Biology subjects

Koehler, A.

Publications and source records attributed to Koehler, A..

6 recordsLinked to original sources

bioRxiv2026

A Neurotensin Brake on Exploratory Drive under Persistent Threat

Avoidance behavior is an adaptive response that delays exploration to promote survival. Avoidance is enhanced by psychological stress and is a hallmark of many neuropsychiatric disorders. Neural circuits that control avoidance by integrating stressful stimuli and modulating exploratory behavior remain underexplored. Elucidating the functional dynamics of this highly conserved phenomenon and the underlying neural mechanism of avoidance is an important open-ended question, with relevance to understanding both innate behaviors and neuropsychiatric disorders. Using predator odor as an innate, chronic stressor to increase avoidance behaviors in mice, we identified a neural population in the lateral septum (LS) that integrates threat information and modulates latency to explore. Calcium recordings in freely exploring mice combined with activity-based transcriptomics revealed that predator-responsive LS neurons are GABAergic and express neurotensin (LSNT). Further, single nuclei RNA-seq analysis revealed that among predator-responsive neurons, NT-enriched inhibitory clusters are predominant. Chronic activation of LSNT neurons induces avoidance behaviors in the absence of predator odor, while synaptic silencing of this population abrogates predator-enhanced avoidance. Using transgenic mouse models to indelibly tag predator-responsive neurons, we defined the downstream circuit that connects the encoding of predator odor information to the lateral hypothalamus. Projection-specific activation of LSNT[->]LHA neurons recapitulate stress-induced avoidance behaviors in mice. Finally, we showed that deletion of neurotensin from LS neurons prevented the effects of predator odor on exploration. Together, these findings offer a genetically-and projection-defined, top-down circuit linking the limbic neurotensinergic system to chronic psychological stress and avoidance behaviors in mice.

neuroscience↗

bioRxiv2026

The Metabolome of Drosophila Reveals Exercise-Induced Stress and Anti-Inflammatory Response

Exercise is a known remedy for metabolic disorders, including obesity and type II diabetes. In humans and some model organisms, exercise is classified into different types and intensities based on the mode of exercise and the devices used. Since Drosophila has emerged as a model for exercise research, several devices have been developed for exercise training. These devices vary in mechanisms of operation; for example, the Power Tower (PT) uses a repeated drop-and-hit mechanism, and the TreadWheel (TW) uses end-over-end rotation. This variation in mechanisms that trigger the negative geotaxis of flies could impact exercise outcomes, and it remains unclear how this variation drives the response of flies to exercise training. Stress is a known response to exercise in humans and mice. Stress in Drosophila can be induced by various conditions, including heat, cold, chemical exposure, and other environmental stressors, but there is little information on exercise-induced stress. It is also unclear whether different devices elicit distinct stress responses or whether the exercise-induced stress response is similar to other stress responses (e.g., thermal, chemical). To explore the effects of device, sex, and genotype on multiple metabolic pathways, we used an untargeted metabolomics approach to further elucidate the molecular mechanisms of exercise. As no studies have directly examined the exercise metabolome of Drosophila, this study is the first to explore the metabolome of flies post-exercise. Our results revealed that exercising on different devices elicits varying responses and reshapes the metabolome of flies. We also identified specific small compounds that may be linked to stress and inflammatory response more in the PT-exercised flies than in the TW-exercised flies. Overall, the exercise device effect interacted with sex effect and genotype, such that male and female flies have different metabolite compositions post-exercise on TW and PT.

Molecular Biology↗

bioRxiv2026

Mesenchymal stroma cell-derived stem cell factor mediates cross-species compatibility of the hematopoietic stem cell niche.

