Sex differences in behavioral and brainstem transcriptomic neuroadaptations following neonatal opioid exposure in outbred mice
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ABSTRACT:
PROVIDER: PRJNA591918 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10539816.fastq.gz | Fastqsanger.gz | |||
| SRR10539817.fastq.gz | Fastqsanger.gz | |||
| SRR10539818.fastq.gz | Fastqsanger.gz | |||
| SRR10539819.fastq.gz | Fastqsanger.gz | |||
| SRR10539820.fastq.gz | Fastqsanger.gz |
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Project description:The Opioid Use Disorder epidemic led to an increase in cases of Nenonatal Opioid Withdrawal Syndrome (NOWS) in infants born to opioid-dependent mothers. Hallmark features include weight loss, irritability, inconsolability, insomnia, and increased pain sensitivity. The neurobiological basis of NOWS is largely unknown. Improved mouse models will facilitate mechanistic and treatment discovery. We treated neonatal outbred Cartworth Farms White (CFW) mice (Swiss Webster) with morphine sulfate (15 mg/kg, s.c.) twice daily on postnatal day (P)1 through P14, the approximate third trimester-equivalent of human gestation. Weight loss was monitored and behavioral symptoms were measured on P7 and P14 at 16 h post-morphine. Brainstem containing pons and medulla was collected on P14 and processed for transcriptome analysis via mRNA sequencing (RNA-seq). Morphine induced weight loss from P2 to P14 that remained at P21 and P50. Repeated morphine also induced a delayed self-righting latency at P4 and a persistent, female-specific delay at P14. Morphine-treated females also showed an earlier increase in ultrasonic vocalizations (USVs) on P7. Both morphine-treated sexes showed a large increase in USVs on P14. Furthermore, thermal nociception via hot plate and tail withdrawal assays indicated that mice exhibited thermal hyperalgesia on P7 and P14, with females showing greater hyperalgesia (tail withdrawal) on P7. Morphine-treated mice also exhibited anxiety-like behavior at P21 (open field). Finally, brainstem transcriptome analysis identified a canonical gene set relevant to opioid signaling in males and a distinct gene set in females that was enriched for ribosomal proteins, mitochondrial function and neurodegenerative disorders. Sex-specific transcriptomic neuroadaptations implicate sex-specific treatments.
2019-11-27 | GSE141066 | GEO
Project description:Prenatal opioid exposure is a major health concern in the United States, with the incidence of neonatal opioid withdrawal syndrome (NOWS) escalating in recent years. NOWS is revealed upon cessation of in utero opioid exposure and is characterized by increased irritability, disrupted sleep patterns, high-pitched crying, and erratic feeding. The main pharmacological treatment strategy for alleviating symptoms is opioid maintenance therapy. The neural mechanisms mediating NOWS and the long-term neurobehavioral effects are poorly understood. We used a third trimester-approximate model in which neonatal outbred pups (Cartworth Farms White; CFW) were administered once-daily morphine (15 mg/kg, s.c.) from postnatal day (P) day 1 through P14 and were then assessed for behavioral and transcriptomic adaptations within the nucleus accumbens (NAc) on P15. We also investigated the long-term effects of perinatal morphine exposure on adult learning and reward sensitivity. We observed significant weight deficits, spontaneous thermal hyperalgesia, and altered ultrasonic vocalization (USV) profiles following repeated morphine and during spontaneous withdrawal. Transcriptome analysis of NAc from opioid-withdrawn P15 neonates via bulk mRNA sequencing identified an enrichment profile consistent with downregulation of myelin-associated transcripts. Despite the neonatal behavioral and molecular effects, there were no significant long-term effects of perinatal morphine exposure on adult spatial memory function in the Barnes Maze, emotional learning in fear conditioning, or in baseline or methamphetamine-potentiated reward sensitivity as measured via intracranial self-stimulation. Thus, the once daily third trimester-approximate exposure regimen, while inducing NOWS model traits and significant transcriptomic effects in neonates, had no significant long-term effects on adult behaviors.
2023-08-03 | GSE239919 | GEO
Project description: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 (15 mg/kg, s.c.) twice daily from postnatal day 1 (P1) to P14, an approximation of the third trimester of human gestation. Female and male 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 to P14, 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 showing greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena on P21. Transcriptome analysis of the brainstem, 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.
