao1#, William W. Yen5, Rhushikesh A. Phadke5,6, Qiu T. Ruan1,3,4, Melanie M. 7 Chen1, Julia C. Kelliher1, Carly R. Langan1, Julia L. Scotellaro1,7, Richard K. Babbs1, Jacob C. Beierle1,3,4, Ryan 8 W. Logan8,9, William Evan Johnson10, Elisha M. Wachman11, Alberto Cruz-Martín5, Camron D. Bryant1* 9 10 1. Laboratory of Addiction Genetics, Departments of Pharmacology and Experimental Therapeutics and 11 Psychiatry, Boston University School of Medicine, Boston, MA, USA 02118 12 2. Graduate Program in Neuroscience, Boston University, Boston, MA, USA 02118 13 3. Transformative Training Program in Addiction Science, Boston University, Boston, MA, USA 02118 14 4. NIGMS Training Program in Biomolecular Pharmacology, Boston University School of Medicine, Boston, MA, 15 USA 02118 16 5. Neurobiology Section, Department of Biology, Boston University, Boston, MA, USA 02215 17 6. Molecular Biology, Cell Biology, and Biochemistry (MCBB), Boston University, Boston, MA, USA 02215 18 7. Undergraduate Research Opportunity Program, Boston University, Boston, MA, USA 02118 19 8. Laboratory of Sleep, Rhythms, and Addiction, Department of Pharmacology and Experimental Therapeutics, 20 Boston University School of Medicine, Boston, MA, USA 02118 21 9. Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME, USA 04609 22 10. Department of Medicine, Computational Biomedicine, Boston University School of Medicine, Boston, MA, 23 USA 02118 24 11. Department of Pediatrics, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA 25 02118 26 27 # equal author contribution 28 29 *Corresponding Author 30 72 E. Concord St. L-606C 31 Boston, MA 02118 USA 32 P: (617) 358-9581 33 F: (617) 358-6583 34 [email protected] 35 36 Keywords: hypernociception, hypernociceptive, Neonatal Opioid Withdrawal Syndrome, NOWS, sex 37 differences, neonates, opiate, neurodevelopment, gene expression, pain, opioid-induced hyperalgesia 38 39 Figures: 12 40 41 Word Counts 42 Abstract: 242 43 Introduction: 654 44 Discussion: 1788 45 46 Conflicts of Interest: None 47 48 Funding Sources: Spivack Center for Clinical and Translational Neuroscience, NIDA U01DA050243 49 and NIDA R01DA039168 (C.D.B.); NHLBI R01150432 (R.W.L); NICHD 50 R01HD096798 (E.W.); NARSAD Young Investigator Grant (A.C-M., #27202), 51 Boston University’s Undergraduate Research Opportunities Program (J.L.S.) 52 53 201 54 ABSTRACT 55 The opioid epidemic led to an increase in the number of Neonatal Opioid Withdrawal Syndrome (NOWS) 56 cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe 57 irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain 58 mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice 59 were administered morphine (15mg/kg, s.c.) twice daily for postnatal days (P) 1-14, an approximate of the third 60 trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine 61 the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body 62 weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal 63 on P14 for RNA-sequencing. Morphine induced weight loss from P2-14, which persisted during adolescence 64 (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and 65 P14, both morphine-exposed female and male mice displayed hyperalgesia on the hot plate and tail flick assays, 66 with females showing greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like 67 behavior in the open-field arena on P21. Transcriptome analysis of the brainstem, an area implicated in opioid 68 withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also 69 found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian 70 entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological 71 mechanisms underlying NOWS-like behaviors. 202 72 SIGNIFICANCE STATEMENT 73 Neonatal opioid withdrawal syndrome (NOWS) is a poorly understood condition that has both a genetic and 74 environmental component and is thought to be mechanistically distinct from opioid withdrawal in adults. The 75 development of murine models for measuring neurobehavioral responses is critical for informing the 76 neurobiological adaptations underlying NOWS. Using outbred mice that more closely model human genetic 77 variation, we discovered several sex differences in behavioral timing and severity of NOWS-model behaviors as 78 well as transcriptomic adaptations in brain tissue that together suggest distinct mechanisms and sex-specific 79 therapeutics for reversing withdrawal symptoms and restoring brain function. 80 203 81 INTRODUCTION 82 The United States is in the midst of an opioid use disorder (OUD) epidemic. A recent report by the Center 83 for Disease Control and Prevention indicated a record 93,000 opioid-related deaths in 2020 – a 29% increase 84 from 2019 (https://www.cdc.gov). The OUD epidemic has been accompanied by a surge in babies exposed to 85 opioids in utero (Jansson and Patrick, 2019) and a rise in rates of Neonatal Opioid Withdrawal Syndrome 86 (NOWS) (Milliren et al., 2018). NOWS is characterized by low birth weight, reduced weight gain, severe irritability, 87 sleep fragmentation and restlessness, hypertonia, elevated pain sensitivity, and high-pitched cry, among others 88 (Sutter et al., 2014). Current standard of treatment for NOWS includes tapered dosing of opioids over days or 89 weeks, and other interventions that promote mother-infant bonding (Ryan et al., 2019; Wachman et al., 2018). 90 Current treatments for NOWS primarily attenuate withdrawal severity for the infant and are believed to mitigate 91 the potential long-term impact on mood, cognition, and pain. Further understanding the impact of opioids on 92 development is critical for the discovery, design, and implementation of new treatments and interventions for 93 NOWS. 94 Several animal models for NOWS have been developed (Byrnes and Vassoler, 2018; Chen et al., 2015; 95 Fodor et al., 2014), differing in time of exposure (i.e., prenatally, postnatally, or both), specific opioid (morphine, 96 heroin, methadone, oxycodone, and/or buprenorphine), and dosing regimen (e.g., injections, pellets, mini- 97 pumps) (Byrnes and Vassoler, 2018; Minakova et al., 2021; Robinson et al., 2019). The physiological and 98 behavioral consequences of opioids on development depends on the timing, duration, and route of drug 99 administration (Byrnes and Vassoler, 2018; Fodor et al., 2014). In rodents, the period between postnatal days 1 100 through 14 (P1-14) is an approximate of the third trimester of human gestation (Barr et al., 2011), characterized 101 by rapid, extensive synaptogenesis and myelination in the brain (Semple et al., 2013). For example, morphine 102 administration between P1-14 (Robinson et al., 2019) in mice induced neurodevelopmental delays, and effects 103 on behaviors later during adolescence and adulthood, including marble burying and morphine locomotor 104 sensitization behaviors (Robinson et al., 2019). Early neonatal opioid exposure in rodents has several key 105 advantages: 1) opioid exposure during third trimester is associated with higher risk for NOWS in human neonates 106 (Desai et al., 2015), providing strong translational relevance; 2) neonatal exposure during third trimester 107 equivalent is sufficient to produce symptoms of withdrawal in mice and rats (Jones and Barr, 2001, 1995; McPhie 204 108 and Barr, 2009; Robinson et al., 2019); 3) postnatal delivery of opioids enable accurate dosing to each pup; 4) 109 avoiding maternal opioid exposure reduces the potential variance introduced by opioid-dependent alterations in 110 maternal caretaking behaviors; and 5) the short-term and long-term effects of opioids on the brain and behavior 111 can be assigned to a specific developmental period using discrete, timed administration of opioids. 112 Given these advantages, in the present study, we employed a similar
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