Biology subjects

Scheller, M.

Publications and source records attributed to Scheller, M..

10 recordsLinked to original sources

bioRxiv2025

Individual differences drive social hierarchies in mouse societies

Social hierarchies structure groups and confer advantages on high-ranking individuals. In mice, individual position in hierarchies may emerge situationally from current group compositions, or, alternatively, may remain largely stable across groups as an internalized feature. Dominance and subordination are expressed in behaviors like tube competitions or agonistic chasing. The interaction of these behaviors in the shaping of social position in larger male mouse groups remains largely unknown. To address these questions, we developed the NoSeMaze, a semi-naturalistic, open-source, modular platform that enables automated long-term tracking of unperturbed groups. Across more than 4,000 mouse-days, hierarchies derived from incidental competitions in the integrated tube tests were non-despotic, transitive, and stable even when group compositions changed. This stability supports an internalized component of competition-based social rank. Chasing was also stable across contexts. Notably, chasing was concentrated among high-ranking individuals, consistent with ongoing negotiation of social rank among individuals at the upper end of the hierarchy. The link between chasing and social rank strengthened in groups with less well-defined rank structure, where mice rely more on aggressive signaling to assert their position. Chasing and social rank were associated with certain dimensions of simultaneously measured physical and cognitive features. In summary, high-dimensional tracking with the NoSeMaze reveals that social position in mice is multifaceted and shaped by stable dimensions of individual behavior that persist across changing social contexts. The approach thus enables longitudinal modeling of individuality and social position as key resilience factors.

neuroscience↗

bioRxiv2025

Learning new perceptual skills: Individual differences in the computations that integrate novel sensory cues into depth perception

Sensory substitution and augmentation rely on the brains ability to integrate novel sensory cues into its perceptual repertoire. However, the flexibility of the computations that support augmented perception is still not fully known. Here, we contrasted how a novel depth cue is processed, as compared with familiar depth cues, following one hour of training. Observers (N=78) made forced-choice comparisons of surface distances (depths), while we assessed three markers of integration with familiar and newly learned cues: (1) cue combination, predicting precision benefits; (2) re-weighting, predicting reliability-weighted biases; and (3) congruence sensitivity, predicting increased sensitivity for the learned cue mapping. We found that, (1) while familiar cues (size and binocular disparity) were combined near-optimally, there was little evidence for a novel cue (auditory pitch) being combined with binocular disparity. Measures of repeatability across two sessions suggest that this was due to reliable inter-individual differences in combination with the novel cue. In contrast, (2) both familiar and novel cue pairs were re-weighted by their relative reliabilities and (3) showed sensitivity to incongruence. These direct comparisons show that, while a novel cue was rapidly mapped onto depth and weighted in line with its relative reliability, it was not integrated into the native perceptual repertoire by everyone. Reliable individual differences suggest that abilities to combine novel sensory cues may vary between people. These findings provide insight into the flexibility of human sensory processing and suggest that learning to interpret new sensory information depends in part on individual flexibility in perceptual computations. Highlights- We evaluated evidence for integration of novel and familiar cues to depth - After short training, direct comparisons show dissociations in integration - At a group level, novel cues, unlike familiar, were not combined overall - Strong individual differences suggest varied abilities to combine new cues - Individual differences seem to play an important role in integration of new cues

neuroscience↗

bioRxiv2024

Self-association enhances early attentional selection through automatic prioritization of socially salient signals

Efficiently processing self-related information is critical for cognition, yet the earliest mechanisms enabling this self-prioritization remain unclear. By combining a temporal order judgement task with computational modelling based on the Theory of Visual Attention (TVA), we show how mere, arbitrary associations with the self can fundamentally alter attentional selection of sensory information into short-term memory/awareness, by enhancing the attentional weights and processing capacity devoted to encoding socially loaded information. This self-prioritization in attentional selection occurs automatically at early perceptual stages but reduces when active social decoding is required. Importantly, the processing benefits obtained from attentional selection via self-relatedness and via physical salience were additive, suggesting that social and perceptual salience captured attention via separate mechanisms. Furthermore, intra-individual correlations revealed an obligatory self-prioritization effect, whereby self-relatedness overpowered the contribution of perceptual salience in guiding attentional selection. Together, our findings provide evidence for the influence of self-relatedness during earlier, automatic stages of attentional section at the gateway to perception, distinct from later post-attentive processing stages.

neuroscience↗

bioRxiv2024

Metabolic alterations drive inflammatory phenotypes in CHIP-associated heart failure

Mutations in DNA methyltransferase 3 alpha (DNMT3A) are the most frequent driver of clonal hematopoiesis of indeterminate potential (CHIP), and associated with higher risk of cardiovascular disease and pro-inflammatory activation of immune cells. Here, we investigated the mechanisms underlying DNMT3A CHIP-associated inflammatory phenotypes in macrophages. We show that monocytes of DNMT3A CHIP-driver mutation carriers are associated with DNA hypomethylation of succinate dehydrogenase A (SDHA) and an altered tricarboxylic acid cycle metabolite profile. Silencing of DNMT3A in monocytes increased SDHA and elevated mitochondria complex II activity. The secreted complex II product, malate, further increased inflammatory activation in wild type monocytes to further augment inflammation in a paracrine manner. Pharmacological inhibition of SDHA (using dimethyl malonate) in mice harboring DNMT3A mutations in hematopoietic stem cells ameliorated the inflammatory response and improved cardiac function after myocardial infarction. Thus, interfering with the altered metabolic state may provide a new therapeutic option to dampen inflammatory activation in DNMT3A CHIP carrying patients.

