Biology subjects

Weiss, G.

Publications and source records attributed to Weiss, G..

16 recordsLinked to original sources

bioRxiv2026

Network and behavioral signatures of postpartum behavioral deficits improve with a neurosteroid-based treatment

Postpartum depression (PPD) impacts nearly 20% of mothers and a much larger percentage (up to 75%) suffer from postpartum blues. Despite this high incidence, we still have an incomplete understanding of the underlying neurobiology of PPD. Deficits in neurosteroid signaling has been implicated in the vulnerability to postpartum behavioral deficits and mice with reduced expression of {delta} subunit-containing GABAA receptors (GABAARs) (Gabrd -/- or Gabrd +/-), the predominant site of action for 5-reduced neurosteroids, exhibit behavioral deficits restricted to the postpartum period. Allopregnanolone and allopregnanolone analogs (SGE-516) can improve postpartum behavioral outcomes and their ability to modulate oscillations in the basolateral amygdala (BLA) involved in emotional processing has been proposed to contribute to their antidepressant effects. Here we demonstrate that the behavioral differences in postpartum wild type, Gabrd+/-, and SGE-516-treated Gabrd+/- dams is largely driven by theta oscillations in the BLA. Previous studies have linked theta oscillations in the BLA to altered behavioral responding in response to stress or threat. Interestingly, here we demonstrate that Gabrd+/- dams exhibit a failure to properly respond to their own pup calls, with reduced theta oscillations that correlates with deficits in maternal approach behavior both of which are restored with SGE-516 treatment. Further, unbiased MoSeq analysis identified altered behavioral syllable expression in Gabrd+/- dams in response to their pup calls compared to wild type dams that are restored with SGE-516 treatment. These findings demonstrate network and behavioral signatures of postpartum behavioral deficits and characterize the effects associated with neurosteroid-based treatment response.

neuroscience↗

bioRxiv2025

An Amygdalar Oscillatory Switch Governs Valence Assignment

Reward pursuit and punishment avoidance are among the most fundamental behaviors necessary for survival. The binary valuation of an experience as either positive or negative - "valence assignment" - is imperative for successful navigation of a regularly updating environment. Mounting evidence highlights the critical role of valence responsive basolateral amygdala (BLA) ensembles in coding valence information. However, how BLA ensembles are recruited to drive real-time valence assignment remains elusive. Here, we show locus coeruleus (LC)-derived norepinephrine coordinates this neural computational process via modulatory control over network-organizing BLA parvalbumin-expressing (PV) interneuron activity. Specifically, optogenetic activation of LC to BLA noradrenergic terminals (LC-BLANE) drives real-time negative valence assignment and suppression of BLA fast gamma oscillatory activity via BLA interneuronal 1a adrenergic receptor signaling. Conversely, positive valence assignment also requires BLA PV interneuron activity but is associated with an enhancement of local fast gamma power. Together, these converging data highlight a PV-driven amygdalar oscillatory switch that governs valence assignment.

neuroscience↗

bioRxiv2025

Motion sequencing reveals hidden patterns of repetitive behavior in a mouse model of epilepsy

Epilepsy is the 4th most prevalent neurological condition with 50 million cases worldwide. Patients with epilepsy bare a disproportionate burden of cognitive decline and psychiatric disorders which remain poorly understood and go unaddressed by current anti-epileptic treatments. Furthermore, pre-clinical work on behavioral comorbidities can be hampered by current testing frameworks which rely on well-defined, discreet tests with limited repeatability. Recent work has demonstrated a role for machine learning modalities such as Motion Sequencing (MoSeq) in assessing behavioral differences between naive and epileptic. In this study we combined MoSeq with a novel analysis pipeline to uncover repetitive behaviors in chronically epileptic mice. These repetitive behaviors emerge alongside epilepsy specific racing behaviors which persist in epileptic mice as disease progresses. We show that epileptic mice have more fragile and dispersed behavioral networks. Finally, we test this pipeline using the FDA approved anti-seizure medication carbamazepine, showing a rescue of racing syllable and a partial rescue of behavioral network dispersion. Together, these results lay a groundwork for extracting clinically relevant phenotypes from MoSeq data throughout disease progression.

