Biology subjects

Engelmann, J.

Publications and source records attributed to Engelmann, J..

8 recordsLinked to original sources

bioRxiv2026

Testosterone Administration Modulates Competitive Choice via Ventral Striatum and TPJ

How does testosterone influence decisions and choice-related neural computations in competitive environments? To address this question, we administered testosterone or placebo to female participants (n = 54) in a double-blind, randomized design. Following drug treatment, participants competed in a dot estimation task that manipulated opponent status (lower, equal, or higher) and outcome feedback (win or loss), after which they decided whether to compete against the same opponent again. All participants adjusted their behavior based on opponent status and outcome feedback. Participants who received testosterone, however, showed significantly greater sensitivity to outcome feedback: they were more willing to compete after winning and less willing after losing, and made those decisions faster - suggesting that testosterone increases the weighting of immediate, salient outcome information in competitive decision-making. At the neural level, a network comprising ventral striatum, vmPFC, bilateral TPJ and ACC processed outcome-related signals during the feedback period. Critically, neural prediction analyses at the trial-level revealed that activity in left ventral striatum and TPJ predicted subsequent decisions to compete, but only in participants who received testosterone. The direction of these effects mirrored the behavioral results: striatal activity amplified the tendency to re-compete after winning, whereas TPJ activity predicted renewed competition after losing. Together, these findings demonstrate that testosterone biases competitive decisions by amplifying the influence of outcome-related activity in reward and social cognition circuits.

neuroscience↗

bioRxiv2026

Cross-Species Adaptation of RETFound for Rodent OCT Age Estimation Reveals Strong CNN Baselines in Data-Scarce Space Biology

Space-biology imaging studies are often constrained by severe data scarcity, limiting the development of robust machine-learning biomarkers. Rodent spaceflight and space-analog datasets provide an important preclinical setting for testing transfer-learning strategies, but the extent to which human retinal foundation models can generalize to rodent optical coherence tomography (OCT) remains unclear. Here, we benchmark cross-species adaptation of RETFound, a human retinal Vision Transformer pretrained on 1.6 million retinal images, for chronological age prediction from Brown Norway rat OCT B-scans in the NASA Open Science Data Repository dataset OSD-679. We adapted RETFound using Low-Rank Adaptation (LoRA) and evaluated performance on control animals under matched 3-fold rat-level cross-validation. We compared RETFound+LoRA with a strong ImageNet-pretrained Xception baseline under matched protocols and included a scratch/random ViT as a supplementary negative-control architecture check. Metrics included mean absolute error (MAE), R2, and inter-eye mean absolute difference (MAD). RETFound+LoRA achieved MAE = 26.20 {+/-} 5.03 days with R2 = 0.744 {+/-} 0.049. However, Xception performed better in the primary benchmark (MAE = 19.01 {+/-} 7.67 days, R2 = 0.853 {+/-} 0.082), and the matched-fold comparison favored Xception, although this result should be interpreted cautiously given the small number of folds. Inter-eye consistency was maintained across the matched control evaluation, and saliency maps localized model attention to anatomically plausible inner retinal regions. Together, these results show that human retinal foundation models can transfer to rodent OCT in a scientifically useful way, but also that strong CNN baselines may outperform transformer-based models in small-sample cross-species settings. This preprint provides a reproducible benchmark and baseline framework for future retinal biomarker development in space biology. Significance StatementSpace-biology imaging studies are intrinsically data-limited. This preprint provides a reproducible cross-species benchmark for adapting Earth-trained retinal models to rodent OCT under small-sample conditions, highlights the value of strong CNN baselines, and offers a reusable starting point for future retinal biomarker development in space-relevant datasets.

bioinformatics↗

bioRxiv2025

Dynamic Epigenetic Changes During Antidepressant Pharmacotherapy in Major Depressive Disorder

Although antidepressants remain the main pharmacological treatment for major depressive disorder (MDD), therapeutic response varies, highlighting the need for molecular markers that predict treatment response, as well as insights into the biological processes underlying antidepressant efficacy. Candidate-gene and cross-sectional epigenome-wide association studies (EWAS) have reported DNA methylation signatures associated with antidepressant response; however, findings remain inconsistent. To date, no longitudinal EWAS has examined methylation trajectories across multiple time points during antidepressant treatment in MDD. Within the Early Medication Change trial, DNA methylation data was generated for 162 patients with MDD (81 responders, 81 non-responders) and 48 matched healthy controls. Patients were assessed at four times across eight-weeks of standardized antidepressant treatment, while controls were assessed twice. Differentially methylated positions (DMPs) and regions (DMRs) were identified using longitudinal EWAS models and the comb-p algorithm. Baseline methylation levels were associated with depressive symptom severity at day 28 and day 56 through two and six DMRs, respectively (e.g., TNRC6C, CAT), whereas no single DMP reached significance. Longitudinal analyses identified one DMP associated with improvement in depressive symptoms (YLMP1) and three DMRs showing methylation changes over time (e.g., GPR126, PM20D1). Combined patient-control analyses revealed additional DMPs and DMRs associated with diagnosis and temporal effects. This study provides first longitudinal evidence of regionally coordinated DNA methylation changes during antidepressant pharmacotherapy, revealing alterations in genes involved in neuroplasticity and inflammatory processes that are associated with clinical response. Replication and functional validation will be essential to determine their relevance for personalized antidepressant treatment.

