Biology subjects

Sommer, T.

Publications and source records attributed to Sommer, T..

16 recordsLinked to original sources

bioRxiv2026

Recent Adversity Shapes Autonomic and Neural Threat Learning and Retrieval Under Imminent Threat: A Prospective Longitudinal Study

Recent adversity (RA) increases the risk of later mental health problems, but the mechanisms underlying this association remain largely unclear. Altered associative learning and specifically threat learning processes may constitute a potential pathway. Cross-sectional studies link RA to reduced threat-safety discrimination, a process crucial for adaptive functioning; however, longitudinal evidence allowing for more causal conclusions is lacking. In this prospective longitudinal study, 69 healthy participants completed fear acquisition, 24h-delayed extinction training and a reinstatement-test at two measurement time points six months apart (T0 and T1). We captured exposure to RA between T0 and T1 as well as autonomic and neural responses (SCRs and BOLD-fMRI), fear ratings, and salivary and hair cortisol at both assessments. During acquisition training, at the beginning of extinction (i.e., fear recall) and reinstatement-test at T1, RA-exposed individuals showed less autonomic threat-safety discrimination than unexposed individuals, mainly driven by blunted threat signal responding. These group differences predicted depression levels at the 1 and 1.5 year follow-ups and were mirrored by distinct activation in key fear-related brain regions, including striatal regions, thalamus, vmPFC, insula, and amygdala, whereas self-reported fear was unrelated to RA. In conclusion, across multiple outcomes, RA shapes threat learning and retrieval under conditions of (potential) imminent threat, with reduced autonomic threat discrimination prospectively predicting elevated depressive symptoms at 1- and 1.5-year follow-up. Overall, these findings implicate altered threat learning and retrieval processes as a potential mechanistic pathway through which RA becomes biologically embedded, potentially elevating psychopathological risk.

physiology↗

bioRxiv2026

Stable Hrd1 tetramers at the heart of the retrotranslocon in living cells

Terminally misfolded or damaged proteins in the endoplasmic reticulum (ER) are degraded by the proteasome in a process termed endoplasmic reticulum-associated degradation (ERAD). To reach the proteasome in the cytosol, cargo proteins must be dislocated across the ER lipid bilayer. Retrograde transport is performed by a set of membrane-spanning multi-protein complexes that are notoriously difficult to study. Despite decades of genetic and biochemical analysis, there is little consensus regarding its molecular mechanism. Here, we characterize the dynamic assembly of the mammalian Hrd1 complex, one of the most thoroughly studied mammalian dislocons, using in situ multicolor single-particle tracking. Surprisingly, quantitative dual-color tracking reveals that the majority of Hrd1 is assembled into stable homo-tetramers in situ. Using a herein developed single-molecule assay based on binding competition, we show that this tetramerization is driven by a short stretch (Hrd1479-530, HAF-H) within the cytosolic domain of Hrd1. Combining classical purification assays, quantitative imaging, and structural predictions, we demonstrate that Hrd1479-530 forms a highly stable tetrameric helix bundle via a conserved hydrophobic coiled-coil motif. While higher order assemblies of Hrd1 have been previously implicated, this work offers direct evidence of their role in dislocation, demonstrating that quantitative single-molecule imaging can yield information on species previously hidden from classical biochemistry.

Cell Biology↗

bioRxiv2025

Human embryo implantation involves Syncytin-2/MFSD2A-mediated heterokaryon formation with maternal endometrium

Human embryo implantation involves attachment of the blastocyst to the endometrial epithelium to subsequently gain access to the underlying stromal compartment. The blastocyst is believed to cross the epithelium either by migration through, or upon apoptosis of, the endometrial epithelial cell layer. Yet, how the blastocyst exactly traverses the endometrial epithelium remains unknown. Here, we describe an in vitro implantation model of human blastoids and hormonally matured endometrial organoids amenable to high-resolution live imaging. We demonstrate that the initial step of implantation is mediated by the direct fusion of blastoid cells with endometrial epithelial cells. Blastoids express the fusion proteins Syncytin-1 and -2, while the endometrial epithelium mainly expresses the fusion co-receptor for Syncytin-2, called MFSD2A. CRISPR-induced loss of MFSD2A in the endometrial epithelium prevents blastoids from attaching and abolishes fusion. Together, these findings support a model in which fetal-maternal cell fusion constitutes the critical initiating mechanism of human embryo implantation, with endometrial MFSD2A playing an indispensable role in this process.

