Biology subjects

Trapp, B.

Publications and source records attributed to Trapp, B..

6 recordsLinked to original sources

bioRxiv2026

NeuroPupil: A generalization-first framework for scalable and biologically informative cross-species pupillometry

Quantitative pupillometry provides a noninvasive window into brain state and neurological function, but its broader use across experimental and clinical settings is limited by challenges in achieving accurate, scalable, and generalizable measurements. Here, we present NeuroPupil, a deep learning framework for high-throughput, cross-species pupillometry that emphasizes robust generalization across subjects, behavioral contexts, and imaging conditions. Through systematic benchmarking of training strategies and network architectures, we identify pooled multi-subject training combined with an optimized U-Net architecture as a key determinant of reliable and transferable pupil tracking performance. Across diverse mouse and human datasets, NeuroPupil achieves improved accuracy and substantial gains in computational efficiency compared to existing approaches, enabling practical analysis of large-scale datasets. We further demonstrate that improved pupil tracking fidelity enhances downstream biological inference: NeuroPupil-derived pupil features significantly improve prediction of distributed cortical activity in behaving mice and preserve diagnostically relevant temporal structure in human clinical recordings. These findings highlight the importance of precise and scalable measurement for linking pupil dynamics to brain activity and clinical phenotypes. By integrating benchmarking, scalability, and accessible software tools, NeuroPupil provides a reproducible framework for large-scale pupillometry and facilitates its application in systems and translational neuroscience.

neuroscience↗

bioRxiv2026

Structural Basis of M1 Muscarinic and H3 Histamine Receptor Inhibition in OPC Differentiation

Muscarinic and histamine receptors are neurotransmitter-binding proteins within the large family of G protein-coupled receptors (GPCRs) and are relevant to human health and disease, including multiple sclerosis (MS), a chronic immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) with neurodegenerative components. MS affects approximately 1 in 333 people, and women are affected at roughly threefold higher rates than men. A major pathological feature of MS is demyelination with incomplete remyelination of axons in the CNS. Because oligodendrocyte progenitor cells (OPCs) can differentiate into mature oligodendrocytes that restore myelin, small molecules that promote OPC differentiation represent a potential therapeutic strategy. High-throughput screening identified 18 hit compounds with EC50 values below 0.2 M, including the lead compound CN045, which showed an EC50 of 40 nM in vitro. Cheminformatic and experimental target-identification studies implicated the M1 muscarinic receptor and the H3 histamine receptor as candidate targets. To interpret these findings, we performed docking, molecular dynamics simulations, and binding free-energy analyses on complexes involving CN045 and clemastine, a known antihistamine with antimuscarinic activity. The simulations support weaker and less stable binding of CN045 to H3 than to M1 and identify residue-level interactions that contribute to stability within the M1 binding pocket. Comparisons between CN045 and clemastine at M1 further suggest that the two ligands sample different local conformational ensembles, including differences in conserved microswitch behavior associated with active-like versus inactive-like receptor states. Together, these results provide a structural framework for understanding ligand-specific M1 engagement and may help guide future optimization of remyelination-promoting compounds.

biophysics↗

bioRxiv2025

Neuronal Silencing and Protection in a Mouse Model of Demyelination

Damage to the myelin sheath that protects axons in the central nervous system is a hallmark pathology of demyelinating diseases like multiple sclerosis. Cuprizone-induced demyelination in mice is a common model for studying demyelination and remyelination. However, the relationship between myelin damage and recovery and neuronal function remains poorly understood. By monitoring hippocampal myelination and neuronal activity in the same mice, we assessed longitudinal changes following cuprizone consumption and remyelination treatment. Upon cuprizone consumption, a rapid decline in neuronal activity preceded slower demyelination. Female mice showed a more intense early decrease in brain activity and a stronger correlation with levels of myelin loss. Remyelination treatment led to increased myelination levels and recovery of neuronal activity compared to vehicle treatment. Changes in single-neuron firing rates during treatment were proportional to the pre-cuprizone firing rate in the same cells, highlighting a potential linkage between the status of myelin recovery and cellular activity.

neuroscience↗

bioRxiv2024

Network medicine informed multi-omics integration identifies drug targets and repurposable medicines for Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a devastating, immensely complex neurodegenerative disease by lack of effective treatments. To date, the challenge to establishing effective treatment for ALS remains formidable, partly due to inadequate translation of existing human genetic findings into actionable ALS-specific pathobiology for subsequent therapeutic development. This study evaluates the feasibility of network medicine methodology via integrating human brain-specific multi-omics data to prioritize drug targets and repurposable treatments for ALS. Using human brain-specific genome-wide quantitative trait loci (x-QTLs) under a network-based deep learning framework, we identified 105 putative ALS-associated genes enriched in various known ALS pathobiological pathways, including regulation of T cell activation, monocyte differentiation, and lymphocyte proliferation. Specifically, we leveraged non-coding ALS loci effects from genome-wide associated studies (GWAS) on brain-specific expression quantitative trait loci (QTL) (eQTL), protein QTLs (pQTL), splicing QTL (sQTL), methylation QTL (meQTL), and histone acetylation QTL (haQTL). Applying network proximity analysis of predicted ALS-associated gene-coding targets and existing drug-target networks under the human protein-protein interactome (PPI) model, we identified a set of potential repurposable drugs (including Diazoxide, Gefitinib, Paliperidone, and Dimethyltryptamine) for ALS. Subsequent validation established preclinical and clinical evidence for top-prioritized repurposable drugs. In summary, we presented a network-based multi-omics framework to identify potential drug targets and repurposable treatments for ALS and other neurodegenerative disease if broadly applied.

systems biology↗

bioRxiv2023

p38γMAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions

Multiple Sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with aging, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPK{gamma} from oligodendrocyte precursors. We found that p38{gamma}MAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38{gamma}MAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38{gamma}MAPK was enriched in samples of leukocortical multiple sclerosis lesions from patients, which represent areas of failed remyelination. Our data suggest that p38{gamma} could be targeted to improve myelin repair in multiple sclerosis.

neuroscience↗

bioRxiv2019

Reversible loss of Hippocampal Function in a Mouse Model of Demyelination/Remyelination

Demyelination of axons in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and other demyelinating diseases. Cycles of demyelination, followed by remyelination, appear in the majority of MS patients, and are associated with the onset and quiescence of disease-related symptoms, respectively. Previous studies have shown in human patients and animal models that vast demyelination is accompanied by wide-scale changes to brain activity, but details of this process are poorly understood. We use electrophysiological recordings and nonlinear imaging of fluorescence from genetically-encoded calcium indicators to monitor the activity of hippocampal neurons during demyelination and remyelination processes over a period of 100 days. We find in vitro that synaptic transmission in CA1 neurons is diminished, and in vivo both CA1 and dentate gyrus (DG) neuronal firing rates are substantially reduced during demyelination and partially recover after a short remyelination period. This new approach allows monitoring how synaptic transmission changes, induced by cuprizone diet, are affecting neuronal activity, and can potentially be used to study the effects of therapeutic interventions in protecting the functionality of CNS neurons.

neuroscience↗