Biology subjects

Gabel, C. V.

Publications and source records attributed to Gabel, C. V..

12 recordsLinked to original sources

bioRxiv2026

Early Amyloid-β Toxicity Disrupts Nervous System Connectivity During Aging in Caenorhabditis elegans

Alzheimers disease (AD) is characterized by progressive functional neuronal decline ultimately resulting in severe cognitive impairment. However, how neuron function is altered at the cellular level during the critical early stages of the disease and how disease progression relates to the process of normal neuronal aging are poorly understood. To address these fundamental questions, we performed comprehensive multi-neuron imaging in Caenorhabditis elegans (C. elegans) with pan-neuronal expression of human amyloid {beta}1-42 peptide (nA{beta}), the major plaque forming peptide in early AD progression. Measuring neuron activity, connectivity and system wide dynamics with single cell resolution across the C. elegans lifespan, we compare A{beta}-associated neuronal dysfunction with that of normal aging. Our experiments revealed that nA{beta} expressing animals exhibit a unique loss of positively correlated neuron connectivity, premature disruption of system wide dynamics, and reduced overall neuronal activity. These neuronal effects correspond to premature impairments in behavior including mechanosensory response as well as the animals ability to navigate its environment (i.e., chemotaxis and thermotaxis). The effects of nA{beta} expression are distinct from, and in addition to, the process of normal aging that is characterized by a progressive loss of anti-correlated (i.e. inhibitory) neuronal signaling and slower behavioral decline. An increase in resistance to aldicarb, an acetylcholinesterase inhibitor, as well as downregulation of key one-carbon metabolism (OCM) genes (metr-1, sams-1, involved in choline metabolism, the precursor of acetylcholine synthesis) implicate compromised acetylcholine-mediated excitatory transmission in nA{beta} expressing worms. Supplementation with OCM metabolites (choline, methionine, cysteine) in nA{beta} expressing worms improved behavior and helped restore OCM gene expression as well as levels of Ach signaling. Likewise, perturbation of the serine synthesis pathway (SSP) that links glycolysis to OCM, altered Ach signaling and OCM gene expression in nA{beta} animals. Genetic mutations that directly regulate excitatory/inhibitory balance neuronal signaling (unc-2/CaV2) also help to reduce nA{beta}-associated behavioral deficits, while NMDA receptor (nmr-1) mutants showed neither protective effect nor it directly rescue the loss of positive neuron correlativity unique to nA{beta} animals. Our results demonstrate the unique effects of nA{beta} toxicity on neuronal dynamics and connectivity as well as the role of key metabolic pathways within the context of a complete, intact, aging nervous system.

neuroscience↗

bioRxiv2026

Stage-specific exposure to an activity-permissive media enhances neuronal maturation in oligodendrocyte-enriched cortical organoids

Oligodendrocyte-enriched cortical organoids (OCOs) are a powerful platform for modeling oligodendrogenesis in a human cellular context. However, neuronal activity is impaired in conventional culture media, limiting assessment of neuronal function in conjunction with oligodendrocyte biology. To address this, we used a modified BrainPhys medium termed neuronal activity medium (NAM) and defined the optimal developmental window for NAM exposure to generate OCOs with robust neuronal activity (NAM-OCOs). Stage-specific exposure to NAM, prior to oligodendrocyte expansion, leads to enhanced structural maturation, as evidenced by increased organoid size, heightened synaptogenesis, and upregulation of transcripts associated with neuronal complexity. Further, NAM-OCOs display increased cellular heterogeneity, including greater representation of GABAergic interneurons while preserving oligodendrocyte development and maturation. Altogether, our studies demonstrate that stage-specific exposure to an activity-permissive environment enhances neuronal activity, establishing an OCO model which integrates neuronal activity with oligodendrocyte development and maturation. HighlightsO_LIIncreased neuronal activity in oligodendrocyte-enriched cortical organoids (OCOs) C_LIO_LIStage-specific Neuronal Activity Medium (NAM) optimizes activity C_LIO_LINAM-OCOs display increased cellular heterogeneity and neuronal maturation C_LIO_LIOligodendrogenesis is preserved in NAM-OCOs C_LI eTOC blurbIn this article, Chung et al enhance neuronal activity in oligodendrocyte-enriched cortical organoids (OCOs) through stage-specific exposure to Neuronal Activity Medium (NAM). OCOs exposed to NAM display elevated cellular heterogeneity, structural maturation, and synaptogenesis, while preserving oligodendrocyte development and maturation. These results establish an increasingly comprehensive OCO model for studying neuronal function and oligodendrogenesis.

