Biology subjects

Barkley-Levenson, A.

Publications and source records attributed to Barkley-Levenson, A..

4 recordsLinked to original sources

bioRxiv2023

NEUROMETABOLOMIC IMPACTS OF MODELED WILDFIRE SMOKE AND PROTECTIVE BENEFITS OF ANTI-AGING THERAPEUTICS IN AGED FEMALE C57BL/6J MICE

Wildland fires have become progressively more extensive over the past 30 years in the US, and now routinely generate smoke that deteriorates air quality for most of the country. We explored the neurometabolomic impact that smoke derived from biomass has on older (18 months) female C57BL/6J mice, both acutely and after 10 weeks of recovery from exposures. Mice (N=6/group) were exposed to wood smoke (WS) 4 hours/day, every other day, for 2 weeks (7 exposures total) to an average concentration of 0.448mg/m3 per exposure. One group was euthanized 24 hours after the last exposure. Other groups were then placed on 1 of 4 treatment regimens for 10 weeks after wood smoke exposures: vehicle; resveratrol in chow plus nicotinamide mononucleotide in water (RNMN); senolytics via gavage (dasatanib+quercetin; DQ); or both RNMN with DQ (RNDQ). Among the findings, the aging from 18 months to 21 months was associated with the greatest metabolic shift, including changes in nicotinamide metabolism, with WS exposure effects that were relatively modest. WS caused a reduction in NAD+ within the prefrontal cortex immediately after exposure and a long-term reduction in serotonin that persisted for 10 weeks. The serotonin reductions were corroborated by forced swim tests, which revealed an increased immobility (reduction in motivation) immediately post-exposure and persisted for 10 weeks. RNMN had the most beneficial effects after WS exposure, while RNDQ caused markers of brain aging to be upregulated within WS-exposed mice. Findings highlight the persistent neurometabolomic and behavioral effects of woodsmoke exposure in an aged mouse model. Significance StatementNeurological impacts of wildfire smoke are largely underexplored but include neuroinflammation and metabolic changes. The present study highlights modulation of major metabolites in the prefrontal cortex and behavioral consequences in aged (18 month) female mice that persists 10 weeks after wood smoke exposure ended. Supplements derived from the anti-aging field were able to mitigate much of the woodsmoke effect, especially a combination of resveratrol and nicotinamide mononucleotide.

pharmacology and toxicology↗

bioRxiv2022

Tissue- and sex-specific DNA damage tracks aging in rodents and humans

DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics1 to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products: N2-CMdG, 1,N6 {varepsilon}-dA, 3,N4-{varepsilon}dC, M1dG, O6/N2-MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, including N2-CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1,N6 {varepsilon}-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.

biochemistry↗

bioRxiv2020

Functional validation of a finding from a mouse genome-wide association study demonstrates that a mutant allele of Azi2 alters sensitivity to methamphetamine

Methamphetamine is a widely abused psychostimulant. In a previous genome-wide association study (GWAS), we identified a locus that influenced the stimulant response to methamphetamine. That locus was also an eQTL for the gene Azi2. Based on those findings, we hypothesized that heritable differences in the expression of Azi2 were causally related to the differential response to methamphetamine. In this study, we created a mutant Azi2 allele that caused lower Azi2 expression and enhanced the locomotor response to methamphetamine; however, based on the GWAS findings, we had expected lower Azi2 to decrease rather than increase the stimulant response to methamphetamine. We then sought to explore the mechanism by which Azi2 influenced methamphetamine sensitivity. A recent publication had reported that the 3UTR of Azi2 mRNA downregulates the expression of Slc6a3, which encodes the dopamine transporter (DAT), which is a key target of methamphetamine. We evaluated the relationship between Azi2/Azi2 3UTR and Slc6a3 expression in the VTA in the mutant Azi2 mice and in a new cohort of CFW mice. We did not observe any correlation between Azi2 and Slc6a3 in the VTA in either cohort. However, RNA sequencing confirmed that the Azi2 mutation altered Azi2 expression and also revealed a number of potentially important genes and pathways that were regulated by Azi2, including the metabotropic glutamate receptor group III pathway and nicotinic acetylcholine receptor signaling pathway. Our results support a role for Azi2 in methamphetamine sensitivity; however, the exact mechanism does not appear to involve regulation of Slc6a3 and thus remains unknown.

animal behavior and cognition↗

bioRxiv2017

Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats

Previous studies showed that the glyoxalase 1 (Glo1) gene modulates anxiety-like behavior, seizure susceptibility, depression-like behavior, and alcohol drinking in the drinking-in-the-dark paradigm in nondependent mice. Administration of the small-molecule GLO1 inhibitor S-bromobenzylglutathione cyclopentyl diester (pBBG) decreased alcohol drinking in nondependent mice, suggesting a possible therapeutic strategy. However, the preclinical therapeutic efficacy of pBBG in animal models of alcohol dependence remains to be demonstrated. We tested the effect of pBBG (7.5 and 25 mg/kg) on operant alcohol self-administration in alcohol-dependent and nondependent rats. Wistar rats were trained to self-administer 10% alcohol (v/v) and made dependent by chronic intermittent passive exposure to alcohol vapor for 5 weeks. Pretreatment with pBBG dose-dependently reduced alcohol self-administration in both nondependent and dependent animals, without affecting water self-administration. pBBG treatment was more effective in dependent rats than in nondependent rats. These data extend previous findings that implicated Glo1 in alcohol drinking in nondependent mice by showing even more profound effects in alcohol-dependent rats. These results suggest that the pharmacological inhibition of GLO1 is a relevant therapeutic target for the treatment of alcohol use disorders.\n\nHighlightsO_LIAlcohol use disorder (AUD) places an enormous burden on society, and there is an urgent need for new druggable targets.\nC_LIO_LIGlo1 inhibition by pBBG dose-dependently reduces alcohol self-administration in both nondependent and dependent animals.\nC_LIO_LIpBBG treatment is more effective in reducing alcohol intake in dependent rats than in nondependent rats.\nC_LI

neuroscience↗