Biology subjects

Zachariou, V.

Publications and source records attributed to Zachariou, V..

5 recordsLinked to original sources

bioRxiv2023

tRNA epitranscriptomic alterations associated with opioid-induced reward-seeking and long-term opioid withdrawal

DNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underling opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m5C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNAGlyGCC) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Strikingly, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronal Nsun2, a tRNA methyltransferase, was associated with disruption of reward-seeking in the conditioned place preference paradigm, and this effect was recapitulated by regional mPFC Nsun2 knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and OUD and highlight the tRNA machinery as a potential therapeutic target in addiction.

neuroscience↗

bioRxiv2022

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

Despite being largely confined to the airways, SARS-CoV-2 infection has been associated with sensory abnormalities that manifest in both acute and long-lasting phenotypes. To gain insight on the molecular basis of these sensory abnormalities, we used the golden hamster infection model to characterize the effects of SARS-CoV-2 versus Influenza A virus (IAV) infection on the sensory nervous system. Efforts to detect the presence of virus in the cervical/thoracic spinal cord and dorsal root ganglia (DRGs) demonstrated detectable levels of SARS-CoV-2 by quantitative PCR and RNAscope uniquely within the first 24 hours of infection. SARS-CoV-2-infected hamsters demonstrated mechanical hypersensitivity during acute infection; intriguingly, this hypersensitivity was milder, but prolonged when compared to IAV-infected hamsters. RNA sequencing (RNA-seq) of thoracic DRGs from acute infection revealed predominantly neuron-biased signaling perturbations in SARS-CoV-2-infected animals as opposed to type I interferon signaling in tissue derived from IAV-infected animals. RNA-seq of 31dpi thoracic DRGs from SARS-CoV-2-infected animals highlighted a uniquely neuropathic transcriptomic landscape, which was consistent with substantial SARS-CoV-2-specific mechanical hypersensitivity at 28dpi. Ontology analysis of 1, 4, and 30dpi RNA-seq revealed novel targets for pain management, such as ILF3. Meta-analysis of all SARS-CoV-2 RNA-seq timepoints against preclinical pain model datasets highlighted both conserved and unique pro-nociceptive gene expression changes following infection. Overall, this work elucidates novel transcriptomic signatures triggered by SARS-CoV-2 that may underlie both short- and long-term sensory abnormalities while also highlighting several therapeutic targets for alleviation of infection-induced hypersensitivity. One Sentence SummarySARS-CoV-2 infection results in an interferon-associated transcriptional response in sensory tissues underlying time-dependent hypersensitivity.

neuroscience↗

bioRxiv2022

SARS-CoV-2 infection results in lasting and systemic perturbations post recovery

SARS-CoV-2 has been found capable of inducing prolonged pathologies collectively referred to as Long-COVID. To better understand this biology, we compared the short- and long-term systemic responses in the golden hamster following either SARS-CoV-2 or influenza A virus (IAV) infection. While SARS-CoV-2 exceeded IAV in its capacity to cause injury to the lung and kidney, the most significant changes were observed in the olfactory bulb (OB) and olfactory epithelium (OE) where inflammation was visible beyond one month post SARS-CoV-2 infection. Despite a lack of detectable virus, OB/OE demonstrated microglial and T cell activation, proinflammatory cytokine production, and interferon responses that correlated with behavioral changes. These findings could be corroborated through sequencing of individuals who recovered from COVID-19, as sustained inflammation in OB/OE tissue remained evident months beyond disease resolution. These data highlight a molecular mechanism for persistent COVID-19 symptomology and characterize a small animal model to develop future therapeutics.

microbiology↗

bioRxiv2021

A Promising Chemical Series of Positive Allosteric Modulators of the μ-Opioid Receptor that Enhance the Antinociceptive Efficacy of Opioids but not their Adverse Effects

Positive allosteric modulators (PAMs) of the {micro}-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.

neuroscience↗

bioRxiv2017

The ventral stream receives spatial information from the dorsal stream during configural face processing

Configural face processing is considered to be vital for face perception. If configural face processing requires an evaluation of spatial information, might this process involve interactions between ventral stream face-processing regions and dorsal stream visuospatial-processing regions? We explored this possibility using thetaburst stimulation (TBS) with fMRI in humans. Participants were shown two faces that differed in either the shape (featural differences) or the spatial configuration (configural differences) of their features. TBS applied on dorsal location-processing regions: 1) reduced fMRI activity within ventral stream face-processing regions during configural but not featural face processing; and 2) reduced functional connectivity between these face regions significantly more for configural than featural face processing. No changes occurred when TBS was delivered on the vertex control site for either face task. We conclude that ventral stream face-processing regions receive visuospatial information from dorsal stream location-processing regions during configural face processing.\n\nSignificance statementFace perception is thought to be mediated exclusively by neural substrates within the ventral visual pathway. However, by using non-invasive brain stimulation (thetabust transcranial magnetic stimulation) in healthy human adults, we demonstrate that the face-processing regions of the ventral visual pathway receive information from visuospatial-processing regions of the dorsal visual pathway during configural face processing, a vital function in face perception. Our findings thus indicate that veridical face perception may depend on both the ventral and dorsal visual pathways.

neuroscience↗