Biology subjects

Schenke, M.

Publications and source records attributed to Schenke, M..

4 recordsLinked to original sources

bioRxiv2026

Encephalitic alphavirus infection reduces neurite outgrowth and downregulates Rho GTPase pathways in human iPSC-derived neurospheres

Venezuelan equine encephalitis virus (VEEV) is a re-emerging neurotropic arbovirus, which affects the developing human brain, potentially leading to miscarriage, stillbirth, or long-term neurological sequelae. Currently, the mechanisms underlying these sequelae remain largely elusive. Using human induced pluripotent stem cell (iPSC)-derived neurospheres as a model for brain development, we show that both human neurons and glial cells are susceptible to VEEV infection. Microscopy-based quantification reveals that VEEV impairs neurite outgrowth in the human neurospheres. To mechanistically assess these observations, we performed multi-omics analyses of VEEV-infected neurospheres and demonstrate translational shutoff including downregulation of Rho GTPase pathways. The transcriptional and proteome profile is indicative of reduced actin cytoskeleton dynamics and consequently migratory defects of cells in the neurospheres. Shotgun secretomics moreover revealed downmodulation of neurite outgrowth associated proteins including midkine (MDK), amyloid-beta precursor protein (APP) and microtubule-associated protein 1B (MAP1B). Our findings reveal mechanistic insights into how VEEV infection impairs neuronal development and demonstrate that neurospheres are a powerful platform for assessing teratogenic effects of viruses on brain development.

neuroscience↗

bioRxiv2025

Genetic Background and Sex Modulate Androgen Responses in Human Brain Microphysiological System

Sex steroids shape human brain development, yet the cellular and molecular consequences of androgen addition need further exploration. Here, we used a human neural organoid model - brain microphysiological system (bMPS), derived from nine induced pluripotent stem cell (iPSC) lines to model the impact of dihydrotestosterone (DHT), a potent non-aromatizable androgen. All lines differentiated reproducibly into electrically active, neuron-glia-oligodendrocyte organoids expressing robust androgen-signaling components. DHT was bioavailable, elicited nuclear androgen receptor (AR) translocation and increased organoid size in most cell lines, consistent with androgen-responsive mTOR and metabolic pathway activation. Bulk RNA-seq across nine lines revealed that transcriptional responses varied across donor backgrounds, but DHT-responsive genes converged on mitochondrial energetics, lysosomal function, glycoprotein processing, apoptosis, and mTOR signaling. Cell-type expression profiling showed an androgen-driven shift primarily in male lines toward astrocytic profiles with reductions in oligodendrocyte, oligodendrocyte progenitor (OPC), excitatory, and inhibitory neuronal signatures, supported by immunohistochemistry and AR enrichment in astrocytes and OPCs. DHT also altered neurodevelopmental pathways, increasing variation in synaptic pruning and decreasing variation in neuronal migration, with autism spectrum disorder (ASD) diagnosis and seizure status of donors moderating these effects more strongly than sex. Baseline transcriptional differences distinguished iPSC lines which responded more strongly to DHT from weak responders: responders displayed enhanced synaptic maturity and reduced ECM gene expression. Using isogenic XX/XY lines, we found that differences in sex-chromosome expression exceeded DHT-induced changes and that DHT decreased expression of inhibitory neuron genes in males and increased it in females. Finally, DHT induced extensive DNA methylation changes, targeting HOX genes, patterning, and synaptic genes. Collectively, these findings reveal that androgen signaling shapes transcription, cell populations, and epigenetic landscapes in a genetic background-dependent manner. This work contributes to understanding how androgens influence human brain development and highlights how in vitro models can contribute to representing inter-individual variability in neurodevelopment and neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Human Neural Organoid Microphysiological Systems Show the Building Blocks Necessary for Basic Learning and Memory

Brain Microphysiological Systems including neural organoids derived from human induced pluripotent stem cells offer a unique lens to study the intricate workings of the human brain. This paper investigates the foundational elements of learning and memory in neural organoids, also known as Organoid Intelligence by quantifying immediate early gene expression, synaptic plasticity, neuronal network dynamics, and criticality to demonstrate the utility of these organoids in basic science research. Neural organoids showed synapse formation, glutamatergic and GABAergic receptor expression, immediate early gene expression basally and evoked, functional connectivity, criticality, and synaptic plasticity in response to theta-burst stimulation. In addition, pharmacological interventions on GABAergic and glutamatergic receptors, and input specific theta-burst stimulation further shed light on the capacity of neural organoids to mirror synaptic modulation and short-term potentiation, demonstrating their potential as tools for studying neurophysiological and neurological processes and informing therapeutic strategies for diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/613333v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@50a256org.highwire.dtl.DTLVardef@1d1f8c9org.highwire.dtl.DTLVardef@24688borg.highwire.dtl.DTLVardef@4ba3b4_HPS_FORMAT_FIGEXP M_FIG C_FIG Overview of the main components of the experiments conducted. Figure created using BioRender.com.

neuroscience↗

bioRxiv2021

EEG-based visual deviance detection in freely behaving mice

The mouse is widely used as an experimental model to study visual processing. To probe how the visual system detects changes in the environment, functional paradigms in freely behaving mice are strongly needed. We developed and validated the first EEG-based method to investigate visual deviance detection in freely behaving mice. Mice with EEG implants were exposed to a visual deviant detection paradigm that involved changes in light intensity as standard and deviant stimuli. By subtracting the standard from the deviant evoked waveform, deviant detection was evident as bi-phasic negativity (starting around 70 ms) in the difference waveform. Additionally, deviance-associated evoked (beta/gamma) and induced (gamma) oscillatory responses were found. We showed that the results were stimulus-independent by applying a "flip-flop" design and the results showed good repeatability in an independent measurement. Together, we put forward a validated, easy-to-use paradigm to measure visual deviance processing in freely behaving mice.

neuroscience↗