genomics↗

bioRxiv2024

Spermidine alleviates depression via control of the stress response

Depression is a stress-associated disorder, and it represents a major global health issue. Its pathophysiology is complex and remains insufficiently understood, with current medications often showing limited efficacy and undesirable side effects. Here, we identify imbalanced polyamine levels and dysregulated autophagy as key components of the acute stress response in humans, and as hallmarks of chronic stress and depressive disorders. Moreover, conventional antidepressant pharmacotherapy increases endogenous plasma concentrations of the polyamine spermidine exclusively in patients who respond to the treatment, suggesting a link between spermidine and successful outcomes. In a clinical trial, involving drug-naive depressed individuals, three weeks of spermidine supplementation increased autophagy and alleviated symptoms of depression. Behavioral and mechanistic findings of spermidine supplementation were validated in various mouse stress and depression models. In summary, spermidine supplementation mitigates polyamine dysregulation and stimulates autophagy under pathological stress conditions, offering a novel and well-tolerated treatment approach for stress-related depressive disorders.

neuroscience↗

bioRxiv2024

Axon demyelination and degeneration in a zebrafishspastizin model of hereditary spastic paraplegia

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are little understood. We studied the pathogenesis of one form of HSP known as spastic paraplegia 15 (SPG15). This disorder is caused by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of Mauthner (M)-cells. M-cell degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the mutation not only compromises axonal integrity but also affects the structural molecules of the myelin sheath, laying the foundation for degeneration and advancing our understanding of the intricate mechanisms underlying HSPs.

neuroscience↗

bioRxiv2024

TAM receptors control actomyosin dynamics in osteoclasts via RHOA-COFILIN-MYOSIN II signaling

The TAM family of receptor tyrosine kinases were recently identified to regulate bone homeostasis by controlling osteoblasts and bone formation. Despite extensive knowledge of TAM receptor function in the mononuclear phagocyte system, the role of TAM receptors in osteoclasts remains largely unknown. Here, we identify a physiological regulatory system including MERTK and TYRO3 in osteoclasts controlling RHOA-ROCK-COFILIN/Myosin II signaling, thereby antagonistically regulating osteoclast-mediated bone remodeling to maintain bone homeostasis. Myeloid-specific lysozyme M-mediated deletion of Mertk led to increased bone mass in mice. In early stages of RANKL-induced osteoclast differentiation MERTK promotes amoeboid migration mode in osteoclast precursor cells by inducing RHOA-COFILIN-MLC2 pathway leading to increased osteoclast formation. In contrast, TYRO3 inhibits RHOA-ROCK signaling in osteoclast precursor cells thereby inhibiting these processes. Furthermore, we unraveled an inhibitory role of MERTK as well as TYRO3 in osteoclast differentiation and function. In line with this, mice with cathepsin K-mediated deletion of Mertk and Tyro3 exhibited an osteoporotic bone phenotype. We found that osteoclast precursor cell morphology dictates its fusion capacity and identified MERTK as a negative regulator of osteoclast fusion. In multinucleated cells, deletion of Mertk inhibits actin ring formation by mediating central actomyosin contraction and inactivation of COFILIN. In contrast, spatially well-ordered RHOA activation at adhesion structures, induced by loss of Tyro3, improves osteoclast biomechanotransduction to ameliorate podosome belt formation and enhance osteoclast function. By using a syngeneic breast cancer bone metastasis osteolysis models we identified TYRO3 as a bone protective receptor for osteolytic bone diseases, whereas MERTK represents a pharmacologic accessible target to inhibit osteoclast formation because its stimulatory effects of osteoclast precursors prevail the inhibitory effects on mature osteoclasts. Next to the recently uncovered role of MERTK as a target for osteoanabolic therapy MERTK may represent a one-drug two-target treatment strategy to increase osteoblast function and reduce osteoclast formation for treatments of bone diseases.

cell biology↗

bioRxiv2023

Neural and computational underpinnings of biased confidence in human reinforcement learning

While navigating a fundamentally uncertain world, humans and animals constantly produce subjective confidence judgments, thereby evaluating the probability of their decisions, actions or statements being correct. Confidence typically correlates with neural activity positively in a ventromedial-prefrontal (VMPFC) network and negatively in a dorsolateral and dorsomedial prefrontal network. Here, combining fMRI with a reinforcement-learning paradigm, we leverage the fact that humans are more confident in their choices when seeking gains than avoiding losses to reveal a functional dissociation: whereas the dorsal prefrontal network correlates negatively with a condition-specific confidence signal, the VMPFC network positively encodes task-wide confidence signal incorporating the valence-induced bias. Challenging dominant neuro-computational models, we found that decision-related VMPFC activity better correlates with confidence than with option-values inferred from reinforcement-learning models. Altogether, these results identify the VMPFC as a key node in the neuro-computational architecture that builds global feeling-of-confidence signals from latent decision variables and contextual biases during reinforcement-learning.

animal behavior and cognition↗

bioRxiv2020

Longitudinal cerebrospinal fluid proteome profiling of acute and sustained antidepressant-like effects of (2R,6R)-hydroxynorketamine (HNK) reveals involvement of glucocorticoid receptor signaling

Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapidacting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as a animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNKs rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNKs rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future.

neuroscience↗