Biology subjects

Gomez, J. L.

Publications and source records attributed to Gomez, J. L..

9 recordsLinked to original sources

bioRxiv2026

Neurometabolic signatures of addiction vulnerability and heroin versus social seeking: a PET study in rats

Only a subset of heroin users develop addiction, characterized by binge-like heroin use and preference for heroin over other rewards, including social rewards. We recently established a rat model of these features. We trained rats to lever-press for social interaction and heroin (or saline, control) infusions and then tested heroin- and social-seeking and heroin-vs.-social choice. During 3-5 abstinence weeks, we used 2-deoxy-2-[{superscript 1}F]fluoro-D-glucose (FDG) PET imaging to assess regional brain metabolic activity at rest (homecage) and during heroin and social seeking. We assessed regional differences in FDG uptake using unbiased voxel-wise analysis and statistical parametric mapping, and correlated FDG uptake with principle-component-analysis-derived addiction severity score incorporating heroin intake, binge-like episodes, and heroin preference. Compared with saline-trained rats, heroin-trained rats showed overall higher FDG uptake across multiple brain regions at rest and during both reward-seeking tests. Comparison of heroin-vs.-social-seeking in heroin-trained rats showed higher uptake in claustrum/lateral striatum and auditory cortex during social seeking. Analysis of individual differences showed that addiction severity was primarily associated with metabolic alterations under resting conditions rather than during heroin- or social-seeking. At rest, higher addiction severity was associated with lower uptake in piriform cortex and higher uptake in ventral hippocampus, whereas during heroin-seeking, addiction severity was associated with lower uptake in post-subiculum and cerebellum. Addiction severity was not associated with differences in social seeking or FDG uptake during social seeking. These findings identify neurometabolic features of social and heroin seeking and heroin addiction vulnerability that can potentially serve as brain biomarkers and targets for neuromodulation. Significance StatementHeroin addiction develops in only a subset of users, yet the determinants of vulnerability versus resilience to addiction remain largely unknown. We combined a rat model capturing key features of heroin addiction, including binge-like heroin intake and preference for heroin over social interaction, with behavioral heroin- and social-seeking assays and longitudinal whole-brain metabolic imaging using FDG-PET. We identified distinct patterns of neurometabolic alterations associated with heroin self-administration and addiction severity at rest and in the context of heroin seeking. In contrast, heroin self-administration and addiction severity were not significantly associated with neurometabolic alterations during social seeking. These findings highlight brain-wide neurometabolic features of vulnerability to heroin addiction that can serve as brain biomarkers and targets for neuromodulation.

neuroscience↗

bioRxiv2026

Identification of Lupus Immune Complex-Driven Pathogenic Pro-inflammatory Monocytes and Macrophages in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease characterized by anti-nuclear antibody (ANA) production and inflammation, though the mechanisms by which ANAs induce inflammation and tissue injury are incompletely understood. Here, we identified distinct subsets of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), driven by lupus immune complex (IC), comprised of ANAs and their target antigens. scRNA-seq of human Mo incubated with U1-snRNP (snRNP) lupus IC revealed expansion of distinct pro-inflammatory Mo subsets with upregulation of inflammatory genes including those encoding cytokines, NLRP3, and transcription factors. These transcriptomic changes strongly correlated with protein expression, as determined by proteomic analysis. Mo developed similar pro-inflammatory transcriptomic changes in response to other lupus ICs containing anti-dsDNA and Ro60 antibodies. Interrogation of scRNA-seq datasets from the skin, kidney, and peripheral blood of lupus patients revealed the presence and expansion of pro-inflammatory Mo and M{Phi} populations exhibiting transcriptomic signatures similar to those observed in lupus IC-stimulated Mo. Some of these cells expressing the snRNP IC gene signature exhibited low expression of the type I IFN signature, suggesting that lupus IC and type I IFN signaling may independently affect Mo subsets. In lupus nephritis, infiltration of CD68+ M{Phi} expressing NLRP3 was associated with treatment outcomes. Inhibiting activation of the transcription factor ETS2, a master regulator of Mo/M{Phi}-driven inflammation, attenuated lupus IC-induced activation of pro-inflammatory Mo. Collectively, these findings provide novel insights into the role of lupus IC-driven pro-inflammatory MPs in the pathogenesis of SLE and highlight their relevance as therapeutic targets. Significance StatementSystemic lupus erythematosus (SLE or lupus) is a multi-systemic autoimmune inflammatory disease characterized by anti-nuclear antibody (ANA) production. Lupus immune complex (IC), consisting of ANAs and their target antigens, likely play a critical role in the pathogenesis of lupus through activation of mononuclear phagocytes (MPs), including monocytes (Mo) and macrophages (M{Phi}), which can produce an array of inflammatory molecules. Using transcriptomic and proteomic analyses, our study identified distinct pro-inflammatory Mo populations driven by lupus IC, along with expansion of similar pro-inflammatory Mo and M{Phi} subsets in the skin, kidneys, and peripheral blood of lupus patients. These findings provide novel insights into the pathogenic role of lupus IC-driven pro-inflammatory MPs and support a scientific rationale for therapeutically targeting these cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=155 HEIGHT=200 SRC="FIGDIR/small/700902v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1839430org.highwire.dtl.DTLVardef@175dd1dorg.highwire.dtl.DTLVardef@107b54forg.highwire.dtl.DTLVardef@11096b0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19

