bioRxiv Subject Collection: Neuroscience's Journal
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Friday, April 11th, 2025
| Time |
Event |
| 8:46a |
Brain pericytes derived from human pluripotent stem cells retain vascular and phagocytic functions under hypoxia
The integrity and function of the blood-brain barrier (BBB) are largely regulated by pericytes. Pericyte deficiency leads to BBB breakdown and neurological dysfunction in major neurological disorders including stroke and Alzheimer's disease (AD). Transplantation of pericytes derived from induced pluripotent stem cells (iPSC-PC) has been shown to restore the BBB and improve functional recovery in mouse models of stroke and pericyte deficiency. However, the molecular profile and functional properties of iPSC-PC under hypoxic conditions, similar to those found in ischemic and neurodegenerative diseases remain largely unexplored. Here, we demonstrate that iPSC-PC under severe hypoxia retain essential functional properties, including key molecular markers, proliferation rates, and the ability to migrate to host brain vessels via function-associated PDGFRB-PDGFBB signaling. Additionally, we show that iPSC-PC exhibit similar clearance of amyloid betaneurotoxins from AD mouse brain sections under both normoxic and hypoxic conditions. These findings suggest that iPSC-PC functions are largely resilient to hypoxia, highlighting their potential as a promising cell source for treating ischemic and neurodegenerative disorders. | | 8:46a |
Feedback-Feedforward Dynamics Shape De Novo Motor Learning
Humans excel at adjusting movements and acquiring new skills through feedback corrections and predictive control, yet how these feedback-feedforward computations evolve in the motor system remains unclear. We investigated this process by examining how humans learned a novel, continuous visuomotor mirror reversal (MR) tracking task over multiple days. Using a frequency-dependent system-identification approach and responses to cursor perturbations, we dissociated feedback-driven corrections from predictive feedforward adjustments. Our findings reveal two distinct learning pathways: early learning relies on rapid, corrective feedback at lower frequencies, while feedforward control gradually emerges at higher frequencies, compensating for feedback limitations. These findings suggest that motor learning involves a dynamic interplay between feedback and feedforward control, providing mechanistic insights into sensorimotor learning, with implications for optimizing motor skill acquisition and neurorehabilitation strategies | | 9:18a |
α7 nicotinic acetylcholine receptors regulate radial glia fate in the developing human cortex
Prenatal nicotine exposure impairs fetal cortical grey matter volume, but the precise cellular mechanisms remain poorly understood. This study elucidates the role of nicotinic acetylcholine receptors (nAChRs) in progenitor cells and radial glia (RG) during human cortical development. We identify two nAChR subunits, CHRNA7 and the human-specific CHRFAM7A expressed in SOX2+ progenitors and neurons, with CHRFAM7A particularly enriched along RG endfeet. nAChR activation in organotypic slices and dissociated cultures increases RG proliferation while decreasing neuronal differentiation, whereas nAChR knockdown reduces RG and increases neurons. Single-cell RNA sequencing reveals that nicotine exposure downregulates key genes in excitatory neurons (ENs), with CHRNA7 or CHRFAM7A selectively modulating these changes, suggesting an evolutionary divergence in regulatory pathways. Furthermore, we identify YAP1 as a critical downstream effector of nAChR signaling, and inhibiting YAP1 reverses nicotine-induced phenotypic alterations in oRG cells, highlighting its role in nicotine-induced neurodevelopmental pathophysiology. | | 9:18a |
Glycogen metabolism acts in neurons to support glycolytic plasticity
Glycogen is the largest energy reserve in the brain, but the specific role of glycogen in supporting neuronal energy metabolism in vivo is not well understood. We established a system in C. elegans to dynamically probe glycolytic states in single cells of living animals via the use of the glycolytic sensor HYlight and determined that neurons can dynamically regulate glycolysis in response to activity or transient hypoxia. We performed an RNAi screen and identified that PYGL-1, an ortholog of the human glycogen phosphorylase, is required in neurons for glycolytic plasticity. We determined that neurons employ at least two mechanisms of glycolytic plasticity: glycogen-dependent glycolytic plasticity (GDGP) and glycogen-independent glycolytic plasticity (GIGP). We uncover that GDGP is employed under conditions of mitochondrial dysfunction, such as transient hypoxia or in mutants for mitochondrial function. We find that the ability of neurons to plastically regulate glycolysis through cell-autonomous GDGP is important for sustaining the synaptic vesicle cycle. Together, our study reveals that, in vivo, neurons can directly use glycogen as a fuel source to sustain glycolytic plasticity and synaptic function. | | 9:18a |
Knock-out of Tpm4.2/actin filaments alters neuronal signaling, neurite outgrowth and behavioral phenotypes in mice.