neuroscience↗

bioRxiv2026

Neuronal Dynamics During Isoflurane Induction in Caenorhabditis elegans

BackgroundHow does neuronal activity change as an animal transitions from being awake to a state of general anesthesia? Previous studies used C. elegans to investigate awake and anesthetized states, emergence from anesthesia, and to establish metrics characterizing how system-wide neuronal dynamics differ under these conditions. This study employs a new technique to image pan-neuronal activity in C. elegans continuously during induction of anesthesia with isoflurane. MethodsC. elegans worms expressing pan-neuronal nuclear RFP and cytosolic GCaMP6s were imaged with light sheet microscopy to measure single cell activity in the majority of neurons in the animals head during induction via isoflurane exposure. Stable concentrations of isoflurane were maintained throughout the experiment by measured flow vaporization of isoflurane into a specially designed gas enclosure compatible with the imaging system. Building on our previous work investigating emergence from anesthesia, we analyzed ensemble neuronal activity, spectrograms of frequency over time, and metrics of information flow between neurons. ResultsInduction of isoflurane anesthesia caused a progressive reduction in neuronal activity over the course of 40 minutes. Spectrograms indicated a loss of bulk signal power across all frequencies, notably in low frequencies too. State Decoupling and Internal Predictability were among the most useful metrics for discriminating the anesthetized state, demonstrating induction kinetics that are the inverse of emergence. However, each animal does not arrive at the anesthetized state at the same time; response times are highly individualized. ConclusionsInformation metrics of neurodynamic activity demonstrate that isoflurane induction results in a gradual increase in neuronal disconnection and disorganization. Thus, at the level of individual neuron connectivity and system dynamics, the induction of anesthesia in C. elegans nematodes is in essence the reverse of emergence. Induction however occurs more rapidly and shows marked variability between individuals. Future genetic studies will show which molecular targets define sensitivity to volatile anesthetics like isoflurane. Summary StatementIsoflurane-induced unconsciousness is a common phenomenon across species. Does the induction of anesthesia arise by distinct state transitions, or through gradual changes in system dynamics when activity is measured at the level of individual neurons?

neuroscience↗

bioRxiv2025

IPSC-based modeling of resiliency in centenarians reveals longevity-specific signatures

Centenarians represent a human model of resilience to age-related decline, yet resiliency mechanisms remain elusive. Here, we establish an induced pluripotent stem cell (iPSC)-based platform to interrogate resilience signatures in centenarians. IPSC-derived neurons from centenarians exhibit transcriptional programs promoting synaptic integrity, calcium homeostasis, and cholesterol biosynthesis, while suppressing proteostatic stress pathways. Functionally, these neurons maintain stable calcium dynamics, reduced baseline mitochondrial activity, and energy-efficient homeostasis. Upon challenge, centenarian-derived neurons mount a robust stress response, in contrast to attenuated responses in non-centenarian controls. This resilience signature parallels adaptations in long-lived mammals and aligns with healthy brain aging, while showing erosion in Alzheimers disease and cancer. Our platform provides a scalable human model for dissecting resilience biology offering a framework to extend healthspan and mitigate age-related decline.

molecular biology↗

bioRxiv2025

Global excitatory synchrony: Ketamine induces global common-mode excitatory network oscillation by decoupling key interneurons

Ketamine is a dissociative anesthetic used in subanesthetic doses with analgesic and anti-depressive properties. However, its mechanistic effects on neuronal signaling and circuit function remain underexplored. We address this shortcoming by employing multi-neuronal imaging in the simple nematode C. elegans that allows measurement of neuron activity across the animals entire head with single-cell resolution. Neuronal imaging during low dose ketamine induction reveals two distinct phases: an early/low dose state of hyperactive synchronized dynamics and late/higher dose state of system disorganization and spastic microscale motion. Specifically examining the activity of the NMDA-receptive interneuron AVA, we find it decouples from the system under low dose ketamine. These results are consistent with the clinical hypothesis that ketamine causes neuronal disinhibition through suppression of key inhibitory interneurons. We identify functional differences between low and high dose activity dynamics and elucidate a mechanism of action of ketamine in a complete, intact nervous system.

biophysics↗

bioRxiv2025

CaNetiCs - An Open-Source Toolbox for Standardized Dimensionality Reduction of Neuronal Calcium Activity

