Biology subjects

Wolstenholme, J. T.

Publications and source records attributed to Wolstenholme, J. T..

5 recordsLinked to original sources

bioRxiv2025

Variation of Myelin-associated Gene Expression and Ndrg1 within the Prefrontal Cortex as Determinants for Initial Level of Response to Alcohol

BackgroundStudies in humans and animal models have documented relationships between initial sensitivity to alcohol and alcohol drinking behavior. Prior expression profiling studies of C57BL/6J and DBA/2J mice and rhesus macaques within the prefrontal cortex (PFC) have shown variation in myelin gene expression may be linked with alcohol sensitivity and consumption. MethodsCombining gene expression studies from human and mouse PFC, we identified a cross-species gene network enriched for myelin-associated genes. Since myelin expression is correlated to alcohol sensitivity and alcohol drinking behavior, we hypothesized basal levels of PFC myelin gene expression may be a genomic determinant for these behavioral responses. Using an animal model of CNS demyelination, and localized knock down of N-myc downstream regulated gene 1 (Ndrg1), we measured effects of cortical myelin reduction on initial alcohol sensitivity and drinking behavior. ResultsReducing myelin-related gene expression significantly altered sensitivity to alcohol and decreased alcohol consumption. Mouse genetic-based studies identified Ndrg1 as a putative quantitative trait gene for sedative-hypnotic responses to alcohol. Site-specific injections of shNdrg1 lentivirus into PFC led to a significant decrease in NDRG1 expression, causing increased alcohol behavioral sensitivity and reduced preference for high concentrations of alcohol. ConclusionMyelin is an important biological component underlying CNS disorders. Our studies demonstrate the role of a novel candidate gene (Ndrg1), and myelin-associated gene expression, as an important factor modulating initial sensitivity to alcohol and alcohol consumption. Differences in the expression of myelin-related genes, including Ndrg1, may serve as future therapeutic targets for the treatment of alcohol use disorders.

neuroscience↗

bioRxiv2024

Genomic and Transcriptomic Analysis of Ninein Alternative Splicing Between C57BL/6J and DBA/2J Mice

Ethanols anxiolytic actions contribute to increased consumption and the development of Alcohol Use Disorder (AUD). Our laboratory previously identified genetic loci contributing to the anxiolytic-like properties of ethanol in BXD recombinant inbred mice, derived from C57BL/6J (B6) and DBA/2J (D2) progenitor strains. That work identified Ninein (Nin) as a candidate gene underlying ethanols acute anxiolytic-like properties in BXD mice. Nin has a complex exonic content with known alternative splicing events that alter cellular distribution of the NIN protein. We hypothesize that strain-specific differences in Nin alternative splicing contribute to changes in Nin gene expression and B6/D2 strain differences in ethanol anxiolysis. Using quantitative reverse-transcriptase PCR to target Nin alternative splicing, we identified isoform-specific exon expression differences between B6 and D2 mice in prefrontal cortex, nucleus accumbens and amygdala. We extended this analysis using deep RNA sequencing in B6 and D2 nucleus accumbens samples and that Nin expression was significantly higher in D2 mice. Furthermore, exon utilization and alternative splicing analyses identified 8 differentially utilized exons and significant exon-skipping events between the strains, including 3 novel splicing events in the 3 end of the Nin gene that were specific to the D2 strain. Our studies provide the first in-depth analysis of Nin alternative splicing in brain and identify a potential genetic mechanism altering Nin expression between B6 and D2 mice, thus contributing to differences in the anxiolytic-like properties of ethanol between these strains. This work contributes to our understanding of genetic differences modulating ethanol actions on anxiety that may contribute to the risk for alcohol use disorder.

genetics↗

bioRxiv2024

A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice

Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3{beta}) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3{beta} inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3{beta} inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on {beta}-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3{beta} in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.

pharmacology and toxicology↗

bioRxiv2021

Prolonged epigenetic and synaptic plasticity alterations following single exposure to a psychedelic in mice

Clinical evidence suggests a potential therapeutic effect of classic psychedelics for the treatment of depression. The most outstanding and distinct characteristic is the rapid and sustained antidepressant action with one single exposure to the drug. However, the biological substrates and key mediators of psychedelics enduring action remain unknown. Here, we show that a single administration of the psychedelic DOI produced fast-acting effects on frontal cortex dendritic spine structure and acceleration of fear extinction via the 5-HT2A receptor. Additionally, a single dose of DOI led to changes in chromatin organization particularly at enhancer regions of genes involved in synaptic assembly that stretched for days after the psychedelic exposure. DOI-induced alterations in neuronal epigenome overlapped with genetic loci associated with schizophrenia, depression and attention deficit hyperactivity disorder. Together, these data support the notion that epigenetic-driven changes in synaptic plasticity operate as the mechanistic substrate of psychedelics long-lasting antidepressant action but also warn on the limitations in individuals with underlying risk for psychosis.

neuroscience↗

bioRxiv2019

A History of Chronic Repeated Predation Stress Reduces Aversion to Ethanol Adulteration in Male, but not Female, C57Bl/6J Mice

BackgroundTrauma related psychiatric disorders, such as posttraumatic stress disorder (PTSD), and alcohol use disorder (AUD) are highly comorbid illnesses that separately present an opposing, sex-specific pattern, with increased prevalence of PTSD in females and increased prevalence of AUD diagnoses in males. Likewise, PTSD is a risk factor in the development of AUD, with conflicting data on the impact of sex in the comorbid development of both disorders. Because the likelihood of experiencing more than one traumatic event is high, we aim to utilize chronic repeated predatory stress (CRPS) to query the extent to which sex interacts with CRPS to influence alcohol consumption, or cessation of consumption. MethodsMale (n=16) and female (n=15) C57BL/6J mice underwent CRPS or daily handling for two weeks during adolescence (P35-P49) and two weeks during adulthood (P65-P79). Following the conclusion of two rounds of repeated stress, behavior was assessed in the open field. Mice subsequently underwent a two-bottle choice intermittent ethanol access (IEA) assessment (P90-131) with the options of 20% ethanol or water. After establishing drinking behavior, increasing concentrations of quinine were added to the ethanol to assess the drinking response to adulteration of the alcohol. ResultsCRPS increased fecal corticosterone concentrations and anxiety-like behaviors in the open field in both male and female mice as compared to control mice that had not been exposed to CRPS. Consistent with previous reports, we observed a sex difference in alcohol consumption such that females consumed more ethanol per gram of body mass than males. In addition, CRPS reduced alcohol aversion in male mice such that higher concentrations of quinine were necessary to reduce alcohol intake as compared to control mice. CRPS did not alter alcohol-related behaviors in female mice. ConclusionCollectively, we demonstrate that repeated CRPS can induce anxiety-like behavior in both sexes but selectively influences the response to ethanol adulteration in males.

neuroscience↗