Biology subjects

Wegener, G.

Publications and source records attributed to Wegener, G..

16 recordsLinked to original sources

bioRxiv2026

High-intensity fear engrams extend beyond threat processing to drive cognitive and affective dysfunction

Maladaptive fear memories are a core feature of stress-related disorders and are often accompanied by cognitive and affective disturbances; yet, it remains unclear whether the same neuronal ensembles link maladaptive fear to these behavioural alterations. Here, we show that activity of fear engrams causally contributes to behavioural consequences of intense fear beyond threat processing. Using activity-dependent tagging in the dorsal dentate gyrus (dDG) of mice, we identify neuronal ensembles recruited during high-intensity fear conditioning and show that chemogenetic inhibition of these neurons restores cognitive performance and reduces behavioural despair. These effects are specific to fear-associated ensembles, as inhibition of randomly tagged neurons fails to reproduce them, and depend on persistence of the fear memory, as they are abolished following extinction. Cell-type-specific manipulations revealed that glutamatergic, but not GABAergic, HI-tagged neurons drive fear expression and the associated cognitive and affective alterations, whereas GABAergic neurons exert an opposing influence on fear expression. Consistent with these findings, high-intensity fear was associated with increased reactivation of excitatory fear-tagged neurons and reduced reactivation of GABAergic fear-tagged neurons during behavioural despair. Together, these findings identify high-intensity fear engrams as a causal substrate linking threat-related experiences to cognitive and affective dysfunction and implicate altered excitatory-inhibitory recruitment within a single memory ensemble in the emergence of multi-domain behavioural alterations associated with stress-related disorders.

neuroscience↗

bioRxiv2026

Alkane-oxidizing consortia produce substantial amounts of disaccharides

1Consortia of archaea and partner bacteria couple the anaerobic oxidation of alkanes to sulfate reduction. While catabolic pathways in anaerobic alkane-oxidizing archaea (ANKA) are increasingly understood, their anabolic capacities remain poorly characterized. Here, we examined nine enrichment cultures dominated by ANKA and their partner bacteria for small-molecular compounds using solvent extraction and gas chromatographic analysis of derivatized extracts. All hydrocarbon-degrading cultures contained substantial amounts of disaccharides in their metabolite pools. Cold-adapted methane-oxidizing cultures dominated by ANME-2c and Seep-SRB2 contained up to 1.5 mg of trehalose per mg soluble protein. Trehalose was also abundant in ethane-oxidizing cultures of Candidatus Ethanoperedens and its distinct partner SRBs, accounting for up to 75 % of the extracted metabolites. In contrast, thermophilic ANKA cultures dominated by ANME-1 or Ca. Syntropharchaeum and Ca. Desulfofervidus contained an abundant as-yet-unidentified glucose-containing disaccharide. Metagenomic analysis revealed widespread trehalose metabolism genes among partner Desulfobacterota and in ANME-2c and Ca. Ethanoperedens, but a lower potential in ANME-1 and Syntropharchaeum, consistent with metabolite profiles. If exogenous trehalose was added to the Ethane50 culture, we observed rapid metabolization by heterotrophic microorganisms, but poor assimilation by the Ca. Ethanoperedens/ Ca. Desulfofervidus core community, indicating that ANKA/SRB consortia do not consume externally supplied trehalose. Instead, Ca. Ethanoperedens/ Ca. Desulfofervidus, as well as other ANKA/SRB consortia, may use the disaccharides as energy-storage molecules, osmolytes, or components of the extracellular matrix. Notably, the disaccharides produced by the consortia also sustain ancillary heterotrophs, thereby linking alkane oxidation to broader sedimentary carbon cycling.

microbiology↗

bioRxiv2026

Antidepressants interact with sex steroid receptors and their intracellular signaling components