The widespread use of calcium imaging has produced large-scale datasets capturing neuronal population activity across diverse experimental contexts, posing challenges for analyzing complex, high-dimensional data. Dimensionality reduction (DR) methods have been pivotal in addressing these challenges by simplifying data into interpretable, low-dimensional structures, while capturing essential network dynamics. Among DR methods, Nonnegative Matrix Factorization (NMF) can produce biologically meaningful representations through its nonnegativity constraint and parts-based decomposition, making it especially suited for analyzing neuronal calcium signals. To enhance accessibility and standardization in the analysis of state-dependent neuronal dynamics, we introduce Calcium Network dynamiCs (CaNetiCs), an open-source toolbox centered on NMF, integrating standardized DR methods (PCA, ICA, UMAP), geometric low-dimensional component space analyses, and neuronal network simulation modules. We validate our toolbox by applying it to two diverse experimental datasets that describe responses to graded anesthesia: whole-ganglion cellular calcium imaging of C. elegans and two-photon imaging of murine somatosensory cortex. Our analyses recapitulate previously observed trends, such as network suppression and decorrelation with anesthesia, while uncovering novel insights into neuronal activity under differing contexts. CaNetiCs provides an accessible, modular, and interpretable framework, facilitating broader adoption of standardized dimensionality reduction methodologies for deeper exploration of neuronal network dynamics across experimental paradigms. The open-source code, along with documentation, is available at https://github.com/dannycarbonero/CaNetiCs.

neuroscience↗

bioRxiv2023

O-GlcNAc Signaling Increases Neuron Regeneration Through One-Carbon Metabolism in Caenorhabditis elegans

Cellular metabolism plays an essential role in the regrowth and regeneration of a neuron following physical injury. Yet, our knowledge of the specific metabolic pathways that are beneficial to neuron regeneration remains sparse. Previously, we have shown that modulation of O-linked {beta}-N-acetylglucosamine (O-GlcNAc), a ubiquitous post-translational modification that acts as a cellular nutrient sensor, can significantly enhance in vivo neuron regeneration. Here we define the specific metabolic pathway by which mutation of the O-GlcNAc transferase (ogt-1) increases regenerative outgrowth. Performing in vivo laser axotomy and measuring subsequent regeneration of individual neurons in C. elegans, we find that the ogt-1 mutation increases regeneration by diverting the metabolic flux of enhanced glycolysis towards one carbon metabolism (OCM) and the downstream transsulfuration metabolic pathway (TSP). These effects are abrogated by genetic and/or pharmacological disruption of OCM or the serine synthesis pathway (SSP) that links OCM to glycolysis. Testing downstream branches of this pathway, we find that enhanced regeneration is dependent only on the vitamin B12 independent shunt pathway. These results are further supported by RNA-sequencing that reveals dramatic transcriptional changes, by the ogt-1 mutation, in the genes involved in glycolysis, OCM, TSP and ATP metabolism. Strikingly, the beneficial effects of the ogt-1 mutation can be recapitulated by simple metabolic supplementation of the OCM metabolite methionine in wild-type animals. Taken together, these data unearth the metabolic pathways involved in the increased regenerative capacity of a damaged neuron in ogt-1 animals and highlight the therapeutic possibilities of OCM and its related pathways in the treatment of neuronal injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/531166v1_ufig1.gif" ALT="Figure UFIG"> View larger version (19K): org.highwire.dtl.DTLVardef@7da18eorg.highwire.dtl.DTLVardef@1f997d6org.highwire.dtl.DTLVardef@15fa337org.highwire.dtl.DTLVardef@1d476bd_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstarct Figure.C_FLOATNO Metabolic pathways involved in the enhanced neuronal regeneration in ogt-1 animalsThe green highlighted pathway illustrates the metabolic rewiring in ogt-1 mutant animals supporting enhanced axonal regeneration of injured neurons in vivo. C_FIG

neuroscience↗

bioRxiv2021

Screening for axon regeneration promoting compounds with human iPSC-derived motor neurons

CNS neurons do not regenerate after injury, leading to permanent functional deficits. Although sensory and motor neuron axons do regrow after peripheral nerve injury, functional outcome is limited due to the incomplete and slow regrowth. The lack of human-relevant assays suitable for large-scale drug screens has limited neuro-repair therapy discovery. To address this we developed a phenotypic screening strategy using human induced pluripotent stem cell-derived motor neurons to identify axon-regeneration promoting compounds and targets. The screens involve both re-plating human motor neurons on chondroitin sulfate proteoglycans and measuring regeneration responses to laser axotomy in spot cultures, and from them we identified multiple hits that promote injured axon regrowth. The top hit blebbistatin, a non-muscle myosin II inhibitor, accelerated axon regeneration and functional recovery after sciatic nerve injury in vivo. Human "injury in a dish" assays are suitable, therefore, to screen for therapeutic interventions that can induce or accelerate axon regeneration.

neuroscience↗

bioRxiv2021

Age-associated changes to neuronal dynamics involve a loss of inhibitory signaling in C. elegans

