Spectrotemporal profiling of ultrasonic vocalizations during neonatal opioid withdrawal reveals a kappa opioid receptor component in female mice
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ABSTRACT:
PROVIDER: PRJNA1130952 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29684015_1.fastq.gz | Fastqsanger.gz | |||
| SRR29684015_2.fastq.gz | Fastqsanger.gz | |||
| SRR29684016_1.fastq.gz | Fastqsanger.gz | |||
| SRR29684016_2.fastq.gz | Fastqsanger.gz | |||
| SRR29684017_1.fastq.gz | Fastqsanger.gz |
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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:Because opioid withdrawal is an intensely aversive experience, persons with opioid use disorder (OUD) often relapse to avoid it. The lateral septum (LS) is a forebrain structure that is important in aversion processing, and previous studies have linked the LS to substance use disorders. It is unclear, however, which precise LS cell types might contribute to the maladaptive state of withdrawal. To address this, we used single-nucleus RNA-sequencing to interrogate cell type specific gene expression changes induced by chronic morphine and withdrawal. We discovered that morphine globally disrupts the transcriptional profile of LS cell types, but neurotensin-expressing neurons (Nts; LS-Nts neurons) are selectively activated by naloxone. Using two-photon calcium imaging and ex vivo electrophysiology, we next demonstrated that LS-Nts neurons receive enhanced glutamatergic drive in morphine-dependent mice and remain hyperactivated during opioid withdrawal. Finally, we showed that activating and silencing LS-Nts neurons during opioid withdrawal regulates pain coping behaviors and sociability. Together, these results suggest that LS-Nts neurons are a key neural substrate involved in opioid withdrawal and establish the LS as a crucial regulator of adaptive behaviors, specifically pertaining to OUD.
2025-05-15 | GSE236007 | GEO
Project description:Here we examined virulence activation in Pseudomonas aeruginosa in response to the synthetic kappa opioid agonist U-50, 488 in nutrient poor media where growth conditions are limited and density dependent quorum sensing is not activated. We used a microarray to define the virulence-related genes in P. aeruginosa grown in liquid poor nutrient medium to determine the effect of kappa-opioid receptor agonist on virulence/lethal phenotype All biological samples for gene expression analysis were prepared in triplicate. P. aeruginosa MPAO1 cells collected from liquid culture at 7 hrs of growth in 1.) 0.1xTY medium containing tryptone 1 g/L and yeast extract, 0.5 g/L, or 2.) 0.1xTY+25 mM potassium phosphate buffer, pH 6.0, or 3.) 0.1xTY+200 uM U-50,488, or 4.) 0.1xTY+ 25 mM potassium phosphate buffer, pH 6.0+ 200 uM U-50,488 were used for RNA isolation. Microarray analysis was performed using Affymetrix P. aeruginosa GeneChips (Affymetrix, Santa Clara, CA) at the University of Chicago Functional Genomics Facility
2012-05-20 | E-GEOD-29946 | biostudies-arrayexpress
Project description:Here we examined virulence activation in Pseudomonas aeruginosa in response to the synthetic kappa opioid agonist U-50, 488 in nutrient poor media where growth conditions are limited and density dependent quorum sensing is not activated. We used a microarray to define the virulence-related genes in P. aeruginosa grown in liquid poor nutrient medium to determine the effect of kappa-opioid receptor agonist on virulence/lethal phenotype
2012-05-21 | GSE29946 | GEO
Project description:The development of substance use disorder (SUD) is a complex process involving multiple neurocircuitries and brain regions. The amygdala is a region that mediates the withdrawal effect as well as anxiety and depression-like behaviors. However, the transcriptional changes in each cell type during SUD is largely unknown. Here we performed single-cell RNA sequencing and classified all cell types in the mouse amygdala under opioid dependence and withdrawal states. Our data revealed distinct changes in key biological processes, such as immune response, inflammation, synaptic transmission, and mitochondrial respiration in different cell populations. Dramatic differences were unraveled in the transcriptional profiles between dependence and withdrawal states. This report is the first single-cell RNA sequencing dataset from the amygdala under opioid dependence and withdrawal conditions, providing unique insights in understanding brain alterations during SUD, especially at the molecular and cellular levels.
2023-11-08 | GSE207128 | 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:RationaleOpioid 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. Variability in NOWS severity necessitates a more individualized treatment approach. Ultrasonic vocalizations (USVs) in neonatal mice are emitted in isolation as a stress response and are increased during opioid withdrawal, thus modeling a negative affective state that can be utilized to test new treatments.ObjectivesWe sought to identify the behavioral and USV profile, brainstem transcriptomic adaptations, and role of kappa opioid receptors in USVs during neonatal opioid withdrawal.MethodsWe employed a third trimester-approximate opioid exposure model, where neonatal inbred FVB/NJ pups were injected twice-daily with morphine (10mg/kg, s.c.) or saline (0.9%, 20 ul/g, s.c.) from postnatal day(P) 1 to P14. This protocol induces reduced weight gain, hypothermia, thermal hyperalgesia, and increased USVs during spontaneous morphine withdrawal.ResultsOn P14, there were increased USV emissions and altered USV syllables during withdrawal, including an increase in Complex 3 syllables in FVB/NJ females (but not males). Brainstem bulk mRNA sequencing revealed an upregulation of the kappa opioid receptor (Oprk1), which contributes to withdrawal-induced dysphoria. The kappa opioid receptor (KOR) antagonist, nor-BNI (30 mg/kg, s.c.), significantly reduced USVs in FVB/NJ females, but not males during spontaneous morphine withdrawal. Furthermore, the KOR agonist, U50,488h (0.625 mg/kg, s.c.), was sufficient to increase USVs on P10 (both sexes) and P14 (females only) in FVB/NJ mice.ConclusionsWe identified an elevated USV syllable, Complex 3, and a female-specific recruitment of the dynorphin/KOR system in increased USVs associated with neonatal opioid withdrawal severity.
| S-EPMC11775077 | biostudies-literature
Project description:After injury, mammalian spinal cords develop scars to confine the lesion and prevent further damage. However, excessive scarring can hinder neural regeneration and functional recovery. These competing actions underscore the importance of developing therapeutic strategies to dynamically modulate scar progression. Previous research on scarring has primarily focused on astrocytes, but recent evidence has suggested that ependymal cells also participate. Ependymal cells normally form the epithelial layer encasing the central canal, but they undergo massive proliferation and differentiation into astroglia following certain injuries, becoming a core scar component. However, the mechanisms regulating ependymal proliferation in vivo remain unclear. Here we uncover an endogenous κ-opioid signalling pathway that controls ependymal proliferation. Specifically, we detect expression of the κ-opioid receptor, OPRK1, in a functionally under-characterized cell type known as cerebrospinal fluid-contacting neuron (CSF-cN). We also discover a neighbouring cell population that expresses the cognate ligand prodynorphin (PDYN). Whereas κ-opioids are typically considered inhibitory, they excite CSF-cNs to inhibit ependymal proliferation. Systemic administration of a κ-antagonist enhances ependymal proliferation in uninjured spinal cords in a CSF-cN-dependent manner. Moreover, a κ-agonist impairs ependymal proliferation, scar formation and motor function following injury. Together, our data suggest a paracrine signalling pathway in which PDYN+ cells tonically release κ-opioids to stimulate CSF-cNs and suppress ependymal proliferation, revealing an endogenous mechanism and potential pharmacological strategy for modulating scarring after spinal cord injury.
2024-06-29 | GSE255883 | GEO
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