| S-EPMC8454922 | biostudies-literature
Project description:Opioid use during pregnancy can lead to negative infant health outcomes, including neonatal opioid withdrawal syndrome (NOWS). NOWS comprises gastrointestinal, autonomic nervous system, and neurological dysfunction that manifest during spontaneous withdrawal. Current treatments involve non-pharmacological and pharmacological interventions, however, there is no one standardized approach, in part because of variability in NOWS severity. To effectively model NOWS traits in mice, we used a third trimester-approximate opioid exposure paradigm, where neonatal inbred FVB/NJ and outbred Carworth Farms White (CFW) pups were injected twice-daily with morphine (10-15 mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day (P) one to P14. We observed reduced body weight gain, hypothermia, thermal hyperalgesia, and increased ultrasonic vocalizations (USVs). Neonatal USVs are emitted exclusively in isolation to communicate distress and thus serve as a model behavior for affective states. On P14, we observed altered USV syllable profiles during spontaneous morphine withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males) and in CFW mice of both sexes. Brainstem transcriptomics revealed an upregulation of the kappa opioid receptor (Oprk1), whose activation has previously been shown to contribute to withdrawal-induced dysphoria. Treatment with the kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USV emission in FVB/NJ females, but not FVB/NJ males during spontaneous morphine withdrawal. Furthermore, treatment with the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USV emission on P10 (both sexes) and on P14 (females only) in FVB/NJ mice. Together, these results indicate a female-specific recruitment of the dynorphin/KOR system in neonatal opioid withdrawal symptom severity.
2024-07-09 | GSE271337 | GEO
Project description:Background: Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown. Methods: Male (n=13) and female (n=12) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h self-administration sessions. After two weeks of this selfadministration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined. Results: Prior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited similar increases in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with a greater number of differentially expressed genes in the NAc and VTA of opioidwithdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females. Conclusions: These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.
2021-05-06 | GSE173959 | GEO
Project description:Decreased myelin-related gene expression in the nucleus accumbens during spontaneous neonatal opioid withdrawal in the absence of long-term behavioral effects in adult outbred CFW mice
| PRJNA1001385 | ENA
Project description:Opioids analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit their use. It has been recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. Further study indicated distinct alterations in the gut microbiome and metabolome following morphine treatment, contributing to the negative consequences associated with opioid use. However, it is unclear how opioids modulate gut homeostasis in the context of a hospital acquired bacterial infection. In the current study, a mouse model of C. rodentium infection was used to investigate the role of morphine in the modulation of gut homeostasis in the context of a hospital acquired bacterial infection. Citrobacter rodentium is a natural mouse pathogen that models intestinal infection by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) and causes attaching and effacing lesions and colonic hyperplasia. Morphine treatment resulted in 1) the promotion of C. rodentium systemic dissemination, 2) increase in virulence factors expression with C. rodentium colonization in intestinal contents, 3) altered gut microbiome, 4) damaged integrity of gut epithelial barrier function, 5) inhibition of C. rodentium-induced increase in goblet cells, and 6) dysregulated IL-17A immune response. This is the first study to demonstrate that morphine promotes pathogen dissemination in the context of intestinal C. rodentium infection, indicating morphine modulates virulence factor-mediated adhesion of pathogenic bacteria and induces disruption of mucosal host defense during C. rodentium intestinal infection in mice. This study demonstrates and further validates a positive correlation between opioid drug use/abuse and increased risk of infections, suggesting over-prescription of opioids may increase the risk in the emergence of pathogenic strains and should be used cautiously. Therapeutics directed at maintaining gut homeostasis during opioid use may reduce the comorbidities associated with opioid use for pain management.
2020-02-18 | E-MTAB-7503 | biostudies-arrayexpress
Project description:Diversity Outbred Liver RNASeq
| PRJNA356251 | ENA
Project description:Linkage analysis of complex traits in mice is a powerful tool to find loci affecting the phenotype but it has a poor resolution making it difficult to identify the underlying genes. We show here, using whole genome association analysis of gene expression traits in an outbred mouse population, the MF1 stock, that mapping resolution is greatly increased as compared to linkage. The fact that eQTLs discovered in other crosses were replicated and successfully mapped with high resolution in this population provides a strong proof of concept. In addition, we show that this population is a useful resource to resolve the eQTL hotspots detected in other studies. Finally, we highlight the importance of correcting for population structure in whole genome association studies in the outbred stock. Keywords: genetic association study in outbred mice
2008-08-22 | GSE10280 | GEO
Project description:Opioid abuse poses significant risk to individuals in the United States and epigenetic changes are a leading potential biomarker of opioid abuse. Current evidence, however, is mostly limited to candidate gene analysis in whole blood. Here, we provide Illumina HumanMethylationEPIC array data generated in dorsolateral prefrontal cortex tissue from 153 deceased invidiuals: 72 who died of acute opioid intoxication, 53 psychiatric controls, and 28 normal controls. Using these data, we conducted an epigenome-wide association study and identified one CpG site within a gene (NTN1) that may be related to opioid use. We also detected accelerated PhenoAge in opioid samples compared to control samples.
2021-04-01 | GSE164822 | GEO