developmental biology↗

bioRxiv2025

Integrated Multi-omic Profiling Reveals Early Regulatory Events in Dexamethasone Muscle Atrophy

Skeletal muscle atrophy and weakness are major contributors to morbidity, prolonged recovery, and long-term disability across a wide range of diseases. Atrophy is caused by breakdown of sarcomeric proteins resulting in loss of muscle mass and strength. Molecular mechanism underlying the onset of muscle atrophy and its progression have been analysed in patients, mice, and cell culture but the complementarity of these model systems remains to be explored. Here, we applied deep-coverage transcriptomic and proteomic profiling to characterize dynamic changes during dexamethasone-induced atrophy in the widely used murine skeletal muscle cell line C2C12. Comparison with published datasets confirmed that muscle differentiation is well recapitulated in C2C12 myotubes. Under dexamethasone treatment, this model was particularly suited to capture early atrophy events. We identified alterations in mitochondrial gene expression and differential alternative splicing events during early-stage myotube atrophy. This dataset complements existing in vivo data and provides novel insights into the regulatory processes during skeletal muscle wasting.

molecular biology↗

bioRxiv2025

Autophagy selectively clears ER in inflammation-induced muscle atrophy

Skeletal muscle atrophy is a pathological condition characterized by the progressive loss of muscle mass and function, driven by factors such as disuse, inflammation, and aging. While the ubiquitin-proteasome system is established as the central mediator of myofibrillar protein degradation, the role of autophagy in selective protein turnover remains largely unexplored. To address this, we employed a quantitative, time-resolved analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF--induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (dynamic SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis of mitochondrial ribosomes and cytoplasmic ribosome degradation, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis maintenance to a stress-induced ER-degradation program. Notably, inhibition of autophagy during atrophy leads to accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling, underscoring an underexplored regulatory mechanism in muscle proteostasis. By elucidating the role of autophagy in degradation of the ER, this study opens new avenues for therapeutic interventions targeting proteostasis regulation in inflammation-induced muscle-wasting disorders, ultimately contributing to a more refined understanding of muscle atrophy beyond proteasomal degradation.

molecular biology↗

bioRxiv2024

Communication with Surprise - Computational and Neural Mechanisms for Non-Verbal Human Interactions

Communication, often grounded in shared expectations, faces challenges without common linguistic backgrounds. Our study explores how people instinctively turn to the fundamental principles of the physical world to overcome communication barriers. Specifically, through the Tacit Communication Game, we investigate how participants develop novel strategies for conveying messages without relying on common linguistic signals. We developed a new computational model built from the principle of expectancy violations of a set of common universal priors derived from movement kinetics. The model closely resembles the Senders messages, with its core variable - the information-theoretic surprise - explaining the Receivers physiological and neural responses. This is evidenced by a significant correlation with the pupil diameter, indicating cognitive effort, and neural activity in brain areas related to expectancy violations. This work highlights the adaptability of human communication, showing how surprise can be a powerful tool in forming new communicative strategies without relying on common language.

neuroscience↗

bioRxiv2024

K48- and K63-linked ubiquitin chain interactome reveals branch- and length-specific interactors.

The ubiquitin (Ub) code denotes the complex Ub architectures, including Ub chains of different length, linkage-type and linkage combinations, which enable ubiquitination to control a wide range of protein fates. Although many linkage-specific interactors have been described, how interactors are able to decode more complex architectures is not fully understood. We conducted a Ub interactor screen, in humans and yeast, using Ub chains of varying length, as well as, homotypic and heterotypic branched chains of the two most abundant linkage types - K48- and K63-linked Ub. We identified some of the first K48/K63 branch-specific Ub interactors, including histone ADP-ribosyltransferase PARP10/ARTD10, E3 ligase UBR4 and huntingtin-interacting protein HIP1. Furthermore, we revealed the importance of chain length by identifying interactors with a preference for Ub3 over Ub2 chains, including Ub-directed endoprotease DDI2, autophagy receptor CCDC50 and p97-adaptor FAF1. Crucially, we compared datasets collected using two common DUB inhibitors - Chloroacetamide and N-ethylmaleimide. This revealed inhibitor-dependent interactors, highlighting the importance of inhibitor consideration during pulldown studies. This dataset is a key resource for understanding how the Ub code is read.

molecular biology↗

bioRxiv2023

Creativity and memory: Cortical representational change along with amygdala activation predict the insight memory effect