molecular biology↗

bioRxiv2023

Monocyte-derived microglia with Dnmt3a mutation cause motor pathology in aging mice

Microglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoM{Phi}) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoM{Phi} adopt bona fide microglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3AR822H, a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.

immunology↗

bioRxiv2023

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and the cardiac tissue. We demonstrate that CHIP augments macrophage-to-cardiac fibroblasts interactions. Mechanistically, the secretome of DNMT3A-silenced monocytes leads to myofibroblast activation, partially through epidermal growth factor (EGFR) signaling. Harboring DNMT3A CHIP-driver mutations is associated with increased cardiac interstitial fibrosis in mice and patients, and, thereby, may contribute to the poor outcome. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/521766v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@10a365aorg.highwire.dtl.DTLVardef@176807borg.highwire.dtl.DTLVardef@ed3f47org.highwire.dtl.DTLVardef@1d572b2_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2022

Inflammatory signals from fatty bone marrow supports the early stages of DNMT3a driven clonal hematopoiesis

Age related cancer is not only due to the random accumulation of mutations, but also how phenotypes are selected by the aging environment. While fatty bone marrow (FBM), is one of the hallmarks of bone marrow ageing, it is unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established FBM mice models and transplanted both human and mice preleukemic hematopoietic stem cells (PreL-HSCs) carrying DNMT3A mutations. We demonstrate that castration which models age related andropenia result in FBM. A significant increase in self-renewal was found when DNMT3AMut - preL-HSPCs were exposed to FBM. To better understand the mechanisms of the FBM-preL-HSPCs interaction, we performed single cell RNA-sequencing on HSPCs three days after FBM exposure. A 20-50 fold increase in DNMT3AMut-preL-HSCs was observed under FBM conditions in comparison to other conditions. PreL-HSPCs exposed to FBM exhibited an activated inflammatory signaling (IL-6 and INF{gamma}). Cytokine analysis of BM fluid demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of DNMT3AMut-preL-HSPCs exposed to FBM. Overall, age related paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.

cancer biology↗

bioRxiv2021

Hierarchical cross-scale analysis identifies parallel ventral striatal networks coding for dynamic and stabilized olfactory reward predictions

The unbiased identification of brain circuits responsible for behavior and their local cellular computations is a challenge for neuroscience. We establish here a hierarchical cross-scale approach from behavioral modeling and fMRI in task-performing mice to cellular network dynamics to identify how reward predictions are represented in the forebrain upon olfactory conditioning. fMRI identified functional segregation in reward prediction and error computations among olfactory cortices and subcortical circuits. Among them, the olfactory tubercle contributed both to dynamic reward predictions and prediction error. In this region, cellular recordings revealed two parallel neuronal populations for prediction coding. One population produced stabilized predictions as distributed stimulus-bound transient network activity; the other evolved during anticipatory waiting and fully reflected predicted value in single-units, dynamically integrating the recent cue-specific history of uncertain outcomes. Thus, the cross-scale approach revealed regional functional differentiation among the distributed forebrain circuits with a limbic hotspot for multiple non-redundant reward prediction coding.

neuroscience↗

bioRxiv2019

Late- but not early-onset blindness impairs the development of audio-haptic multisensory integration

Integrating different senses to reduce sensory uncertainty and increase perceptual precision can have an important compensatory function for individuals with visual impairment and blindness. However, how visual impairment and blindness impact the development of optimal multisensory integration in the remaining senses is currently unknown. Here we first examined how audio-haptic integration develops and changes across the life span in 92 sighted (blindfolded) individuals between 7 to 70 years of age by using a child-friendly size discrimination task. We assessed whether audio-haptic performance resulted in a reduction of perceptual uncertainty compared to auditory-only and haptic-only performance as predicted by maximum-likelihood estimation model. We then tested how this ability develops in 28 children and adults with different levels of visual experience, focussing on low vision individuals, and blind individuals that lost their sight at different ages during development. Our results show that in sighted individuals, adult-like audio-haptic integration develops around 13-15 years of age, and remains stable until late adulthood. While early blind individuals, even at the youngest ages, integrate audio-haptic information in an optimal fashion, late blind individuals do not. Optimal integration in low vision individuals follows a similar developmental trajectory as that of sighted individuals. These findings demonstrate that visual experience is not necessary for optimal audio-haptic integration to emerge, but that consistency of sensory information across development is key for the functional outcome of optimal multisensory integration.\n\nResearch HighlightsO_LIAudio-haptic integration follows principles of statistical optimality in sighted adults, remaining stable until at least 70 years of life\nC_LIO_LINear-optimal audio-haptic integration develops at 13-15 years in sighted adolescents\nC_LIO_LIBlindness within the first 8 years of life facilitates the development of optimal audio-haptic integration while blindness after 8 years impairs such development\nC_LIO_LISensory consistency in early childhood is crucial for the development of optimal multisensory integration in the remaining senses\nC_LI

neuroscience↗

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↗