There is growing interest in understanding how hormonal signaling pathways contribute to the pathophysiology of mood disorders, based on the premise that fluctuations in sex hormones influence mood, a relationship particularly evident in conditions such as premenstrual dysphoric disorder, prenatal depression, postpartum depression, and perimenopausal depression. Estrogen receptor alpha (ER) is predominantly localized in the nucleus, but can also be associated with the cell membrane, thus mediating a broad range of genomic and non-genomic effects through distinct intracellular pathways. By employing a combination of computational simulations and in vitro biochemical and cell-based assays, we systematically evaluated the potential binding and functional interactions of antidepressant compounds with ER. Our results provide compelling evidence that antidepressants may not only affect classical monoaminergic targets but also modulate hormone receptor activity, particularly that of ER. These findings are consistent with the hypothesis that ER plays an important role in mood regulation and highlight it as a potential therapeutic target. Moreover, this work raises the possibility that the clinical efficacy of certain antidepressants may, at least in part, derive from their capacity to influence estrogen receptor-mediated signaling. Significance statementClinical observations suggest a link between female sex hormones and mood, highlighted by the higher prevalence of depression in women and increased vulnerability to depression during hormonal fluctuations. Here, we report that structurally diverse conventional and rapid-acting antidepressants directly interact with estrogen receptor alpha (ER). This interaction is associated with rapid intracellular signaling in cellular models. These findings indicate that, alongside their conventional targets, antidepressants may also engage sex steroid receptor components and signaling. This work broadens our basic understanding of antidepressant pharmacology at the cellular level, offering an additional perspective that may inform future research into the biological mechanisms of mood disorders and suggest a framework for developing targeted therapies for hormone-associated depressive disorders.

pharmacology and toxicology↗

bioRxiv2026

Anaerobic oxidation of methane supports a minimal microbial community in a subsurface biofilm at Ginsburg Mud Volcano

Deep marine sediments generate large amounts of methane, but most of this gas is consumed by the anaerobic oxidation of methane (AOM) mediated by microscopic consortia of anaerobic methane-oxidizing archaea (ANME) and sulfate-reducing bacteria (SRB). In this study, we investigated the AOM within a sulfate-methane transition zone (SMTZ) at a depth of [~]9.6 m at the rim of the Ginsburg mud volcano in the Gulf of Cadiz. The SMTZ is supplied with sulfate from both, overlying seawater and an underlying evaporitic deposit, and it coincides with a fracture zone that hosts a visible biofilm. Here, carbon dioxide shows the strongest 13C-depletion, indicating intense methane consumption. Metagenomic and lipid biomarker analysis of the biofilm revealed an exceptionally simple microbial community dominated by ANME-1b archaea (63%), which predominantly produce strongly 13C-depleted glycerol dialkyl glycerol tetraethers and, to a lesser extent, the less common macrocyclic archaeols. The putative partner bacterium Seep-SRB1c (Desulfobacterota) is less abundant (9%). Additionally, the biofilm contained five low-abundance heterotrophs that likely rely on biomass or metabolites released from the ANME-SRB consortium. Our study highlights the presence of active methanotrophic biofilms in subsurface sediments and suggests that these communities may play an overlooked role in mitigating seafloor methane emissions.

microbiology↗

bioRxiv2025

Porcine model of BRD1 haploinsufficiency reveals neurodevelopmental, behavioral, and molecular altera-tions relevant to psychiatric disorders

Psychiatric disorders are complex conditions characterized by substantial overlap in genetic risk and shared biological mechanisms. However, how individual risk genes contribute to shared disease mechanisms and disorder-specific phenotypes remains poorly understood. BRD1 has emerged as a chromatin-associated regulator with transdiagnostic relevance across psychiatric disorders and a central role in gene regulatory networks enriched for psychiatric risk genes. To investigate the biological consequences of reduced BRD1 function in a translationally relevant system, we generated a minipig model harboring a monoallelic deletion in BRD1 and performed longitudinal neuroimaging together with behavioral and multi-omics profiling. BRD1 haploinsufficient minipigs displayed normal growth and exploratory behavior but exhibited subtle age-dependent differences in motivational behavior. Despite the absence of overt developmental abnormalities, longitudinal neuroimaging revealed genotype-associated structural differences primarily involving the cerebral cortex and caudate nucleus, suggestive of altered neurodevelopmental trajectories. Integrated multi-omics analyses revealed striking convergence across transcriptomic and metabolomic datasets, identifying coordinated perturbations of mitochondrial function, redox regulation, and phospholipid metabolism across multiple brain regions. Notably, these molecular alterations were not restricted to the central nervous system, as peripheral multi-omics profiling revealed systemic metabolic alterations, including altered phospholipid composition and glucose metabolism. Together, these findings indicate that BRD1 haploinsufficiency is associated with coordinated neurodevelopmental and metabolic alterations across brain and peripheral tissues. More broadly, this study provides systems-level insight into how a psychiatric risk gene influences interconnected neurodevelopmental and metabolic processes across multiple levels of biological organization and highlights the value of large-animal multi-omics models for translational neuropsychiatric research.

genetics↗

bioRxiv2025

Marine cold seep ANME-2/SRB consortia produce their lipid biomass from inorganic carbon