Despite the need for innovative solutions to contemporary challenges, the neural mechanisms driving creative problem-solving, including representational change and its relation to memory, still remain largely unknown. We focused on the powerful creative process of insight, wherein rapid knowledge reorganisation and integration--termed representational change--yield solutions that evoke suddenness, certainty, positive emotion, and enduring memory. We posit that this process manifests as stronger shifts in activation patterns within brain regions housing solution-relevant information, including the visual cortex for visual problems, alongside regions linked to feelings of emotion, suddenness and subsequent memory. Our findings substantiate these hypotheses, revealing stronger representational changes in visual cortex, conjoined with activations in the amygdala and hippocampus--forming an interconnected network. Importantly, the representational change and hippocampal effects serve as predictive markers of subsequent memory. This study provides evidence of an integrated insight mechanism influencing memory. Implications extend to education, emphasising the significance of discovery-based learning approaches for boosting knowledge retention.

neuroscience↗

bioRxiv2022

Dopamine regulates decision thresholds in human reinforcement learning.

Dopamine fundamentally contributes to reinforcement learning by encoding prediction errors, deviations of an outcome from expectation. Prediction error coding in dopaminergic regions in human functional neuroimaging studies is well replicated. In contrast, replications of behavioral and neural effects of pharmacological modulations of the dopamine system in human reinforcement learning are scarce. Additionally, dopamine contributes to action selection, but direct evidence and process-specific accounts in human reinforcement learning are lacking. Here we examined dopaminergic mechanisms underlying human reinforcement learning in a within-subjects pharmacological approach in male human volunteers (n=31, within-subjects design; Placebo, 150mg L-dopa, 2mg Haloperidol) in combination with functional magnetic resonance imaging and a stationary reinforcement learning task. We had two aims. First, we aimed to replicate previously reported beneficial effects of L-dopa vs. Haloperidol on reinforcement learning from gains. This replication was not successful. We observed no performance benefit of L-Dopa vs. Haloperidol, and no evidence for alterations in neural prediction error signaling. In contrast, Bayesian analyses provided moderate evidence in favor of the null hypothesis. This unsuccessful replication is likely at least partly due to a number of differences in experimental design. Second, using combined reinforcement learning drift diffusion models, we tested the recent proposal that dopamine contributes to action selection by regulating decision thresholds. Model comparison revealed that the data were best accounted for by a reinforcement learning drift diffusion model with separate learning rates for positive and negative prediction errors. The model accounted for both reductions in RTs and increases in accuracy over the course of learning. The only parameter showing robust drug effects was the boundary separation parameter, which revealed reduced decision thresholds under both L-Dopa and Haloperidol, compared to Placebo, and the degree of threshold reduction accounted for individual differences in RTs between conditions. Results are in line with the idea that striatal dopamine regulates decision thresholds during action selection, and that lower dosages of D2 receptor antagonists increase striatal DA release via an inhibition of autoreceptor-mediated feedback mechanisms.

neuroscience↗

bioRxiv2021

Incidental reinstatement of faces and scenes in medial temporal lobe subregions during word recognition

During associative retrieval, the brain reinstates neural representations that were present during encoding. The human medial temporal lobe (MTL) with its subregions hippocampus (HC), perirhinal cortex (PRC), and parahippocampal cortex (PHC) plays a central role in neural reinstatement. Previous studies have given compelling evidence for reinstatement in the MTL during explicitly instructed associative retrieval. High-confident recognition may be similarly accompanied by recollection of associated information from the encoding context. It is unclear, however, whether high-confident recognition memory elicits reinstatement in the MTL even in the absence of an explicit instruction to retrieve associated information. Here, we addressed this open question using high-resolution fMRI. Twenty-eight male and female human volunteers engaged in a recognition memory task for words that they had previously encoded together with faces and scenes. Using complementary uni- and multivariate approaches, we show that MTL subregions including the PRC, PHC, and HC differentially reinstate category-specific representations during high-confident word recognition, even though no explicit instruction to retrieve the associated category was given. This constitutes novel evidence that high-confident recognition memory is accompanied by incidental reinstatement of associated category information in MTL subregions, and supports a functional model of the MTL that emphasises content-sensitive representations during both encoding and retrieval.

neuroscience↗

bioRxiv2020

Evaluation of a large-scale flow manipulation to the upper San Francisco Estuary: Response of habitat conditions for an endangered native fish

