Biology subjects

Pfister, C.

Publications and source records attributed to Pfister, C..

4 recordsLinked to original sources

bioRxiv2026

Individual behavioral signatures shape processing of context-dependent social fear

Context processing is an essential function in the cognitive repertoire of numerous species, including humans and mice, allowing them to learn from their environment and adapt their future behavior. Impairments or alterations in context processing are hypothesized to represent one of the core etiological mechanisms underlying trauma- and stressor-related disorders such as post-traumatic stress disorder (PTSD). Individual behavioral traits are key determinants of post-stress responses; however, how they influence distinct phases of contextual encoding and processing remains incompletely understood. This knowledge gap is further exacerbated by the limited availability of contextual fear protocols based on social stress, even though the latter is among the most frequent and impactful forms of stress exposure. Here, based on social defeat paradigms, we establish a longitudinal social conditioned place aversion (sCPA) protocol that leads to avoidance of the defeat-associated chamber in adult male mice. Prior characterization of mice according to anxiety-related phenotypes revealed that mice displaying high novelty-induced thigmotaxic (i.e. high anxiety-like) behavior showed lasting long-term memory of the defeat-associated chamber as denoted by persistent avoidance. On the other hand, lower levels of exploration/locomotor behaviors prior to stress exposure predicted greater avoidance of the defeat-associated chamber in the short-term. Finally, we reveal that inhibiting the activity of VTAVgat neurons during conditioning sessions abolished sCPA acquisition, while disrupting the predictive ability of locomotor/exploratory profiles derived prior to the sCPA. Our data establishes a robust temporally structured social stress-based conditioning protocol and reveals how prior individual anxiety- and exploration/locomotion-related traits influence distinct stages of context processing.

animal behavior and cognition↗

bioRxiv2025

Deep Learning Bridges Histology and Transcriptomics to Predict Molecular Subtypes and Outcomes in Muscle-Invasive Bladder Cancer

Muscle-Invasive Bladder Cancer (MIBC) is a heterogeneous disease with distinct molecular subtypes influencing prognosis and therapeutic response. However, molecular profiling through RNA sequencing remains costly, time-consuming and complicated by intratumoral heterogeneity. We developed a Deep Learning (DL) approach to infer molecular subtypes from routine histopathological slides and to evaluate its prognostic value in patients treated with neoadjuvant chemotherapy (NAC). We developed an DL-model predicting the expression of 848 subtype-associated genes from histological images of transurethral resection of bladder tumor, enabling spatial molecular subtyping at tile level. The model was trained on 297 NAC-treated patients from the VESPER clinical trial and evaluated on three independent cohorts (COBLAnCE, n=224; Saint-Louis, n=30 and TCGA, n=315), covering diverse staining protocols and scanner types. Spatial transcriptomics from six VESPER patients confirmed the spatial consistency of the inferred expression profiles. Our approach achieved a ROC AUC of 0.94 for molecular subtype prediction, with 95% of genes significantly predicted, demonstrating its ability to capture transcriptomic dysregulations from histological morphology. Predicted expression maps revealed spatially coherent patterns and intratumoral molecular heterogeneity. Importantly, tumors predicted with basal/squamous features (pure or mixed), were associated with significantly worse progression-free and overall survival after NAC (log-rank p=0.014 and 0.037, respectively). This DL-based framework enables accurate and spatially resolved inference of gene expression and molecular subtypes in MIBC without sequencing. These findings could improve patient stratification in clinical practice and support the design of more targeted clinical trials. Further validation in larger cohorts is needed before routine clinical implementation.

cancer biology↗

bioRxiv2025

HydroMEA: A 3D Hydrogel Based Microfluidic Device to Study Electrophysiology for Myelinated Nerve-on-Chip

Engineered in vitro platforms are powerful systems to study information flow in the nervous system. While existing polydimethylsiloxane (PDMS)-based microfluidic platforms offer precise architectures, the cultured neurons grow on two-dimensional (2D) planar multielectrode arrays (MEA). To mimic the native microenvironment, where neurons grow in three-dimensional (3D) extracellular matrices (ECM), 3D hydrogels can be designed to encapsulate cells and enable physiologically-mimicked behaviors. Here, we describe hydroMEA, a 3D platform fabricated by placing PDMS microstructures on a high-density MEA and filled with a desired hydrogel, to offer controlled topologies, physiologically-relevant microenvironments, and real-time electrophysiological measurements. First, we developed a gelatin methacryloyl (GelMA) hydrogel with incorporated ECM components and tuned the mechanical properties to match those of nerve tissue. The hydrogel was able to support: 1) the growth of iPSC-derived sensory neurons (hSNs) for >100 days; 2) co-cultures of hSN with human embryonic stem cell-derived Schwann cells (hSCs), to enable reliable 3D myelination. Next, hydroMEA were prepared for topologically- defined 3D growth and myelination in designated compartments. Finally, electrophysiological evaluation of hSN-hSCs co-cultures revealed increased conduction speeds indicating functional myelin. This platform is a promising tool to study cell-cell interactions and to functionally evaluate the effect of pharmacological compounds in a more translational manner.

bioengineering↗

bioRxiv2021

Narcolepsy with cataplexy is caused by epigenetic silencing of hypocretin neurons

Narcolepsy with cataplexy is a chronic sleep disorder characterized by hypocretin deficiency. The condition is believed to result from autoimmune destruction of hypocretin (HCRT) neurons, although direct evidence is lacking and mere Hcrt gene inactivation causes full-blown narcolepsy in mice. Here we show that the expression of another hypothalamic neuropeptide, QRFP, is lost in mouse models with HCRT cell-ablation, but tends to be even increased in Hcrt gene knockout mice, suggesting that QRFP expression can be used as a proxy for the presence or absence of HCRT neurons. Similar to Hcrt knockout mice, narcolepsy patients show intact hypothalamic QRFP expression, and cerebrospinal fluid levels of QRFP peptide are increased, suggesting their HCRT neurons are intact. We show that the human HCRT gene promoter is methylation-sensitive in vitro, and is hypermethylated in the hypothalamus of patients selectively at a putative PAX5:ETS1 binding site within the proximal HCRT promoter. Ets1-KO mice display downregulated Hcrt expression, while pax5-ets1 knockdown in zebrafish causes decreased hcrt expression, decreased activity and sleep fragmentation, similar to narcolepsy patients. Our results suggest that HCRT neurons are alive, but epigenetically silenced, in the hypothalamus of narcolepsy patients, opening the possibility to reverse or cure narcolepsy.

neuroscience↗