Sigma-1 receptor (S1R) is a Ca2+ sensitive, ligand-operated receptor chaperone protein present on the endoplasmic reticulum (ER) membrane and more specifically at the mitochondria-associated ER membrane (MAM). Upon activation by ER calcium depletion or ligand binding, S1R can increase calcium efflux from the ER into the mitochondria by chaperoning IP3 receptor type3 (Ip3R3). Mitochondrial metabolism has an intricate relationship with glycolysis. Despite S1R affecting mitochondria, the relevance of S1R to glycolysis and its impact on the overall cellular energy metabolism is not known. This study utilizes wild-type (Wt) and S1R knockout (S1R KO) Neuro2a (N2a) cells and Wt and S1R KO mice for primary culture of cortical neurons studies and longitudinal in-vivo imaging. In this manuscript we describe the fundamental functions of S1R on glycolysis, mitochondrial activity and NAD+/NADH metabolism, keystone coenzymes essential for glycolysis and for mitochondrial activity. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 but no change in mitochondrial oxygen consumption. Furthermore, we observed an increased NAD+/NADH ratio in S1R KO condition. Positron emission tomography revealed decreased [18F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking down GRIM19 in S1R KO condition rescued the glycolysis deficit. Altogether, these data show for the first time that S1R modulates glycolysis and NAD metabolism in various neuronal systems. This new insight on the S1R function may lead to new therapeutic applications of S1R ligands where compromised glycolysis and cellular NAD+/NADH ratios occur such as aging and neurodegeneration.

cell biology↗

bioRxiv2024

The role of GPR87 in Pulmonary Fibrosis

RationaleG- protein coupled receptor 87 (GPR87), an alternative lysophosphatidic acid (LPA) receptor previously implicated in cancer, is highly expressed in basal and aberrant basaloid cells in idiopathic pulmonary fibrosis (IPF). We sought to determine whether signaling through GPR87 is important to the development of pulmonary fibrosis. MethodsReanalysis of bulk and single cell RNA sequencing dataset was performed to confirm the increased expression of GPR87 in pulmonary fibrosis. The role of GPR87 in fibrosis in-vivo was assessed using global GPR87 knockout (GPR87-/-) and wildtype mice in the bleomycin model of pulmonary fibrosis, in-vitro in induced pluripotent stem cells (iPSCs) derived airway basal cells (iBC) using GPR87 siRNAs, and ex-vivo in human precision cut slices using disease free tissues in the fibrotic cocktail model as well as IPF tissues treated with GPR87 siRNA. ResultsGPR87 is highly expressed in IPF lungs, and its expression correlates with disease severity. Furthermore, It is highly expressed in basal and aberrant basaloid cells. GPR87-/- mice are protected against bleomycin induced pulmonary fibrosis. GPR87 knockdown is protective against fibrosis development in normal PCLS treated with fibrotic cocktail and leads to fibrosis regression in IPF PCLS. In iBC, GPR87 knockdown leads to decreased expression of fibrosis related genes, proteins and microRNAs. GPR87 stimulation with LPA leads to the opposite results. The main downstream pathways are PI3K, mTOR, and TNF/NFkB; stimulation or inhibition of PI3K pathway mimics GPR87 stimulation or inhibition responses, respectively. ConclusionGPR87 is highly expressed in basal and aberrant basaloid cells in IPF lungs and seems to mediate profibrotic effects based on in-vivo, ex-vivo and in-vitro models of disease, suggesting that it should be studied as a potential epithelial specific therapeutic target in pulmonary fibrosis.

