Biology subjects

Kiaris, H.

Publications and source records attributed to Kiaris, H..

8 recordsLinked to original sources

bioRxiv2026

Cue-Dependent Fear Learning Drives Nucleus Accumbens Spine Plasticity

Nucleus accumbens (NAc) dopamine 2 receptor expressing medium spiny neurons (D2-MSNs) are involved in stress and aversive learning, where repeated stress increases excitatory spine density. Whether this plasticity reflects cue-specific learning or generalized stress response remains unknown. Using Pavlovian fear conditioning in Tac1-Cre/Tdtomato mice, we dissociated associative plasticity from the effects of foot shock stress. Acute fear conditioning produced distinct physiological outcomes between stress in the presence or absence of a cue. Conditioning for 7 days consolidated cue learning and increased excitatory transmission frequency via an increase in the total spine density. However, repeated exposure to foot shock did not lead to this synaptic remodeling. Our results suggest that morphological changes supporting synaptic plasticity on NAc D2-MSNs are due to cue-dependent learning, but not foot shock stress alone. We propose that NAc D2-MSNs encode learning and response to threat cues, which may heighten later stress responsivity.

neuroscience↗

bioRxiv2023

Variations in cellular unfolded protein response, respiratory capacity, and stress tolerance in skin and lung fibroblasts of deer mice (Peromyscus maniculatus)

Evolutionary physiologists have long been interested in physiological mechanisms underpinning variation in life-history performance. Recent efforts to elucidate these mechanisms focused on bioenergetics and oxidative stress. One underappreciated area that could play a role in mediating variation in performance is the unfolded protein response (UPR), a cellular stress response that reduces secretory protein load, enhances endoplasmic reticulum (ER) protein folding and clearance capacity during stress and during its adaptive phase. Given that the ER and mitochondria interact to regulate cellular homeostasis, it seems intuitive that UPR phenotype would correlate strongly with mitochondrial physiology, which in turn would contribute to variations in whole-organism metabolism. One way researchers have been studying cellular controls of life-history traits is by assessing stress resistance and bioenergetic properties of primary dermal fibroblasts. However, it is unclear if findings from dermal fibroblasts can be generalized to other cell and tissue types, and if fibroblasts phenotypes are repeatable across different life-history stages. This study aimed to explore the relationships between UPR profile, cellular respiration, and stress resistance using primary dermal fibroblasts isolated at puberty and primary lung fibroblasts isolated at adulthood. Specifically, we tested if 1) UPR profile of dermal fibroblasts isolated at puberty corresponds to UPR profile of lung fibroblasts isolated at adulthood, 2) UPR profile of dermal fibroblasts isolated at puberty and lung fibroblasts isolated at adulthood correspond to cellular bioenergetics of lung fibroblasts isolated at adulthood, and 3) UPR profile of dermal fibroblasts isolated at puberty corresponds to multiplex stress resistance (ER stress, oxidative stress, DNA damage) of lung fibroblasts isolated at adulthood. We found that only tunicamycin induced BiP expression was repeatable in skin and lung fibroblasts. Tunicamycin induced expressions of BiP, GRP94, and CNX in skin fibroblasts predicted resistance of lung fibroblasts to tunicamycin, (but not thapsigargin and other inducers of lethal stress), which is indicative for the pro-survival role of UPR during stress. Tunicamycin induced BiP expression in skin and lung fibroblasts also predicted multiple cellular bioenergetics parameters in lung fibroblasts. Statements and DeclarationsNo competing interests declared. This work was supported by National Science Foundation grants IOS1453784 and OIA1736150 to W.R.H., IOS1755670 to the PGSC, and a National Science Foundation EPSCoR pilot grant to K.N.Y. The funders did not have any input into the content of the manuscript nor require approval prior to submission.

physiology↗

bioRxiv2023

The SARS-CoV-2 Spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice

BackgroundAs the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy. MethodsA Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post introducing (wpi) Spp using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions. ResultsLow-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory chain genes including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1 and signal transducer and activator of transcription 5A, and increases in expression of glucose metabolism-associated genes. As compared with the age-matched HFD control mice, cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly elevated, and cardiac fibrosis was increased in HFD mice at 24 wpi. ConclusionOur data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.

microbiology↗

bioRxiv2022

SARS-CoV-2 infects multiple species of North American deer mice and causes clinical disease in the California mouse

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-19 (COVID-19), emerged in late 2019 in Wuhan, China and its rapid global spread has resulted in millions of deaths. An important public health consideration is the potential for SARS-CoV-2 to establish endemicity in a secondary animal reservoir outside of Asia or acquire adaptations that result in new variants with the ability to evade the immune response and reinfect the human population. Previous work has shown that North American deer mice (Peromyscus maniculatus) are susceptible and can transmit SARS-CoV-2 to naive conspecifics, indicating its potential to serve as a wildlife reservoir for SARS-CoV-2 in North America. In this study, we report experimental SARS-CoV-2 susceptibility of two additional subspecies of the North American deer mouse and two additional deer mouse species, with infectious virus and viral RNA present in oral swabs and lung tissue of infected deer mice and neutralizing antibodies present at 15 days post-challenge. Moreover, some of one species, the California mouse (P. californicus) developed clinical disease, including one that required humane euthanasia. California mice often develop spontaneous liver disease, which may serve as a comorbidity for SARS-CoV-2 severity. The results of this study suggest broad susceptibility of rodents in the genus Peromyscus and further emphasize the potential of SARS-CoV-2 to infect a wide array of North American rodents. ImportanceA significant concern is the spillback of SARS-CoV-2 into North American wildlife species. We have determined that several species of peromyscine rodents, the most abundant mammals in North America, are susceptible to SARS-CoV-2 and that infection is likely long enough that the virus may be able to establish persistence in local rodent populations. Strikingly, some California mice developed clinical disease that suggests this species may be useful for the study of human co-morbidities often associated with severe and fatal COVID-19 disease.