Tropomyosins (Tpm) are master regulators of actin dynamics through forming co-polymers with filamentous actin. Despite the well-understood function of muscle Tpms in the contractile apparatus of muscle cells, much less is known about the diverse physiological function of cytoplasmic Tpms in eukaryotic cells. Here, we investigated the role of the Tpm4.2 isoform in neuronal processes including signaling, neurite outgrowth and receptor recycling using primary neurons from Tpm4.2 knock-out mice. Live imaging of calcium and electrophysiology data demonstrated increased frequency, yet reduced strength of single neuron spikes. Calcium imaging further showed increase in neuronal networks. In vitro assays of Tpm4.2 knock-out neurons displayed impaired recycling of the AMPA neurotransmitter receptor subunit GluA1. Morphometric analysis of neurite growth showed increased dendritic complexity and altered dendritic spine morphology in Tpm4.2 knock-out primary neurons. Behavioral analysis of Tpm4.2 knock-out mice displayed heightened anxiety in Open field test whilst Elevated Plus maze displayed heightened anxiety only in females. A sex-dependent phenotype was also seen in the Social Preference test with impaired social memory and socialization in female Tpm4.2 knock-out mice, whilst male and female knock-out mice had impaired recognition memory in a Novel Object Recognition test. Our study depicts the multi-faceted role of the Tpm4.2 isoform and its co-polymer F-actin population in neurons, with potential im-plications for better understanding diseases of the nervous system which involve actin cytoskeleton dysfunction. | | 9:18a |
DTX4 regulates neural progenitor transitions during cortical development
Neural progenitors drive cellular diversification in the neocortex. Prolongation of their proliferative capacity and increased diversity underpins the evolutionary expansion and morphological complexity of the human neocortex. Here, we investigate the mechanisms that regulate maintenance of the highly proliferative early neural progenitor subtypes and transition to subsequent progenitors of limited proliferative capacity during human and murine neocortical development. We identify DTX4, a Deltex family member, as an evolutionarily conserved molecular determinant of neural progenitor identity in the mammalian neocortex. DTX4 sustains the identity of radial glia, a highly proliferative progenitor subtype. Loss of DTX4, on the other hand, is a prerequisite for the generation of intermediate progenitors which possess low proliferative capacity. Perturbing DTX4 expression in human cerebral organoids and in the murine neocortex, alters progenitor composition, thereby inducing changes in neuronal diversity and cortical morphology. Mechanistically, we reveal that DTX4 controls progenitor identity by regulating the length of the cell cycle. Our findings underscore the critical role of cell cycle dynamics and of DTX4 in determining progenitor identity and thereby defining neuronal outcome during mammalian development. | | 9:47p |
Candidate NAMPT modulators from traditional African, Chinese, and Russian medicinal plants
The mitochondrial bioenergetics hypothesis postulates a critical role of mitochondrial activity in aging, which leads to the development of age-related diseases if disturbed. NAD+ and NADH generate a powerful oxidoreductive system driving ATP production in mitochondria, therefore, the maintenance of the NAD+/NADH ratio is crucial for the metabolic homeostasis in cells. The activation of nicotinamide phosphoribosyl transferase (NAMPT) is a superior approach to increase cellular levels of NAD+ since it is a rate-limiting enzyme of NAD+ salvage pathway producing NAD+ precursor nicotinamide mononucleotide. NAMPT inhibitors are, however, also desired by pharmaceutical applications due to their potency in limiting the growth of cancer cells. The present work demonstrates an in-silico approach for screening NAMPT activity modulators using compound libraries from traditional African, Chinese, and Russian medicinal plants. The compounds predicted to pass the blood-brain barrier, with low predicted toxicity and desirable pharmacokinetic and drug-likeness characteristics, were subjected to further selection by molecular docking using CB-Dock2. A panel of 21 compounds, including known NAMPT activators, inhibitors, negative controls, and randomly chosen compounds, was used to validate the docking method. The selection yielded 17 compounds with increased docking scores when tested against 6 co-crystallized structures of NAMPT. Their 2D protein-ligand interactions were critically evaluated and correlated with known interactions of the NAMPT activators and inhibitors with the active and allosteric sites of the enzyme. The selected compounds are suitable for the experimental pharmaceutical developments of drugs for aging, neurological diseases, and cancer treatments. |
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