neuroscience↗

bioRxiv2025

The Ca2+-binding protein CSE links Ca2+-signaling with cell-cell communication in multicellular cyanobacteria

Abstract/SummaryBecause of their multicellular lifestyle, filamentous cyanobacteria have evolved sophisticated cell-cell communication machinery to exchange, synchronize, and coordinate the efforts of individual cells in the filament. Analogous to gap junctions that were regarded as a purely Eukaryotic feature, multicellular cyanobacteria were found also to coordinate their cell-cell communication via septal junctions (SJs). However, the molecular signals that regulate the cell-cell communication machinery and SJs assembly are largely unknown. Lately, Ca2+- signaling has been implicated in regulating cell junctions in neurons. We recently discovered a new Ca2+-sensor protein, CSE, exclusively found in multicellular cyanobacteria. Here, we investigated CSE as a potential link between intracellular Ca2+-signaling and cell-cell communication. We solved the solution NMR structure of CSE in its Ca2+-bound state and revealed that CSE acts as Ca2+-buffer protein. Using cryo-electron tomography, we showed that CSE is not only essential for Ca2+ homeostasis, but also mediates cell-cell communication via regulating the formation of nanopores -- a necessary precursor of SJs -- as {Delta}cse mutant shows a strong reduction in the number of both nanopores and SJs. This determines for the first time Ca2+-signaling as a novel mechanism controlling cell-cell communication and establishes CSE as a key player regulating cyanobacterial multicellularity. This highlights also Ca2+-signaling as a common conserved principle for regulating cell junctions between organisms that deviated billion years ago.

microbiology↗

bioRxiv2024

Mitochondrial cardiolipin metabolism controlled by tafazzin enables ferroptosis

Mitochondria are important producers of reactive oxygen species, which are involved in triggering ferroptosis, a lipid peroxidation driven form of cell death. Paradoxically, in the rare inherited metabolic disease Barth Syndrome, we discovered a protection from erastin-induced ferroptosis, despite intrinsically elevated mitochondrial ROS levels. The affected transacylase tafazzin, which is mutated in Barth Syndrome, is pivotal for remodeling of the dimeric phospholipid cardiolipin. They unique to mitochondria and essential for shaping their membrane functionalities. We investigated which downstream effects of the pathogenic membrane alterations are responsible for the protective effect against ferroptosis. We found that while iron metabolism, the unsaturation of membrane lipids, and the metabolic activity of the cells were modifying factors, they were not causal. However, we observed that cardiolipin abnormalities are not limited to impair only inner, but also outer mitochondrial membrane protein complexes. Specifically, they impact abundance and oligomerization of voltage-dependent anion channels (VDAC) in response to oxidative stress. We found that tafazzin deficiency via alteration of cardiolipins affects VDAC functionality, thereby modulating small molecule transport and signaling between mitochondria and the remaining cell. This is in line with a reduction of mitochondria-associated membranes (MAM) sites that are formed through VDACs and trapping ROS in mitochondria where they are unable to contribute to ferroptosis. These findings demonstrate that the mitochondrial membrane architecture impacting on subcellular small molecule distribution crucially impact on the manifestation of cell fate decisions, including ferroptosis.

molecular biology↗

bioRxiv2024

Sex-dependent effects of early life stress on network and behavioral states.