microbiology↗

bioRxiv2022

The Spike protein of SARS-CoV-2 impairs lipid metabolism and increases susceptibility to lipotoxicity: implication for a role of Nrf2

Background/objectivesCoronavirus disease 2019 (COVID-19) patients exhibit lipid metabolic alterations, but the mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in host cells. MethodsA Spike cell line in HEK293 was generated using the pcDNA vector carrying the Spike gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. ResultsAs compared with controls, the Spike cells showed a significant increase in lipid depositions on cell membranes as well as dysregulation of expression of a panel of molecules involved lipid metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis, which could be attenuated by the Nrf2 inhibitor trigonelline. ConclusionsThe Spike protein impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments. HighlightsO_LIThe Spike protein increases lipid deposition in host cell membranes C_LIO_LIThe Spike protein impairs lipid metabolic and autophagic pathways C_LIO_LIThe Spike protein exaggerates PA-induced lipotoxicity in host cells via ferroptosis C_LIO_LINrf2 inhibitor Trigonelline can mitigate the Spike protein-induced necrosis C_LI

cell biology↗

bioRxiv2021

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long living rodents that have emerged as an informative model to study aging, adaptation at extreme environments, and monogamous behavior. In the present study we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissue sources (tail, liver, brain). Two dual species human-peromyscus clocks accurately measure age and relative age defined as the ratio of chronological age to maximum age. These analyses also allowed us to accurately manifest the increasing impact of age, sex, genetic relatedness, and ultimately tissue identity, in that order, in the acquisition of specific methylation patterns in the genome. Genes that were differentially methylated across different biological variables were determined and their potential impact is discussed. This study describes highly accurate DNA methylation-based estimators of age in deer mice and illustrates how differential methylation may be linked to adaptation at different conditions.

developmental biology↗

bioRxiv2021

DNA Methylation Networks Underlying Mammalian Traits

Epigenetics has hitherto been studied and understood largely at the level of individual organisms. Here, we report a multi-faceted investigation of DNA methylation across 11,117 samples from 176 different species. We performed an unbiased clustering of individual cytosines into 55 modules and identified 31 modules related to primary traits including age, species lifespan, sex, adult species weight, tissue type and phylogenetic order. Analysis of the correlation between DNA methylation and species allowed us to construct phyloepigenetic trees for different tissues that parallel the phylogenetic tree. In addition, while some stable cytosines reflect phylogenetic signatures, others relate to age and lifespan, and in many cases responding to anti-aging interventions in mice such as caloric restriction and ablation of growth hormone receptors. Insights uncovered by this investigation have important implications for our understanding of the role of epigenetics in mammalian evolution, aging and lifespan.

evolutionary biology↗

bioRxiv2020

The infection-tolerant mammalian reservoir of Lyme disease and other zoonoses broadly counters the inflammatory effects of endotoxin

Animals that are competent natural reservoirs of zoonotic diseases commonly suffer little morbidity from the pathogens they persistently harbor. The mechanisms of this infection tolerance and the trade-off costs are poorly understood. We used exposure to a single dose of lipopolysaccharide (LPS) endotoxin as an experimental model of inflammation to compare the responses of the cricentine rodent Peromyscus leucopus, the white-footed deermouse, to that of Mus musculus, the standard laboratory model for pathogenesis studies. Four hours after injection with either LPS or saline, blood and spleen and liver tissues were collected postmortem and subjected to RNA-seq, untargeted metabolomics, and specific RT-qPCR. This was followed by analysis of differential expression at the gene, pathway, and empirical network levels. The deermice showed the same signs of sickness as the mice with LPS exposure, and in addition demonstrated comparable increases in levels of corticosterone and expression of interleukin (IL)-6, tumor necrosis factor, IL-1{beta}, and acute phase reactants, including C-reactive protein. But whereas the M. musculus response to LPS was best-characterized by network analysis as cytokine-associated, the P. leucopus response was dominated by pathway terms associated with neutrophil activity. Dichotomies between the species in expression profiles of arginase 1 and nitric oxide synthase 2, as well as the ratios of IL-10 to IL-12, were consistent with a type M1 polarized macrophage response in the mice and a type M2 or alternatively-activated response in the deermice. Analysis of metabolites in the plasma and RNA in the tissues revealed differences between the two species in tryptophan metabolism during response to LPS. Two up-regulated genes in particular signified the difference between the species: Slpi (secretory leukocyte proteinase inhibitor) and Ibsp (integrin-binding protein sialoprotein). The latter was previously unrecognized in the context of inflammation or infection. Key RNA-seq findings in P. leucopus were replicated in a second LPS experiment with older animals, in a systemic bacterial infection model, and with cultivated fibroblasts. Taken together, the results indicate that the deermouse possesses several adaptive traits to moderate effects of inflammation and oxidative stress ensuing from infection. This seems to be at the cost of infection persistence and that is to the benefit of the pathogen.

systems biology↗