In cold seeps, anaerobic methanotrophic archaea (ANME) and sulfate-reducing bacteria (SRB) oxidize methane to inorganic carbon (IC) coupled to sulfate reduction. While catabolic pathways are well resolved, carbon flow into biomass remains unclear. We conducted lipid stable isotope probing (lipid-SIP) experiments with Astoria Canyon sediments dominated by ANME-2/SRB consortia and incubated samples with either 13C-labeled methane (13CH4) or dissolved IC (DI13C). Lipid-specific {delta}13C analysis showed higher 13C incorporation from DI13C than from 13CH4. After 30 days, {delta}13C values were up to +417{per thousand} in SRB-specific fatty acids (e.g., C16:1{omega}5c, cyC17:0{omega}5,6) and +126{per thousand} in ANME-2-specific isoprenoid lipids (e.g., archaeol, crocetane). Based on these values, we calculated carbon assimilation rates and found that both partners primarily assimilate IC. Remarkedly, IC assimilation in SRB lipids was eight times higher than in ANME lipids, suggesting that ANME either rely on fixation of internally generated CO2 from 13C-label-free methane before it can be exchanged with the environment or they utilize an additional, yet unknown carbon source for lipid biosynthesis. By examining the step-wise 13C-enrichment of ANME- and SRB-derived lipids, we further delineate biosynthetic pathways for archaeal and bacterial diether lipid formation and highlight crocetane as a bilayer-modulating isoprenoid hydrocarbon potentially affecting membrane fluidity and proton permeability. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=88 SRC="FIGDIR/small/667857v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@a70354org.highwire.dtl.DTLVardef@cb95acorg.highwire.dtl.DTLVardef@1cf6d5corg.highwire.dtl.DTLVardef@114b912_HPS_FORMAT_FIGEXP M_FIG C_FIG Lipid-SIP experiments in Astoria Canyon sediments revealed that both ANME-2 and SRB primarily assimilate inorganic carbon (IC), not methane, into biomass. SRB-specific lipids showed eightfold higher I13C-assimilation than ANME lipids, suggesting SRB directly assimilate environmental IC, while ANME rely on internally produced CO2 or alternative carbon sources, potential provided by SRBs.

microbiology↗

bioRxiv2025

Viral communities from long-term anaerobic alkane-oxidizing enrichments may promote cell surface adhesion

The anaerobic oxidation of methane and higher C2+ alkanes is a dominant metabolism within hydrocarbon-rich deep-sea sediments and is largely mediated by alkane-oxidizing archaea in metabolic partnership with syntrophic sulfate-reducing bacteria. While these processes feed a diverse ecosystem, the viral component of alkane-rich sediments has historically been overlooked. We analyzed the viral community in long-term sediment-free enrichments of alkane-degrading organisms and found that abiotic factors such as incubation temperature had a greater correlation with community composition than with the phylogenetic patterns among individual viral species. No auxiliary metabolic genes directly involved in hydrocarbon oxidation or sulfate reduction were found, but the presence of AMGs involved in heme synthesis pathways common in methane oxidizers hints at a possible viral impact on alkane degradation. We also found evidence supporting the presence of a viral genus infecting several phyla across both the bacterial and archaeal domains, including one of the sulfate-reducing bacterial partners in the alkane-oxidizing syntrophy. Lastly, we report the presence of nosD-like proteins in viruses from sediment-derived systems that are not present in water column datasets; their distribution, genomic context, and lack of canonical nosD characteristics suggest an alternate adhesion-related role in sediment communities. The number of novel viruses obtained from these enrichment cultures and their potential roles in mediating host physiology illustrate the importance of studying the viral component in laboratory and environmental systems.

ecology↗

bioRxiv2025

Atomic resolution structures of key enzyme MCR in anaerobic methanotrophy reveal novel and extensive post-translational modifications.

