Biology subjects

Schmidt, M. H.

Publications and source records attributed to Schmidt, M. H..

5 recordsLinked to original sources

bioRxiv2024

Exploring social modulation: Microglia as a key mediator of individual immune response, plasticity and pathology in App-NL-G-F mouse model of Alzheimer's disease

This study explores the influence of lifestyle on Alzheimers disease (AD) progression using App-NL-G-F mice in a complex enrichment system. Mice exhibited social deficits before plaque pathology or memory impairment, revealing a crucial link between lifestyle, behavior, and neuroinflammation. Plasma analysis indicates early inflammation and apoptosis-related changes, setting the stage for identifying markers predicting plaque manifestation. Beyond pathology, social behavior is linked to adult neurogenesis and microglia coverage, forming a dynamic connection with microglia activation. Further, sc-RNA sequencing unveiled a decrease in interferon-responsive microglia and alteration in antigen processing with enrichment. These findings underscore the beneficial impact of social housing on microglia and interconnected factors, pointing to microglia as a critical mediator of the behavior-pathology-plasticity interplay in AD. The study enhances our understanding of AD complexity and offers insights into potential therapeutic strategies, emphasizing the multifaceted nature of AD progression and the role of lifestyle in shaping its course.

neuroscience↗

bioRxiv2022

Less is more - loss of EGFL7 improves memory by upregulation of VEGF-D

Neural stem cells reside in a specialized neurogenic niche of the hippocampus termed the subgranular zone. Throughout life, they give rise to adult-born neurons in the dentate gyrus thereby contributing to learning and memory. Here, we report that neurons together with neural stem and precursor cells secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this niche. EGFL7 knock-out in vivo promoted adult neurogenesis generating neurons forming additional spines which permanently integrated into the neural circuit until old age. RNA-sequencing identified the cytokine VEGF-D as a major molecular driver of this process in vivo. In behavioral studies EGFL7 knock-out mice displayed stronger maintenance of memory suggesting longer-lasting spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation in young and aged mice. Taken together, EGFL7 is an upstream regulator of the VEGF-D in adult neurogenesis and a key regulator of learning and memory.

neuroscience↗

bioRxiv2021

Narcolepsy and the Dissociation of REM Sleep and Cataplexy through Ambient Temperature Manipulation

Narcolepsy is characterized by increased REM sleep propensity and cataplexy. Although narcolepsy is caused by the selective loss or dysfunction of hypocretin (Hcrt) neurons within the lateral hypothalamus (LH), mechanisms underlying REM sleep propensity and cataplexy remain to be elucidated. We have recently shown that wild type (WT) mice increase REM sleep expression when exposed to thermoneutral ambient temperature (Ta) warming during the light (inactive) phase. We hypothesized that the loss of Hcrt may lead to exaggerated responses with respect to increased REM sleep and cataplexy during Ta warming. To test this hypothesis, Hcrt-KO mice were implanted for chronic sleep recordings and housed in a temperature-controlled cabinet. Sleep-wake expression and both spontaneous cataplexy and food-elicited cataplexy were evaluated at constant Ta and during a Ta manipulation protocol. Here we show several unexpected findings. First, Hcrt-KO mice show opposite circadian patterns with respect to REM sleep responsiveness to thermoneutral Ta warming compared to WT mice. As previous demonstrated, WT mice increased REM sleep when Ta warming is presented during the inactive (light) phase, whereas Hcrt-KO showed a significant decrease in REM sleep expression. In contrast, Hcrt-KO mice increased REM sleep expression upon exposure to Ta warming when presented during the active (dark) phase, a circadian time when WT mice showed no significant changes in REM sleep as a function of Ta. Second, we found that REM sleep and cataplexy can be dissociated through Ta manipulation. Specifically, although Ta warming significantly increased REM sleep expression in Hcrt-KO mice during the active phase, cataplexy bout number and total cataplexy duration significantly decreased. In contrast, cataplexy expression was favoured during Ta cooling when REM sleep expression significantly decreased. Finally, video actigraphy and sleep-wake recordings in Hcrt-KO mice demonstrated that Ta manipulation did not significantly alter waking motor activity patterns or waking or NREM sleep durations. These data suggest that neural circuits gating REM sleep and cataplexy expression can be dissociated with Ta manipulation. Statement of SignificanceCataplexy and the loss of muscle tone has historically been viewed as a component of REM sleep that inappropriately intrudes into wakefulness. In addition to fragmented sleep, the intrusion of REM-like events into wakefulness has led to the hypothesis that narcolepsy represents a dysregulation of boundary state control. We show that REM sleep and cataplexy can be dissociated during the dark (active) phase through Ta manipulation. Such dissociation may provide clues regarding the cause of boundary state instability in Hcrt-KO mice, as well as provide a new method to interrogate mechanisms of REM sleep and cataplexy.

neuroscience↗

bioRxiv2020

Transparency and open science reporting guidelines in sleep research and chronobiology journals

"Open science" is an umbrella term describing various aspects of transparent and open science principles. The adoption of open science principles at different levels of the scientific process (e.g., individual researchers, laboratories, institutions) has been rapidly changing the scientific research landscape in the past years, but uptake of these principles differ from discipline to discipline. Here, we asked to what extent journals in the field of sleep and chronobiology research encourage or even require following transparent and open science principles in their author guidelines. To this end, we scored the author guidelines of a comprehensive set of 28 sleep and chronobiology journals, including the major outlets in the field, using the standardised Transparency and Openness (TOP) Factor. This instrument rates the extent to which journals encourage or require following various aspects of open science, including data citation, data transparency, analysis code transparency, materials transparency, design and analysis guidelines, study pre-registration, analysis plan pre-registration, replication, registered reports, and the use of open science badges. Across the 28 journals, we find low values on the TOP Factor (median [25th, 75th percentile] 2.5 [1, 3], min. 0, max. 9, out of a total possible score of 28). This suggests an opportunity for sleep and chronobiology journals to further support the recent developments by implementing transparency and openness principles in their guidelines and making adherence to them mandatory.

scientific communication and education↗

bioRxiv2017

Targeting xCT-Mediated Glutamate Release Normalizes Tumor Angiogenesis In The Brain

Brain tumors are among the most malignant primary tumors, hallmarked by angiogenesis, neuronal destruction and brain swelling. Inhibition of the glutamate-cystein antiporter xCT (system xc-/SLC7A11) alleviates seizures, neuronal cell death and tumor-associated brain edema. Here we show enhanced tumor vessel growth and increased brain edema in xCT-expressing brain tumors. Furthermore, xCT-mediated glutamate impacts directly on endothelial cells in an N-methyl-D-aspartate receptor (NMDAR) dependent manner with intracellular Ca2+ release. Cerebral intravital microscopy revealed that xCT-driven tumor vessels are functional and display increased permeability. Endothelial-cell-specific NMDAR1 knockout mice (GRINi{Delta}EC) show suppressed endothelial sprouting and vascular density compared to control littermates. In addition, implanted gliomas in GRINi{Delta}EC mice display reduced tumor vessels in contrast to gliomas in wildtype animals. Moreover, therapeutic targeting of xCT in gliomas alleviates tumor angiogenesis to normalized levels comparable to controls. Our data reveal that xCT and its substrate glutamate specifically operate on endothelial cells and promote neoangiogenesis. Thus, targeting xCT expression and glutamate secretion in gliomas provides a novel therapeutic roadmap for normalizing tumor angiogenesis.

cell biology↗