While flow is known to be a major driver of estuarine ecosystems, targeted flow manipulations are rare because tidal systems are extremely variable in space and time, and because the necessary infrastructure is rarely available. In summer 2018 we used a unique water control structure in the San Francisco Estuary (SFE) to direct a managed flow pulse into Suisun Marsh, one of the largest contiguous tidal marshes on the west coast of the United States. The action was designed to increase habitat suitability for the endangered Delta Smelt Hypomesus transpacificus, a small osmerid fish endemic to the upper SFE. The approach was to operate the Suisun Marsh Salinity Control Gates (SMSCG) in conjunction with increased Sacramento River tributary inflow to direct an estimated 160 x 106 m3 pulse of low salinity water into Suisun Marsh during August, a critical time period for juvenile Delta Smelt rearing. Three-dimensional modeling showed that directing additional low salinity water into Suisun Marsh ("Flow Action") substantially increased the area of low salinity habitat for Delta Smelt that persisted beyond the period of SMSCG operations. Field monitoring showed that turbidity and chlorophyll were at higher levels in Suisun Marsh, representing better habitat conditions, than the upstream Sacramento River region throughout the study period. The Flow Action had no substantial effects on zooplankton abundance, nor did Suisun Marsh show enhanced levels of these prey species in comparison to the Sacramento River. Fish monitoring data suggested that small numbers of Delta Smelt colonized Suisun Marsh from the Sacramento River during the Flow Action, further supporting our hypothesis that the Flow Action would benefit this rare species. Our study provides insight into both the potential use of targeted flow manipulations to support endangered fishes such as Delta Smelt, and into the general response of estuarine habitat to flow management.

ecology↗

bioRxiv2020

Dopaminergic modulation of human inter-temporal choice: a diffusion model analysis using the D2-receptor-antagonist haloperidol.

The neurotransmitter dopamine is implicated in diverse functions, including reward processing, reinforcement learning and cognitive control. The tendency to discount future rewards in value over time has long been discussed in the context of potential dopaminergic modulation. Here we examined the effect of a single dose of the D2 receptor antagonist Haloperidol (2mg) on temporal discounting. Our approach extends previous human pharmacological studies in two ways. First, we applied state-of-the-art computational modeling based on the drift diffusion model to comprehensively examine choice dynamics. Second, we examined dopaminergic modulation of reward magnitude effects on temporal discounting. Drift diffusion modeling revealed reduced temporal discounting and substantially faster non-decision times under Haloperidol. Temporal discounting was substantially increased for low vs. high reward magnitudes, but this magnitude effect was largely unaffected by Haloperidol. These results were corroborated by model-free analyses as well as modeling via more standard approaches using softmax action selection. We previously reported elevated caudate activation under Haloperidol in this sample of participants, supporting the idea that Haloperidol elevated dopamine neurotransmission, e.g. by blocking inhibitory feedback via presynaptic D2 autoreceptors. The present modeling results show that during inter-temporal choice, this leads to attenuated temporal discounting and increased response vigor (shorter non-decision times).

neuroscience↗

bioRxiv2018

Dark aerobic sulfide oxidation by anoxygenic phototrophs in the anoxic waters of Lake Cadagno

SUMMARYAnoxygenic phototrophic sulfide oxidation by green and purple sulfur bacteria (PSB) plays a key role in sulfide removal from anoxic shallow sediments and stratified waters. Although some PSB can also oxidize sulfide with nitrate and oxygen, little is known about the prevalence of this chemolithotrophic lifestyle in the environment. In this study, we investigated the role of these phototrophs in light-independent sulfide removal in the chemocline of Lake Cadagno. Our temporally resolved, high-resolution chemical profiles indicated that dark sulfide oxidation was coupled to high oxygen consumption rates of ~9 M O2{middle dot}h-1. Single-cell analyses of lake water incubated with 13CO2 in the dark revealed that Chr. okenii was to a large extent responsible for aerobic sulfide oxidation and it accounted for up to 40 % of total dark carbon fixation. The genome of Chr. okenii reconstructed from the Lake Cadagno metagenome confirms its capacity for microaerophilic growth and provides further insights into its metabolic capabilities. Moreover, our genomic and single-cell data indicated that other PSB grow microaerobically in these apparently anoxic waters. Altogether, our observations suggest that aerobic respiration may not only play an underappreciated role in anoxic environments, but also that organisms typically considered strict anaerobes may be involved.\n\nORIGINALITY-SIGNIFICANCE STATEMENTThis study reveals that dark aerobic sulfide oxidation within an anoxic layer dominated by anoxygenic phototrophic bacteria in the stratified water column of Lake Cadagno is to a large extent carried out by the anoxygenic phototrophic bacterium Chromatium okenii. Our findings imply that aerobic metabolisms may be more prevalent in anoxic zones than previously thought. We also present an environmental metagenome-assembled genome of Chr. okenii which is the first genome sequence for the genus Chromatium and reveals new interesting physiological features of this environmentally relevant organism, including its capacity for aerobic respiration.