BackgroundAdverse childhood experiences (ACEs) are associated with numerous detriments in health, including increased vulnerability to psychiatric illnesses. Early life stress (ELS) in rodents has been shown to effectively model several of the behavioral and endocrine impacts of ACEs and has been utilized to investigate the underlying mechanisms contributing to disease. However, the precise neural mechanisms responsible for mediating the impact of ELS on vulnerability to psychiatric illnesses remain largely unknown. MethodsWe use behavior, immunoassay, in vivo LFP recording, histology, and patch clamp to describe the effects of ELS on stress behaviors, endocrinology, network states, protein expression, and cellular physiology in male and female mice. ResultsWe demonstrate that a murine maternal separation (MS) ELS model causes sex-dependent alterations in behavioral and hormonal responses following an acute stressor. Local field potential (LFP) recordings in the basolateral amygdala (BLA) and frontal cortex (FC) reveal similar sex-dependent alterations at baseline, in response to acute ethological stress, and during fear memory extinction, supporting a large body of literature demonstrating that these network states contribute to stress reactivity and vulnerability to psychiatric illnesses. Sex differences were accompanied by altered physiology of BLA principal neurons in males and BLA PV interneurons in females. ConclusionsCollectively, these results implicate novel, sex-dependent mechanisms through which ACEs may impact psychiatric health, involving altered cellular physiology and network states involved in emotional processing.

neuroscience↗

bioRxiv2023

Dopamine-iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinsons disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the -synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment affected the expression of transmembrane iron transporters and cellular iron accumulation. Furthermore, dopamine supplementation led to decreased mitochondrial respiration and reduced mitochondrial fitness, including reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of these PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore this disturbed regulatory network in PD cells.

neuroscience↗

bioRxiv2023

Early life stress impairs VTA coordination of BLA network and behavioral states

Motivated behaviors, such as social interactions, are governed by the interplay between mesocorticolimbic structures, such as the ventral tegmental area (VTA), basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adverse childhood experiences and early life stress (ELS) can impact these networks and behaviors, which is associated with increased risk for psychiatric illnesses. While it is known that the VTA projects to both the BLA and mPFC, the influence of these inputs on local network activity which govern behavioral states - and whether ELS impacts VTA-mediated network communication - remains unknown. Our study demonstrates that VTA inputs influence BLA oscillations and mPFC activity, and that ELS weakens the ability of the VTA to coordinate BLA network states, likely due to ELS-induced impairments in dopamine signaling between the VTA and BLA. Consequently, ELS mice exhibit increased social avoidance, which can be recapitulated in control mice by inhibiting VTA-BLA communication. These data suggest that ELS impacts social reward via the VTA-BLA dopamine network.

neuroscience↗

bioRxiv2023

Experience-dependent information routing through the basolateral amygdala

The basolateral amygdala (BLA) is an emotional processing hub and is well-established to influence both positive and negative valence processing. Selective engagement of a heterogeneous cell population in the BLA is thought to contribute to this flexibility in valence processing. However, how this process is impacted by previous experiences which influence valence processing is unknown. Here we demonstrate that previous positive (EE) or negative (chronic unpredictable stress) experiences differentially influence the activity of specific populations of BLA principal neurons projecting to either the nucleus accumbens core or bed nucleus of the stria terminalis. Using chemogenetic manipulation of these projection-specific neurons we can mimic or occlude the effects of chronic unpredictable stress or enriched environment on valence processing to bidirectionally control avoidance behaviors and stress-induced helplessness. These data demonstrate that previous experiences influence the responsiveness of projection-specific BLA principal neurons, biasing information routing through the BLA, to govern valence processing.

neuroscience↗

bioRxiv2022

Hypothalamic-pituitary-adrenal axis dysfunction worsens epilepsy outcomes and increases SUDEP risk

