Biology subjects

Wieland, S.

Publications and source records attributed to Wieland, S..

6 recordsLinked to original sources

bioRxiv2024

Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety

Childhood adversity increases the risk of developing a vicious cycle of chronic pain and comorbid anxious avoidance, yet the underlying biological mechanisms remain unclear. Here, we investigated the role of a brain circuit from the paraventricular thalamus (PVT) to the central amygdala (CeA) in mediating hyperalgesia and comorbid anxiety following early life stress. Using a vulnerability-stress model, we exposed both male and female mice to early social isolation (vulnerability) followed by nerve injury (stress) and showed increased hyperalgesia and anxious avoidance behavior in nerve-injured female mice following early adversity. Chemogenetic, electrophysiological, and optophysiological analyses revealed a causal contribution of a hyperexcitable PVT-CeA circuit dysfunction to chronic hyperalgesia and anxiety in nerve-injured female mice after early life stress. Our findings reveal a neural mechanism linking childhood adversity to chronic pain and anxiety, and suggest that reprogramming this pathway may reverse the impact of childhood adversity.

neuroscience↗

bioRxiv2024

Meta-analysis reveals limited reproducibility of lncRNA-related findings in hepatocellular carcinoma research

Background & AimsThe human genome comprises tens of thousands of long non-coding RNAs (lncRNAs), whose functionality is highly debated. In the field of hepatocellular carcinoma (HCC) research, as for other cancer types, lncRNAs are increasingly reported to act as oncogenes or tumor suppressors and are put forward as useful diagnostic or prognostic biomarkers. Here, we investigate the reliability of these claims by performing a meta-analysis of the associations between HCC and lncRNAs reported in the scientific literature, and by assessing lncRNA expression patterns in two HCC patient cohorts. Approach & ResultsWhile nowadays up to 6% of all HCC-related publications cite lncRNAs, we show that most reported associations between HCC and lncRNAs have not been reproduced. In general, lncRNAs are less often differentially expressed between HCC tissues and controls compared to protein-coding genes. However, HCC-associated lncRNAs are frequently up-regulated in tumor samples, consistent with the fact that they are often selected based on transcriptome-wide comparative analyses. We perform a detailed examination of the 25 lncRNAs that are most frequently cited in association with HCC. For 10 out of these 25 lncRNAs, including well known lncRNAs such as MALAT1, NEAT1, H19 and XIST, we identify important conflicts between the biological roles and expression patterns previously reported for them in HCC and the expression patterns that we observe here. Finally, we observe that HCC-associated publications that cite lncRNAs are retracted three times more often than publications that cite protein-coding genes. ConclusionsOur results thus highlight the poor reproducibility of lncRNA-related claims in association with HCC, which is problematic in a context where new biomarkers and molecular targets for therapy are greatly needed.

cancer biology↗

bioRxiv2022

3MDR, a microcomputer-controlled visual stimulation device for psychotherapy-like treatments of mice

Post-traumatic stress disorder and other mental disorders can be treated by an established psychotherapy called Eye Movement Desensitization and Reprocessing (EMDR). In EMDR, patients are confronted with traumatic memories while they are stimulated with alternating bilateral stimuli (ABS). How ABS affect the brain and whether ABS could be adapted to different patients or mental disorders is unknown. Interestingly, ABS reduced conditioned fear in mice. Yet, an approach to systematically test complex visual stimuli and compare respective differences in emotional processing based on (semi-)automated behavioral analysis is lacking. We developed 3MDR (Model for MultiModal visual stimulation to Desensitize Rodents) - a novel, open-source, low-cost, customizable device that can be integrated in and TTL-controlled by commercial rodent behavioral setups. 3MDR allows to design and precisely steer multimodal visual stimuli in the head direction of freely-moving mice. Optimized videography allows to semi-automatically analyze rodent behavior during visual stimulation. Detailed building, integration, and treatment instructions along with open-source software provide easy access for inexperienced users. Using 3MDR, we confirmed that EMDR-like ABS persistently improve fear extinction in mice and showed for the first time that ABS-mediated anxiolytic effects strongly depend on physical stimulus properties such as ABS brightness. 3MDR not only enables researchers to interfere with mouse behavior in an EMDR-like setting, but demonstrates that visual stimuli can be used as a noninvasive brain stimulation to differentially alter emotional processing in mice. SIGNIFICANCE STATEMENTAlternating bilateral stimuli (ABS) reduce fear in post-traumatic stress disorder patients and in mice. The mechanism of how classic ABS - typically used in Eye Movement Desensitization and Reprocessing (EMDR) - reduce fear is enigmatic. We provide detailed resources to build a cost-effective, computer-controlled device called 3MDR to perform and semi-automatically analyze EMDR-like treatments in freely-moving mice and to test behavioral effects of multiple ABS variants. Using the 3MDR device, this study confirmed that classic ABS strongly and persistently improve the extinction of conditioned fear in mice - an effect that depended on the brightness of ABS. This novel method may ultimately contribute to a deeper translational and neurobiological understanding of how visual stimuli affect emotional processing in mice.