Anaerobic methanotrophic archaea (ANME) are crucial to planetary carbon cycling. They oxidise methane in anoxic niches by transferring electrons directly to nitrate or metal oxides and alternatively to sulfate-reducing bacteria. Due to their physiological complexity, no ANME species have been isolated, hampering the biochemical investigation of the enzymatic processes involved in anaerobic methane oxidation. To study the methane-capturing enzyme of these microorganisms, we circumvented the isolation barrier by exploiting microbial enrichments of freshwater nitrate-reducing ANME-2d grown in bioreactors, and marine ANME-2c in syntrophy with bacterial partners. The crystal structures of their Methyl-Coenzyme M Reductases (MCRs), refined to true atomic resolution, provided the most precise image of the enzyme to date. Despite their physiological differences, these ANMEs have extremely conserved MCR structures, similar to homologs from methanogenic Methanosarcinales, rather than the phylogenetically distant MCR of ANME-1 isolated from Black Sea mats. The three studied MCRs are highly modified, with seven post-translational modifications. Among them was a novel 3(S)-methylhistidine on the {gamma}-chain of both ANME-2d MCRs. Labelling with gaseous krypton did not reveal any internal channels that would facilitate alkane diffusion to the active site as observed in the ethane-specialized enzyme. Based on our data, the methanotrophic MCRs should follow the same radical reaction mechanism proposed for the methane-generating homologues. The described pattern of post-translational modifications underscores the importance of native purification as a powerful approach to discovering intrinsic enzymatic features in uncultivated microorganisms existing in nature.

microbiology↗

bioRxiv2024

F420 reduction as a cellular driver for anaerobic ethanotrophy

The anaerobic ethane oxidation performed by seafloor archaea and sulfate-reducing partner bacteria involves largely uncharted biochemistry. This study deciphers the molecular basis of the CO2-generating steps by characterizing the native archaeal enzymes isolated from a thermophilic enrichment culture. While other microorganisms couple these steps to ferredoxin reduction, we found that the CO-dehydrogenase and the formylmethanofuran-dehydrogenase are bound to an F420-reductase module. The crystal structures of these multi-metalloenzyme complexes revealed a [4Fe-4S]-cluster networks electronic bridges coupling C1-oxidation to F420-reduction. Accordingly, both systems exhibit robust F420-reductase activities, which are not detected in methanogenic or methanotrophic relative organisms. We speculate that the whole catabolism of these archaea is reoriented towards F420-reduction, which facilitates the electron transfer to the sulfate-reducing partner, therefore representing the driving force of ethanotrophy.

biochemistry↗

bioRxiv2022

Characterization of a novel gene-environment-based animal model to study resilience and susceptibility to PTSD and co-morbid depression

BACKGROUNDPost-traumatic stress disorder (PTSD) and co-morbid depression are frequently associated with severe symptoms, poor response to treatment and worse prognosis. Due to the absence of a suitable animal model, little is known about the biological basis of the comorbidity, severely limiting the discovery of new and more effective treatment options. The Flinders Sensitive Line rats (FSL) is a well-validated, selectively bred animal model of depression. However, several of its features, such as cognitive deficits and altered hypothalamic-pituitary-adrenal (HPA) axis response, also match symptomatic clusters of PTSD. In parallel, its resistant counterpart, the Flinders Resistant Line (FRL), is extensively used as a simple control. Still, little is known about its performance compared to the original strain, Sprague Dawley (SD), from which the FSL/FRL was originally derived. AIMSCharacterizing the behavioural performance and mechanisms involved in FSL, FRL and SD rats in fear-memory paradigms. METHODSFSL, SD and FRL animals were submitted to tests assessing hippocampal-dependent and fear-related memory. Subsequently, plasticity factors and endocrine responses to stress were analysed to elucidate the molecular basis for the observed behavioural alterations. RESULTSWe found that FRL animals presented intact recognition memory and innate fear responses but could not properly display conditioned responses in the Conditioned Fear Conditioning (CFC) paradigm. FSL animals, despite a poor performance in the Novel Object Recognition task (NOR), showed similar levels of conditioned responses compared to SD, but impairments in extinction learning, a feature highly related to PTSD. The behavioural alterations were accompanied by alterations in plasma corticosterone levels and hippocampal expression of the glucocorticoid receptor and FKBP51. CONCLUSIONFor the first time, we demonstrate an animal model of resilience and vulnerability to PTSD and co-morbid depression. The results suggest that the endophenotypes may be based on aberrant endocrine stress responses in the hippocampus.

neuroscience↗

bioRxiv2022

The majority of microorganisms in gas hydrate bearing subseafloor sediments ferment macromolecules