The regulation of human hematopoietic stem cell (HSC) function within its native bone marrow microenvironment remains poorly understood due to the limitations of existing humanized models. Here, we present a non-conditioned human HSC xenotransplantation platform that serves as a physiologically relevant in vivo surrogate to study these complex cellular interactions. Using this system, we uncover a dynamic, cross-species communication between human HSCs and the murine niche, revealing a profound cellular and molecular plasticity of the bone marrow microenvironment in response to humanization. Upon engraftment, platelet-derived growth factor receptor alpha positive (Pdgfra+) mesenchymal stromal cells (MSCs) undergo significant numerical expansion and a major transcriptional shift, transitioning from a mixed adipo- and osteo-primed state toward a leptin receptor positive (Lepr+) predominantly adipo-primed, hematopoiesis-supporting signature. Functional validation demonstrates that this niche plasticity is a critical determinant of stem cell engraftment: the targeted depletion of Lepr+ MSCs or the genetic deletion of stem cell factor results in the rapid mobilization and lack of engraftment of human HSCs, respectively. Our findings establish niche plasticity as a primary regulator of human HSC function and demonstrate the utility of this cross-species platform as a modular genetic toolbox for precise in vivo engineering of the bone marrow microenvironment. Ultimately, this adaptable system provides a powerful framework for elucidating human stem cell biology and advancing bone marrow transplantation therapies.

cell biology↗

bioRxiv2025

Gene model for the ortholog of Ilp4 in Drosophila grimshawi

Gene Model for the Insulin-like peptide 4 (Ilp4) ortholog in the D. grimshawi (dgriCAF1) assembly (GeneBank Accession: GCA_000005155.1) of Drosophila grimshawi. The characterization of this ortholog was conducted as part of a broader, developing dataset aimed at investigating the evolution of the Insulin/insulin-like growth factor signaling (IIS) pathway across the genus Drosophila, using the Genomics Education Partnership gene annotation protocol within Course-based Undergraduate Research Experiences.

genomics↗

bioRxiv2022

Protein compactness and interaction valency define the architecture of a biomolecular condensate across scales

Non-membrane-bound biomolecular condensates have been proposed to represent an important mode of subcellular organization in diverse biological settings. However, the fundamental principles governing the spatial organization and dynamics of condensates at the atomistic level remain unclear. The S. cerevisiae Lge1 protein is required for histone H2B ubiquitination and its N-terminal intrinsically disordered fragment (Lge11-80) undergoes robust phase separation. This study connects single- and multi-chain all-atom molecular dynamics simulations of Lge11-80 with the in vitro behavior of Lge11-80 condensates. Analysis of modelled protein-protein interactions elucidates the key determinants of Lge11-80 condensate formation and links configurational entropy, valency and compactness of proteins inside the condensates. A newly derived analytical formalism, related to colloid fractal cluster formation, describes condensate architecture across length scales as a function of protein valency and compactness. In particular, the formalism provides an atomistically resolved model of Lge11-80 condensates on the scale of hundreds of nanometers starting from individual protein conformers captured in simulations. The simulation-derived fractal dimensions of condensates of Lge11-80 and its mutants agree with their in vitro morphologies. The presented framework enables a multiscale description of biomolecular condensates and embeds their study in a wider context of colloid self-organization.

biophysics↗

bioRxiv2020

Ebola and Marburg virus matrix layers are locally ordered assemblies of VP40 dimers

A key step in the life cycle of enveloped viruses is the budding of nascent virions from the host membrane. In filoviruses such as Ebola and Marburg virus, this process is achieved by the matrix protein VP40. When expressed alone, VP40 induces the budding of filamentous virus-like particles, suggesting that localization to the plasma membrane, oligomerization into a matrix layer, and the generation of membrane curvature are intrinsic properties of VP40. While a number of crystal structures of VP40 have been determined in various oligomerization states, there has been no direct information on the structure of assembled VP40 matrix layers within viruses or virus-like particles. Here, we present structures of Ebola and Marburg VP40 matrix layers in intact virus-like particles, as well as within intact Marburg viruses. We find that the matrix layers are formed from VP40 dimers which assemble into extended chains via C-terminal domain interactions. These chains stack into layers, forming a 2D lattice below the membrane surface. However, these 2D lattices are only locally ordered, forming a patchwork assembly across the membrane surfaces and suggesting that assembly may begin at multiple points. These observations define the structure and arrangement of the matrix protein layer that mediates the formation of filamentous filovirus particles.

microbiology↗