Epilepsy is often comorbid with psychiatric illnesses, including anxiety and depression. Despite the high incidence of psychiatric comorbidities in people with epilepsy, few studies address the underlying mechanisms. Stress can trigger both epilepsy and depression and significant accumulating evidence, from both human and animal studies, support that hypothalamic-pituitary-adrenal (HPA) axis dysfunction may contribute to the comorbidity of these two disorders1. Here we directly investigate the contribution of HPA axis dysfunction to epilepsy outcomes and psychiatric comorbidities. We generated a novel mouse model (KCC2/Crh mice) that lacks the K+/Cl- co-transporter, KCC2, in corticotropin-releasing hormone (CRH) neurons, which exhibit stress- and seizure-induced hyperactivation of the HPA axis.2,3 Here we demonstrate that HPA axis dysfunction in KCC2/Crh mice is associated with increased vulnerability to behavioral deficits in chronically epileptic mice and more severe neuropathological features associated with chronic epilepsy (e.g. increased mossy fiber sprouting). Despite equivalent seizure burden, HPA axis dysfunction in these chronically epileptic mice increased the incidence of sudden unexpected death in epilepsy (SUDEP). Suppressing HPA axis hyperexcitability in this model using a pharmacological or chemogenetic approach decreased SUDEP incidence, supporting HPA axis dysfunction in SUDEP vulnerability. We also observed changes in neuroendocrine markers in individuals that died of SUDEP compared to people with epilepsy or individuals without a history of epilepsy. Together, these findings describe a novel, nongenetic mouse model of SUDEP which will benefit preclinical SUDEP research to gain a better understanding of the underlying pathological mechanisms contributing to SUDEP. HPA axis dysfunction increases vulnerability to psychiatric comorbidities in epilepsy and may be a risk factor for SUDEP.

neuroscience↗

bioRxiv2022

A Protective Inter-Organ Communication Response Against Life-Threatening Malarial Anemia

Anemia is a clinical hallmark and independent risk factor of malaria mortality, the disease caused by Plasmodium spp. infection. While malarial anemia arises from parasite-induced hemolysis, whether and how host metabolic adaptation to malaria regulates anemia severity is less understood. Here we demonstrate that reprogramming of organismal iron (Fe) metabolism by the kidneys is a central component of the host metabolic response regulating the pathogenesis of life-threatening malarial anemia. Renal proximal tubule epithelial cells (RPTEC) are the main cell compartment responsible for Fe storage and recycling during Plasmodium infection in mice. Transcriptional reprogramming of RPTEC couples immune resistance to Plasmodium infection to renal Fe export via the induction of the cellular Fe exporter SLC40A1/ferroportin 1. This integrated defense strategy is essential to deliver Fe to erythroblasts and support compensatory erythropoiesis to prevent the development of life-threatening anemia. Failure to mobilize Fe from RPTEC causes acute kidney injury (AKI) and is associated with life-threatening anemia in P. falciparum-infected individuals. These findings reveal an unexpected role of the kidneys in the control of organismal Fe metabolism and anemia severity during malaria.

pathology↗

bioRxiv2021

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies

SARS-CoV-2 Beta variant of concern (VOC) resists neutralization by major classes of antibodies from non-VOC COVID-19 patients and vaccinated individuals. Here, serum of Beta variant infected patients revealed reduced cross-neutralization of non-VOC virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of novel VOC-specific clonotypes and accommodation of VOC-defining amino acids into a major non-VOC antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with non-VOC-elicited antibodies, including a public VH1-58 clonotype targeting the RBD ridge independent of VOC mutations. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift with implications for design of next-generation vaccines and therapeutics. One sentence summarySARS-CoV-2 Beta variant elicits lineage-specific antibodies and antibodies with neutralizing breadth against wild-type virus and VOCs.

immunology↗

bioRxiv2021

Defective Slc7a7 transport reduces systemic arginine availability compromising erythropoiesis and iron homeostasis