BackgroundGas hydrate-bearing subseafloor sediments harbor a large number of microorganisms. Sedimentary organic matter and upward methane fluids represent two important sources of carbon and energy for deep biosphere. However, which metabolism dominates the deep subseafloor of gas hydrate zone is poorly constrained. Here we studied the microbial communities in gas-hydrate rich sediments up to 49 meters below seafloor recovered by drilling in the South China Sea. We focused on distinct geochemical conditions, and performed metagenomic and metatranscriptomic analyses to characterize microbial diversity and their role in carbon mineralization. ResultsComparative microbial community analysis revealed that samples above and in sulfate-methane interface (SMI) zones clearly distinguish from those below the SMI. Chloroflexota, are most abundant above the SMI, whereas Caldatribacteriota dominate below the SMI. Verrucomicrobiota, Bathyarchaeia and Hadarchaeota were similarly present in both types of sediment. The genomic inventory and transcriptional activity suggest roles in fermentation of macromolecule. By contrast, sulfate reducers and methanogens, organisms that catalyze the consumption or production of commonly observed chemical compounds in sediments are rare. Methanotrophs of the ANME-1 group thrived in or slightly below the current sulfate methane interface. Rare members from Heimdallarchaeia were identified to encode the potential for anaerobic oxidation of short-chain hydrocarbons. ConclusionsThese findings indicate that fermentation of macromolecules is the predominant energy source for microorganisms in deep subseafloor sediments that are experiencing upward methane fluxes.

microbiology↗

bioRxiv2021

Comparative genomics reveals electron transfer and syntrophic mechanisms differentiating methanotrophic and methanogenic archaea

The anaerobic oxidation of methane coupled to sulfate reduction is a microbially mediated process requiring a syntrophic partnership between anaerobic methanotrophic (ANME) archaea and sulfate reducing bacteria (SRB). Based on genome taxonomy, ANME lineages are polyphyletic within the phylum Halobacterota, none of which have been isolated in pure culture. Here we reconstruct 28 ANME genomes from environmental metagenomes and flow sorted syntrophic consortia. Together with a reanalysis of previously published datasets, these genomes enable a comparative analysis of all marine ANME clades. We review the genomic features which separate ANME from their methanogenic relatives and identify what differentiates ANME clades. Large multiheme cytochromes and bioenergetic complexes predicted to be involved in novel electron bifurcation reactions are well-distributed and conserved in the ANME archaea, while significant variations in the anabolic C1 pathways exists between clades. Our analysis raises the possibility that methylotrophic methanogenesis may have evolved from a methanotrophic ancestor.

microbiology↗

bioRxiv2020

Early life stress targets the transcriptional signature and functional properties of voltage gated-sodium (Nav) channels in hippocampal NG2+ glia.

The precise mechanisms underlying the detrimental effects of early life stress (ELS) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELS on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. ELS shifted the NG2+ transcriptome towards more mature stages, and these transcriptional effects were dependent on stress-induced glucocorticoids. The functional relevance of one candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in ELS animals, and these same animals displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings suggest novel insights into the pathophysiology of stress-related mental disorders.

neuroscience↗

bioRxiv2020

Candidatus Ethanoperedens, a thermophilic genus of archaea mediating the anaerobic oxidation of ethane

Cold seeps and hydrothermal vents deliver large amounts of methane and other gaseous alkanes into marine surface sediments. Consortia of archaea and partner bacteria thrive on the oxidation of these alkanes and its coupling to sulfate reduction. The inherently slow growth of the involved organisms and the lack of pure cultures have impeded the understanding of the molecular mechanisms of archaeal alkane degradation. Here, using hydrothermal sediments of the Guaymas Basin (Gulf of California) and ethane as substrate we cultured microbial consortia of a novel anaerobic ethane oxidizer Candidatus Ethanoperedens thermophilum (GoM-Arc1 clade) and its partner bacterium Candidatus Desulfofervidus auxilii previously known from methane-oxidizing consortia. The sulfate reduction activity of the culture doubled within one week, indicating a much faster growth than in any other alkane-oxidizing archaea described before. The dominance of a single archaeal phylotype in this culture allowed retrieving a closed genome of Ca. Ethanoperedens, a sister genus of the recently reported ethane oxidizer Candidatus Argoarchaeum. The metagenome-assembled genome of Ca. Ethanoperedens encoded for a complete methanogenesis pathway including a methyl-coenzyme M reductase (MCR) that is highly divergent from those of methanogens and methanotrophs. Combined substrate and metabolite analysis showed ethane as sole growth substrate and production of ethyl-coenzyme M as activation product. Stable isotope probing showed that the enzymatic mechanisms of ethane oxidation in Ca. Ethanoperedens is fully reversible, thus its enzymatic machinery has potential for the biotechnological development of microbial ethane production from carbon dioxide. IMPORTANCEIn the seabed gaseous alkanes are oxidized by syntrophic microbial consortia that thereby reduce fluxes of these compounds into the water column. Because of the immense quantities of seabed alkane fluxes, these consortia are key catalysts of the global carbon cycle. Due to their obligate syntrophic lifestyle, the physiology of alkane-degrading archaea remains poorly understood. We have now cultivated a thermophilic, relatively fast-growing ethane oxidizer in partnership with a sulfate-reducing bacterium known to aid in methane oxidation, and have retrieved the first complete genome of a short-chain alkane-degrading archaeon. This will greatly enhance the understanding of non-methane alkane activation by non-canonical methyl-coenzyme M reductase enzymes, and provide insights into additional metabolic steps and the mechanisms underlying syntrophic partnerships. Ultimately, this knowledge could lead to the biotechnological development of alkanogenic microorganisms to support the carbon neutrality of industrial processes. EtymologyEthanoperedens. ethano, (new Latin): pertaining to ethane; peredens (Latin): consuming, devouring; thermophilum. (Greek): heat-loving. The name implies an organism capable of ethane oxidation at elevated temperatures. LocalityEnriched from hydrothermally heated, hydrocarbon-rich marine sediment of the Guaymas Basin at 2000 m water depth, Gulf of California, Mexico. DiagnosisAnaerobic, ethane-oxidizing archaeon, mostly coccoid, about 0.7 m in diameter, forms large irregular cluster in large dual-species consortia with the sulfate-reducing partner bacterium Candidatus Desulfofervidus auxilii.