cell biology↗

bioRxiv2023

In vivo photopharmacology with light-activated opioid drugs

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action. HighlightsA photoactivatable opioid agonist (PhOX) and antagonist (PhNX) for in vivo photopharmacology. Systemic pro-drug delivery followed by local photoactivation in the brain. In vivo photopharmacology produces behavioral changes within seconds of photostimulation. In vivo photopharmacology enables all-optical pharmacology and physiology.

neuroscience↗

bioRxiv2022

Unexpected finding of Fusobacterium varium abundance in cattle rumen: implications for liver abscess interventions

Fusobacterium varium has been generally overlooked in cattle rumen microbiome studies relative to the presumably more abundant, liver abscess-causing Fusobacterium necrophorum. Here, we revisit that conventional wisdom and report greater relative abundance of F. varium than F. necrophorum in both raw rumen samples and in lactate-supplemented enrichments tailored for F. necrophorum growth, despite its consistent inadvertence in past ruminal surveys and putative inability to metabolize lactate. Our observation that F. varium grows under restrictive conditions used to enumerate F. necrophorum suggests that previous estimations were inaccurate and F. varium is an underestimated player within the ruminal community. Exposure to tylosin, the current gold standard among prophylactic liver abscess prevention strategies in cattle, consistently reduced growth of all F. necrophorum strains screened by greater than 67% relative to unexposed controls. In contrast, F. varium strains were completely or highly resistant (0 - 11% reduction in maximum yield). Monensin, an ionophore fed to cattle to improve feed efficiency also had stronger inhibitory activity against F. necrophorum than against F. varium. Finally, preliminary genomic analysis of two F. varium bovine isolates revealed the presence of virulence genes related to those of pathogenic F. varium human isolates associated with active invasion of mammalian cells. ImportanceJudicious antibiotic use is essential to mitigate the spread of antimicrobial resistance. Dogmatic prophylactic use of in-feed tylosin to control cattle liver abscesses hinges on the assumption that F. necrophorum in the rumen is the main etiologic agent. However, our unexpected finding of abundance of F. varium in the rumen and its resistance to antibiotics, in hand with the potential pathogenicity of this species, calls for increased attention to F. varium. Further investigation into F. varium is necessary to better understand bovine liver abscess development and devise higher-precision alternatives to antibiotic treatment.

microbiology↗

bioRxiv2022

Effect of selective lesions of nucleus accumbens μ-opioid receptor-expressing cells on heroin self-administration in male and female rats: a study with novel Oprm1-Cre knock-in rats

The brain {micro}-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell-type specific genetic access to MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the role of nucleus accumbens (NAc) MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and fluorescence in situ hybridization chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum (DS), and dorsal hippocampus, or MOR receptor density (except DS) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly co-expressed with Oprm1 (95-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells and report sex-specific effects: the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study with these rats suggests a sex-specific role of NAc MOR-expressing cells in heroin self-administration. Significance statementThe brain {micro}-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell-type specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show a potential sex-specific role of nucleus accumbens MOR-expressing cells in heroin self-administration. The new Oprm1-Cre rats can be used to study both the general and sex-specific role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

neuroscience↗

bioRxiv2020

Zinc potentiates dopamine neurotransmission and cocaine seeking

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically-evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically-released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaines pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally-derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

neuroscience↗

bioRxiv2018

Chemogenetic ligands for translational neurotheranostics

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

neuroscience↗