neuroscience↗

bioRxiv2021

Proteogenomic characterization of hepatocellular carcinoma

We performed a proteogenomic analysis of hepatocellular carcinomas (HCCs) across clinical stages and etiologies. We identified pathways differentially regulated on the genomic, transcriptomic, proteomic and phosphoproteomic levels. These pathways are involved in the organization of cellular components, cell cycle control, signaling pathways, transcriptional and translational control and metabolism. Analyses of CNA-mRNA and mRNA-protein correlations identified candidate driver genes involved in epithelial-to-mesenchymal transition, the Wnt-{beta}-catenin pathway, transcriptional control, cholesterol biosynthesis and sphingolipid metabolism. The activity of targetable kinases aurora kinase A and CDKs was upregulated. We found that CTNNB1 mutations are associated with altered phosphorylation of proteins involved in actin filament organization, whereas TP53 mutations are associated with elevated CDK1/2/5 activity and altered phosphorylation of proteins involved in lipid and mRNA metabolism. Integrative clustering identified HCC subgroups with distinct regulation of biological processes, metabolic reprogramming and kinase activation. Our analysis provides insights into the molecular processes underlying HCCs.

genomics↗

bioRxiv2021

LncRNA analyses reveal increased levels of non-coding centromeric transcripts in hepatocellular carcinoma

The search for new biomarkers and drug targets for hepatocellular carcinoma (HCC) has spurred an interest in long non-coding RNAs (lncRNAs), often proposed as oncogenes or tumor suppressors. Furthermore, lncRNA expression patterns can bring insights into the global de-regulation of cellular machineries in tumors. Here, we examine lncRNAs in a large HCC cohort, comprising RNA-seq data from paired tumor and adjacent tissue biopsies from 114 patients. We find that numerous lncRNAs are differentially expressed between tumors and adjacent tissues and between tumor progression stages. Although we find strong differential expression for most lncRNAs previously associated with HCC, the expression patterns of several prominent HCC-associated lncRNAs disagree with their previously proposed roles. We examine the genomic characteristics of HCC-expressed lncRNAs and reveal an enrichment for repetitive elements among the lncRNAs with the strongest expression increases in advanced-stage tumors. This enrichment is particularly striking for lncRNAs that overlap with satellite repeats, a major component of centromeres. Consistently, we find increased non-coding RNA transcription from centromeres in tumors, in the majority of patients, suggesting that aberrant centromere activation takes place in HCC.

cancer biology↗

bioRxiv2019

Phasic dopamine enhances the distinct decoding and perceived salience of stimuli

Subjects learn to assign value to stimuli that predict outcomes. Novelty, rewards or punishment evoke reinforcing phasic dopamine release from midbrain neurons to ventral striatum that mediates expected value and salience of stimuli in humans and animals. It is however not clear whether phasic dopamine release is sufficient to form distinct engrams that encode salient stimuli within these circuits. We addressed this question in awake mice. Evoked phasic dopamine induced plasticity selectively to the population encoding of coincidently presented stimuli and increased their distinctness from other stimuli. Phasic dopamine thereby enhanced the decoding of previously paired stimuli and increased their perceived salience. This dopamine-induced plasticity mimicked population coding dynamics of conditioned stimuli during reinforcement learning. These findings provide a network coding mechanism of how dopaminergic learning signals promote value assignment to stimulus representations.

neuroscience↗