microbiology↗

bioRxiv2018

Elevated P2x7r and P2x4r transcripts levels in the Flinders Sensitive Line Rats, a genetic animal model of depression

P2x7 and P2x4 receptors (P2x7R and P2x4R, respectively) are ligand-gated ion channels activated by adenosine triphosphate (ATP), which have been associated to dysfunctional processes in stress responses linked to depression, such as neurotransmitter release, cognition, sleep, energy, appetite, immune and endocrine dysfunction. Clinical studies indicate that polymorphisms in the P2x7r gene results in increased susceptibility for development of depression. Existing studies have investigated the role of P2x7R and P2x4R in animal models based on stress exposure. Therefore, the present work aimed to investigate the transcript and protein levels of these receptors in a genetic animal model of depression, the Flinders Sensitive Line (FSL) and its control group, the Flinders Resistant Line (FRL) rats. We found that FSL rats have increased transcript levels of P2x7R and P2x4R in frontal cortex (FC), ventral and dorsal hippocampus (vHip and dHip, respectively) compared to FRL rats. There were no alterations in the protein levels in the FC and dHip, but the P2x7R was lower in FSL than in FRL rats in the vHip. The results suggest that increased transcripts levels of P2x7r and P2x4r in the FSL rats may contribute to the stress-susceptibility observed in these animals.

neuroscience↗

bioRxiv2018

The behavioral and neurobiological effects of reduced Brd1 expression in mice are sex-biased and implicate gender dependent dysregulation of nuclear receptor mediated signaling in mental disorders

The schizophrenia and bipolar disorder associated gene, BRD1, encodes a scaffold protein that in complex with epigenetic modifiers regulate gene sets enriched for psychiatric disorder risk. Preclinical evidence from male Brd1+/- mice has previously implicated BRD1 with phenotypes of translational relevance to schizophrenia. Here we describe the phenotype of female Brd1+/- mice and report attenuated dendritic architecture and monoaminergic dysregulation accompanied by sex-specific changes in affective behaviors. In accordance, global gene expression profiling reveals regional dysregulation of gene sets enriched with major depressive disorder and schizophrenia risk in female and male Brd1+/- mice, respectively. Independent of sex, however, differentially expressed genes cluster in common functional pathways associated with psychiatric disorders, including mitochondrial dysfunction and oxidative phosphorylation as well as G-protein coupled-, and nuclear receptor mediated signaling. Accordingly, we provide in vitro evidence that BRD1 modulates the transcriptional drive of a subset of nuclear receptors (e.g. the vitamin D and glucocorticoid receptors). Moreover, we demonstrate enrichment of psychiatric disorder risk in the target genes of nuclear receptors, sex-biased expression of several nuclear receptor genes in the adult brain of Brd1+/- mice, and that sex-biased genes in general are enriched with nuclear receptor genes particularly at the earliest developmental stage of the human brain. Overall, our data suggests that the spatio-temporal interaction between BRD1 and subsets of nuclear receptors in the brain is sex-biased and that hampered BRD1 mediated regulation of target genes governed by certain nuclear receptors may significantly contribute to sex differences in psychopathology.

neuroscience↗