Biology subjects

Knobloch, M.

Publications and source records attributed to Knobloch, M..

4 recordsLinked to original sources

bioRxiv2024

Astrocyte-derived PEA116 increases adult hippocampal neurogenesis and confers stress resilience

In the dentate gyrus of the hippocampus, the neurogenic niche regulates several steps of adult neurogenesis, from the proliferation to the integration of newly formed neurons in the hippocampal network. However, the role of astrocytes in the regulation of adult neural stem cell (aNSC) proliferation is still little described. Here, we found that blocking vesicular release from astrocytes decreased cell proliferation in the dentate gyrus, resulting in impaired adult neurogenesis. Inversely, astrocyte-conditioned medium increased cell proliferation in a vesicular release-dependent manner. We identified PEA116 as a peptide released by astrocytes, that is derived from the c-terminal portion of the PEA15 protein and increased cell proliferation. PEA116 increased ERK2 phosphorylation, decreased the expression of genes involved in aNSC quiescence, resulting in aNSC quiescence exit. The ensuing increase in hippocampal neurogenesis improved resilience to chronic stress. These findings highlight a novel peptide produced by astrocytes that regulates the early steps of adult neurogenesis, with an implication for mood disorders.

neuroscience↗

bioRxiv2024

An optimized method to visualize lipid droplets in brain tissue demonstrates their substantial accumulation in aged brains

Lipid droplets (LDs) are cellular stores for lipids. These organelles have recently gained interest in neuroscience because they accumulate in various cell types in neurodegenerative diseases. However, their role under physiological conditions is still not fully understood. Classical LD staining methods, which use lipophilic dyes like BODIPY 493/503 (BD493) or antibodies against LD coat proteins, show very few LDs in healthy brain tissue. Our recently developed novel endogenous LD reporter mouse challenges this view. We have been able to detect numerous LDs in healthy brain tissue from both adult and developing mice without staining. To understand why classical staining and endogenous labeling yield different results, we thoroughly investigated the effects of tissue preparation and detergent used in LD detection. We found that BD493 works poorly in brain tissue, while other lipophilic dyes visualize many LDs. We also found that antibody-based LD detection depends on tissue pretreatment and detergent concentration but can reveal a similar number of LDs as observed with the endogenous LD reporter mouse. Taken together, we here present an optimized procedure for LD detection in brain tissue using commercially available dyes and antibodies. Using these methods, we demonstrate that LDs are numerous in healthy brain tissue and substantially accumulate in aged brains in various cell types, including neurons.

neuroscience↗

bioRxiv2022

A fluorescent perilipin 2 knock-in mouse model visualizes lipid droplets in the developing and adult brain

Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by endogenously labelling the LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are present in various cells in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we show that LDs are abundant during brain development and can be visualized using live-imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2.

cell biology↗

bioRxiv2022

Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells

Cellular metabolism is important for adult neural stem/progenitor cell (NSPC) behavior. However, its role in the transition from quiescence to proliferation is not fully understood. We here show that the mitochondrial pyruvate carrier (MPC) plays a crucial and unexpected part in this process. MPC transports pyruvate into mitochondria, linking cytosolic glycolysis to mitochondrial tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS). Despite its metabolic key function, the role of MPC in NSPCs has not been addressed. We show that quiescent NSPCs have an active mitochondrial metabolism and express high levels of MPC. Pharmacological MPC inhibition increases aspartate and triggers NSPC activation. Furthermore, genetic MPC-ablation in vivo also activates NSPCs, which differentiate into mature neurons, leading to overall increased hippocampal neurogenesis in adult and aged mice. These findings highlight the importance of metabolism for NSPC regulation and identify a novel pathway through which mitochondrial pyruvate import controls NSPC quiescence and activation. Highlights* Quiescent NSPCs have high levels of MPC and an active mitochondrial network * The import of pyruvate into mitochondria is necessary to maintain quiescence of NSPCs * MPC inhibition increases intracellular aspartate levels and triggers the activation of quiescent NSPCs * MPC-knockout NSPCs generate mature newborn neurons, leading to overall increased neurogenesis in adult and advanced age mice Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/494137v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ee8788org.highwire.dtl.DTLVardef@1040633org.highwire.dtl.DTLVardef@1330d26org.highwire.dtl.DTLVardef@a474e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