In the aging brain, many of the alterations underlying cognitive and behavioral decline remain opaque. C. elegans offers a powerful model for aging research, with a simple, well-studied nervous system to further our understanding of the cellular modifications and functional alterations accompanying senescence. We perform multi-neuronal functional imaging across the aged C. elegans nervous system, measuring an age-associated breakdown in system-wide functional organization. At single-cell resolution, we detect shifts in activity dynamics toward higher frequencies. In addition, we measure a specific loss of inhibitory signaling that occurs early in the aging process and alters the systems critical excitatory/inhibitory balance. These effects are recapitulated with mutation of the calcium channel subunit UNC-2/CaV2. We find that manipulation of inhibitory GABA signaling can partially ameliorate or accelerate the effects of aging. The effects of aging are also partially mitigated by disruption of the insulin signaling pathway, known to increase longevity, or by a reduction of caspase activation. Data from mammals are consistent with our findings, suggesting a conserved shift in the balance of excitatory/inhibitory signaling with age that leads to breakdown in global neuronal dynamics and functional decline.

neuroscience↗

bioRxiv2020

Wide field-of-view volumetric imaging by a mesoscopic scanning oblique plane microscopy with switchable objective lens

Conventional light sheet fluorescence microscopy (LSFM), or selective plane illumination microscopy (SPIM), enables high resolution 3D imaging over a large volume by using two orthogonally aligned objective lenses to decouple excitation and emission. The recent development of oblique plane microscopy (OPM) simplifies LSFM design with only one single objective lens, by using off-axis excitation and remote focusing. However, most reports on OPM has a limited microscopic field of view (FOV), typically within 1×1 mm2. Our goal is to overcome the limitation with a new variant of OPM to achieve mesoscopic FOV. We implemented an optical design of mesoscopic scanning OPM to allow using low numerical aperture (NA) objective lens. The angle of the intermediate image before the remote focusing system was increased by a demagnification under Scheimpflug condition such that the light collecting efficiency in the remote focusing system was significantly improved. We characterized the 3D resolutions and FOV by imaging fluorescence microspheres, and demonstrated the volumetric imaging on intact whole zebrafish larvae, mouse cortex, and multiple Caenorhabditis elegans (C. elegans). We demonstrate a mesoscopic FOV up to ~6× 5×0.6 mm3 volumetric imaging, the largest reported FOV by OPM so far. The angle of the intermediate image plane is independent of the magnification. As a result, the system is highly versatile, allowing simple switching between different objective lenses with low (10x, NA 0.3) and median NA (20x, NA 0.5). Detailed microvasculature in zebrafish larvae, mouse cortex, and neurons in C. elegans are clearly visualized in 3D. The proposed mesoscopic scanning OPM allows using low NA objective such that centimeter-level FOV volumetric imaging can be achieved. With the extended FOV, simple sample mounting protocol, and the versatility of changeable FOVs/resolutions, our system will be ready for the varieties of applications requiring in vivo volumetric imaging over large length scales.Competing Interest StatementThe authors have declared no competing interest.View Full Text

bioengineering↗

bioRxiv2019

Ytterbium-doped fibre femtosecond laser offers robust design with deep and precise microsurgery

Laser microsurgery is a powerful tool for neurobiology used to ablate cells and sever neurites in-vivo. We compare a relatively new laser source to two well-established designs. Rare-earth-doped mode-locked fibre laser that produce high power pulsed radiation recently gained popularity for industrial uses. Such systems are manufactured at high standards of robustness and low maintenance requirements typical of solid-state lasers. We demonstrate that an Ytterbium-doped fibre femtosecond laser is comparable in precision to other femtosecond lasers, but with added reliability. It is more precise and can lesion deeper in tissue than a solid-state nanosecond laser. These advantages are not specific to the model system ablated for our demonstration, namely neurites in the nematode C. elegans, but are applicable to other systems and transparent tissue where a precise submicron resolution dissection is required.

neuroscience↗

bioRxiv2019

Sustained Ca2+ mobilizations: a quantitative approach to predict their importance in cell-cell communication and wound healing

Epithelial wound healing requires the coordination of cells to migrate as a unit over the basement membrane after injury. To understand the process of this coordinated movement, it is critical to study the dynamics of cell-cell communication. We developed a method to characterize the injury-induced sustained Ca2+ mobilizations that travel between cells for periods of time up to several hours. These events of communication are concentrated along the wound edge and are reduced in cells further away from the wound. Our goal was to delineate the role and contribution of these sustained mobilizations and using MATLAB analyses, we determined the probability of cell-cell communication events in in vitro models and ex vivo organ culture models. We demonstrated that the injury response was complex and represented the activation of a number of receptors. In addition, we found that pannexin channels mediated the cell-cell communication and motility. Furthermore, the sustained Ca2+ mobilizations are associated with changes in cell morphology and motility during wound healing. The results demonstrate that both purinoreceptors and pannexins regulate the sustained Ca2+ mobilization necessary for cell-cell communication in wound healing.

cell biology↗