AbstractLysinuric Protein Intolerance (LPI) is an inborn error of metabolism resulting from SLC7A7 deficiency that causes diminished plasma concentration of cationic amino acids. The clinical picture is highly heterogeneous among patients, who commonly present intolerance to protein intake and more severe complications such as hematological abnormalities and kidney failure. Although current treatments aim to address the metabolic defects of LPI, they have been unsatisfactory when treating the most severe symptoms. Here we show that the absence of Slc7a7 in mice causes iron overload as a result of erythropoiesis failure. Regarding iron metabolism, we demonstrate that reduced plasma erythropoietin triggers a strong iron overload, as erythropoietin administration restores normal iron levels and mitigate hematological alterations. Interestingly, we found that human LPI is associated with hyperferritinemia but not iron overload, a trait that might be influenced by the citrulline treatment. Furthermore, we show that erythropoietin is a key factor in the hematological abnormalities in LPI. Our study reveals a mechanism leading to LPI-induced hematological complications and identifies erythropoietin supplementation as a promising therapeutic strategy for human LPI. Significance StatementThe systemic metabolic environment derived from Slc7a7-ablation in epithelial cells from kidney and intestine causes erythropoiesis failure prompting therefore iron overload. Here, we identify erythropoietin as the main driver of erythropoiesis failure as exogenous erythropoietin administration restores normal erythroblast population. In addition, we have also analyzed human data and found that patients with LPI have abnormal ferritin levels. Finally, as human LPI, citrulline treatment in mice restores normal iron homeostasis, highlighting the relevance of the systemic environment in LPI. Erythropoietin supplementation emerges as a promising therapeutic strategy for human LPI without the inflammatory effect associated with citrulline supplementation.

molecular biology↗

bioRxiv2020

Glycan-Protein Interactions Determine Kinetics of N-Glycan Remodeling

A hallmark of N-linked glycosylation in the secretory compartments of eukaryotic cells is the sequential remodeling of an initially uniform oligosaccharide to a site-specific, heterogeneous ensemble of glycostructures on mature proteins. To understand site-specific processing, we used protein disulfide isomerase (PDI), a model protein with five glycosylation sites, for molecular dynamics (MD) simulations and compared the result to a biochemical in vitro analysis with four different glycan processing enzymes. As predicted by an analysis of the accessibility of the N-glycans for their processing enzymes derived from the MD simulations, N-glycans at different glycosylation sites showed different kinetic properties for the processing enzymes. In addition, altering the tertiary structure context of N-glycan substrates affected N-glycan remodeling in a site-specific way. We propose that differential, tertiary structure context dependent N-glycan reactivities lead to different glycan structures in the same protein through kinetically controlled processing pathways.

biochemistry↗

bioRxiv2020

Mutational dynamics and transmission properties of SARS-CoV-2 superspreading events in Austria

Superspreading events shape the COVID-19 pandemic. Here we provide a national-scale analysis of SARS-CoV-2 outbreaks in Austria, a country that played a major role for virus transmission across Europe and beyond. Capitalizing on a national epidemiological surveillance system, we performed deep whole-genome sequencing of virus isolates from 576 samples to cover major Austrian SARS-CoV-2 clusters. Our data chart a map of early viral spreading in Europe, including the path from low-frequency mutations to fixation. Detailed epidemiological surveys enabled us to calculate the effective SARS-CoV-2 population bottlenecks during transmission and unveil time-resolved intra-patient viral quasispecies dynamics. This study demonstrates the power of integrating deep viral genome sequencing and epidemiological data to better understand how SARS-CoV-2 spreads through populations. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

microbiology↗

bioRxiv2019

Vortex fluidics-mediated DNA rescue from formalin-fixed museum specimens

DNA from formalin-preserved tissue could unlock a vast repository of genetic information stored in museums worldwide. However, formaldehyde crosslinks proteins and DNA, and prevents ready amplification and DNA sequencing. Formaldehyde acylation also fragments the DNA. Treatment with proteinase K proteolyzes crosslinked proteins to rescue the DNA, though the process is quite slow. To reduce processing time and improve rescue efficiency, we applied the mechanical energy of a vortex fluidic device (VFD) to drive the catalytic activity of proteinase K and recover DNA from American lobster tissue (Homarus americanus) fixed in 3.7% formalin for >1-year. A scan of VFD rotational speeds identified the optimal rotational speed for recovery of PCR-amplifiable DNA and while 500+ base pairs were sequenced, shorter read lengths were more consistently obtained. This VFD-based method also effectively recovered DNA from formalin-preserved samples. The results provide a roadmap for exploring DNA from millions of historical and even extinct species.

biochemistry↗