microbiology↗

bioRxiv2018

Dopamine is a double-edged sword: Enhancing memory retrieval performance at the expense of metacognition

While memory encoding and consolidation processes have been linked with dopaminergic signaling for a long time, the role of dopamine in episodic memory retrieval remained mostly unexplored. Based on previous observations of striatal activity during memory retrieval, we used pharmacological fMRI to investigate the effects of dopamine on retrieval performance and metacognitive memory confidence in healthy humans. Dopaminergic modulation by the D2 antagonist haloperidol administered acutely during the retrieval phase improved recognition accuracy of previously learned pictures significantly and was associated with increased activity in the SN/VTA, locus coeruleus, hippocampus and amygdala during retrieval. In contrast, confidence for new-decisions was impaired by unsystematically increased activity of the striatum across confidence levels and restricted range of responsiveness in frontostriatal networks under haloperidol. These findings offer new insights into the mechanisms underlying memory retrieval and metacognition and provide a broader perspective on the presence of memory problems in dopamine-related diseases and the treatment of memory disorders.

neuroscience↗

bioRxiv2018

Dissociable contributions of the amygdala to the immediate and delayed effects of emotional arousal on memory

Emotionally arousal enhances memory encoding and consolidation leading to better immediate and delayed memory. Although the central noradrenergic system and the amygdala play critical roles in both effects of emotional arousal, we have recently shown that these effects are at least partly independent of each other, suggesting distinct underlying neural mechanisms. Here we aim to dissociate the neural substrates of both effects in 70 female participants using an emotional memory paradigm to investigate how neural activity, as measured by fMRI, and a polymorphism in the 2B-noradrenoceptor vary for these effects. To also test whether the immediate and delayed effects of emotional arousal on memory are stable traits, we invited back participants who were a part of a large-scale behavioral memory study about 3.5 years ago. We replicated the low correlation of the immediate and delayed emotional enhancement of memory across participants (r = 0.16) and observed, moreover, that only the delayed effect was, to some degree, stable over time (r = 0.23). Bilateral amygdala activity, as well as its coupling with the visual cortex and the fusiform gyrus, was related to the preferential encoding of emotional stimuli, which is consistent with affect-biased attention. Moreover, the adrenoceptor genotype modulated the bilateral amygdala activity associated with this effect. The left amygdala and its coupling with the hippocampus was specifically associated with the more efficient consolidation of emotional stimuli, which is consistent with amygdalar modulation of hippocampal consolidation.

neuroscience↗

bioRxiv2018

Dissociation of immediate and delayed effects of emotional arousal on episodic memory

Emotionally arousing events are usually better remembered than neutral ones. This phenomenon is in humans mostly studied by presenting mixed lists of neutral and emotional items. An emotional enhancement of memory is observed in these studies often already immediately after encoding and increases with longer delays and consolidation. A large body of animal research showed that the more efficient consolidation of emotionally arousing events is based on an activation of the central noradrenergic system and the amygdala (Modulation Hypothesis; Roozendaal & McGaugh, 2011). The immediately superior recognition of emotional items is attributed primarily to their attraction of attention during encoding which is also thought to be based on the amygdala and the central noradrenergic system. To investigate whether the amygdala and noradrenergic system support memory encoding and consolidation via shared neural substrates and processes a large sample of participants (n = 690) encoded neutral and arousing pictures. Their memory was tested immediately and after a consolidation delay. In addition, they were genotyped in two relevant polymorphisms (2B-adrenergic receptor and serotonin transporter). Memory for negative and positive emotional pictures was enhanced at both time points where these enhancements were correlated (immediate r = 0.60 and delayed test r = 0.46). Critically, the effects of emotional arousal on encoding and consolidation correlated only very low (negative r = 0.14 and positive r = 0.03 pictures) suggesting partly distinct underlying processes consistent with a functional heterogeneity of the central noradrenergic system. No effect of genotype on either effect was observed.

neuroscience↗