Biology subjects

Gewirtz, J. C.

Publications and source records attributed to Gewirtz, J. C..

4 recordsLinked to original sources

bioRxiv2024

Differential gene expression and chromatin accessibility in the rat medial prefrontal cortex mediating individual variability in vulnerability to opioid use

We characterized gene transcriptional activity in the medial prefrontal cortex of rats associated with individual differences in vulnerability to three distinct phases of opioid use disorder (OUD). Resilient rats showed many more changes in canonical pathway activity than Vulnerable rats in models of both early and advanced OUD, involving passive opioid exposure and opioid self-administration (SA), respectively. The Resilient/Vulnerable phenotype was also associated across phases with functionally specific gene networks, including those mediating epigenetic, neuroimmune, and neuroplasticity function. In contrast, we identified two phase-specific effects. First, differential activity of a myelination-related gene network was associated with Resilience/Vulnerability measured after passive morphine exposure. Second, expression of the calmodulin-inhibitor Pcp4, a gene recently implicated in a rat opioid SA GWAS analysis, was associated with Resilience/Vulnerability measured after SA but not after passive morphine exposure. Thus, we have identified both general and phase-specific transcriptional signatures involved in OUD vulnerability across its trajectory. TeaserAdaptations in the brain transcriptome are associated with resilience and vulnerability to opioid use disorder.

neuroscience↗

bioRxiv2022

ATAC and histone H3K9me3 landscapes revealed the altered epigenome by fetal-neonatal iron deficiency in the adult male rat hippocampus

Iron deficiency during the fetal-neonatal period results in long-term neurodevelopmental impairments associated with pervasive and widespread hippocampal gene dysregulation. Globally, fetal-neonatal iron deficiency produces both long-term activation and repression of hundreds of loci in the adult rat hippocampus. Prenatal choline (a methyl donor) supplementation can partially reverse these effects, suggesting an interaction between iron and choline in regulating the hippocampal transcriptome. To gain insights into the underlying epigenetic signatures, we integrate hippocampal transcriptomes and epigenetic marks of active (transposase accessible chromatin/ATAC) and repressed (H3K9me3 enrichment) genes in adult rats that had been exposed to fetal-neonatal iron deficiency with or without prenatal choline supplementation. Rats were made iron-deficient during fetal and neonatal period by limiting maternal iron intake from gestational day (G) 2 through postnatal day (P) 7. Choline (5.5 g/kg) was given to half of the pregnant dams during G11-18. This paradigm produced four comparison groups (Iron-sufficient [IS], Iron-deficient [ID], IS+choline [ISch], and ID+choline [IDch]). Hippocampi were collected from P65 males and analyzed for changes in chromatin conformation and histone H3K9me3 enrichment. ATAC-seq results accounted for 22% and 24%, whereas H3K9me3 enrichment accounted for 1.7% and 13% of differences in ID- and IDch-altered gene expression. These epigenetic changes were annotated onto gene networks regulating synaptic structure and plasticity, neuroinflammation, and reward circuits. The low correlation between gene dysregulation and changes in ATAC or H3K9me3 signatures indicate involvements of other epigenetic modifications. This study provides a genome-wide findings of stable epigenetic changes and lays a foundation for further analyses to elucidate more fully iron-dependent epigenetic mechanisms that underlie iron deficiency, choline supplementation, and their interactions in mediating long-term neural gene dysregulation. SIGNIFICANCE STATEMENTEarly-life iron deficiency can lead to long-term neurocognitive dysfunction and persistent neural gene dysregulation, despite prompt iron replenishment, suggesting that iron deficiency results in long-term neuroepigenomic changes. This study combined RNA-seq, ATAC-seq, and ChIP-seq to provide the epigenetic basis for gene dysregulation due to fetal-neonatal iron deficiency and prenatal choline supplementation. We found that early-life iron deficiency alters epigenetic regulation of genes involved in neuronal development, cell signaling, neuroinflammation, and reward-related cognition. While choline supplementation to iron-deficient animals partially reverses these effects, it also leads to dysregulation of genes in iron-sufficient animals. The patterns of gene dysregulation were positively correlated with differences in chromatin accessibility and negatively correlated with repressive histone H3K9me3 modification. Our results indicate that these changes at the epigenetic level partially account for the long-term hippocampal gene dysregulation.

neuroscience↗

bioRxiv2020

Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the prefrontal cortex of male and female rats

BackgroundOpioid abuse is a chronic disorder likely involving stable neuroplastic modifications. While a number of molecules contributing to these changes have been identified, the broader spectrum of genes and gene networks that are affected by repeated opioid administration remain understudied. MethodsWe employed Next-Generation RNA-sequencing (RNA-seq) to investigate changes in gene expression in adult male and female rats prefrontal cortex (PFC) following daily injection of morphine (5.0 mg/kg) for 10 days. Ingenuity Pathway Analysis (IPA) was used to analyze affected molecular pathways, gene networks, and associated regulatory factors. Results90% of differentially expressed genes (DEGs) were upregulated in both males and females, with a 35% overlap between sexes. A substantial number of DEGs play roles in synaptic signaling and neuroplasticity. Although broadly similar, some differences were revealed in the gene ontology networks enriched in females and males (e.g., the endocannabinoid pathway in females and neuroinflammation in males). ConclusionsOur results cohere with findings from previous studies based on a priori gene selection, while identifying broader gene networks activated by repeated opioid exposure. Our results also reveal novel genes and molecular pathways that are upregulated by repeated morphine exposure.

neuroscience↗

bioRxiv2019

Higher anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid self-administration in rats.

Understanding factors contributing to individual differences in vulnerability to opioid addiction is essential for developing more effective preventions and treatments, yet few reliable behavioral predictors of subsequent opioid self-administration have been identified in rodents. Sensitivity to the acute effects of initial drug exposure predicts later addiction vulnerability in both humans and animals, but the relationship of sensitivity to withdrawal from initial drug exposure and later drug use vulnerability is unclear. The goal of the current study was to evaluate whether the degree of anhedonia experienced during withdrawal from early opioid exposure predicts subsequent vulnerability to opioid addiction. Rats were first tested for withdrawal sensitivity following acute injections of morphine (i.e., "acute dependence"), measured as elevations in intracranial self-stimulation (ICSS) thresholds (anhedonia-like behavior) during naloxone-precipitated and spontaneous withdrawal. Rats were then tested for addiction vulnerability using various measures of i.v. morphine self-administration (MSA) including acquisition, demand, extinction, and reinstatement induced by morphine, stress, and/or drug-associated cues. Greater naloxone-precipitated withdrawal across repeated morphine injections and greater peak spontaneous withdrawal severity following a single morphine injection were associated with lower addiction vulnerability on multiple MSA measures. Withdrawal-induced anhedonia predicted a wider range of MSA measures than did any individual measure of MSA itself. These data suggest that high anhedonia during withdrawal from initial opioid exposure is protective against subsequent opioid addiction vulnerability in rodents, thereby establishing one of the first behavioral measures to predict individual differences in opioid SA. This model promises to be useful for furthering our understanding of behavioral and neurobiological mechanisms underlying vulnerability to opioid addiction.

animal behavior and cognition↗