Biology subjects

Nguyen, D. L.

Publications and source records attributed to Nguyen, D. L..

5 recordsLinked to original sources

bioRxiv2026

Stem cell function in vivo is supported by an alternative glycolysis endpoint

Carbohydrates are classically catabolized by fermentation or oxidation, a choice that impacts many cellular functions including proliferation. Proliferating cells including somatic stem and progenitor cells are thought to favor fermentation over oxidation, and most proliferating cells in vitro depend on lactate production. However, it has not been tested if fermentation and oxidation are the universal obligatory terminal fates for carbohydrates in vivo because the key enzymes, lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), have not been simultaneously deleted in any cell type. Here we show that both fermentation and oxidation are dispensable for the survival and function of hematopoietic stem cells (HSC). Combined LDHA and LDHB deletion to ablate LDH did not impair HSC function, suggesting that HSCs and rapidly proliferating hematopoietic progenitors surprisingly do not require fermentation. Combined LDHA, LDHB, and PDH deletion abolished both glucose oxidation and fermentation, but did not impair HSC function. Glycolysis was preserved, suggesting the operation of an alternative endpoint. LDH/PDH-deficient HSCs terminated glycolysis through pyruvate export. Pyruvate export by HSCs and progenitors was a physiological response to changing nutrient levels. Quadruple deletion of LDHA/B, PDH, and the pyruvate transporter MCT1 impaired HSC function. This suggested that an essential role of glycolysis termination is not to produce acetyl-CoA or lactate but to remove pyruvate. Therefore, in contrast to classical theories and to in vitro metabolism, carbohydrate metabolism in vivo does not require oxidation or fermentation but can terminate directly in pyruvate export, and this alternative pathway is sufficient to support stem cell function.

biochemistry↗

bioRxiv2026

Metaplastic sleep regulation in Drosophila determined by microscale circadian neural dynamics

The biophysical mechanisms by which circadian clock neurons integrate temporal coding signals to regulate sleep remain elusive. Here, using Drosophila, we identify Rabphilin (Rph) in DN1p clock neurons as a key stabilizer of the metaplasticity setpoint governing circadian regulation of sleep. Rph protein levels are elevated at night relative to daytime and modulate stochastic process of DN1p membrane potential dynamics linked to variability in synaptic activity at connections between DN1p neurons and their downstream postsynaptic partners. We find that Rph acts as a bidirectional regulator of synaptic plasticity thresholds. Under dim nocturnal light stimulation, Rph knockdown permits synaptic potentiation, whereas synthesized Rph introduction induces synaptic depression. In contrast, under optogenetic manipulation mimicking daytime spiking in DN1p neurons, these effects are reversed. We further show that spike-timing-dependent plasticity emerges when postsynaptic spiking is engaged, with nocturnal dim light conditions determining the direction of plasticity. Together, these findings establish a mechanistic link between microscale circadian neural dynamics and hierarchical metaplastic regulation, demonstrating how circadian regulation of sleep dynamically balances stability and adaptive flexibility through circadian setpoints and environmental nocturnal light interactions. Significance StatementWe show that circadian metaplasticity regulates sleep through membrane potential dynamics. Circadian clock neurons implement flexible metaplasticity, whereby the direction can be determined by internal circadian setpoints and interactions with nocturnal environmental light. This mechanism engages spike-timing-dependent plasticity to determine plasticity polarity. Our findings identify membrane potential dynamics as a computational substrate for physiological state control, linking molecular mechanisms to circuit-level circadian regulation of sleep. Together, they reframe sleep regulation as an active metaplastic process that hierarchically integrates microscale circadian neural dynamics to optimize circuit function.

neuroscience↗

bioRxiv2026

Metaplastic neuronal state transition regulates species-specific interoceptive processing in Drosophila

Interoceptive processing, which involves the sensing and integration of internal physiological states, is fundamental to maintaining homeostasis. However, how species-specific interoceptive features arise from the underlying biophysical properties of neural circuit physiology remains unclear. We investigate the biophysical basis of species-specific interoception by examining protein-hunger dopamine neurons (DA-WED) in two Drosophila species with divergent dietary ecologies. We find that DA-WED neurons in D. melanogaster exhibit weak persistence of internal states, enabling flexible behavioral transitions during nutrient stress. In contrast, D. sechellia shows strong state persistence, locking neurons into a "preferred" configuration during protein deprivation. This divergence is supported by distinct intrinsic membrane properties, including protein deprivation-induced rebound spikes unique to D. sechellia. Analysis of synaptic dynamics and cardiomyocyte electrophysiology reveals species-specific physiological regulations coordinating central and peripheral systems. Behavioral assays confirm corresponding differences in protein consumption strategies, directly linking neural state geometry to ecologically relevant feeding behavior. Our findings establish metaplastic regulation of neural state transitions as a fundamental mechanism through which ecological specialization shapes interoceptive processing and brain-body coordination. Significance StatementWe identify physiological regulations of neural state transitions as a core mechanism underlying species-specific interoceptive processing. Through comparative electrophysiology in D. melanogaster and D. sechellia, we demonstrate that ecological specialization manifests through distinct intrinsic membrane properties of DA-WED neurons, fundamentally altering neural state space geometry during protein deprivation. Species-specific synaptic plasticity gates these transitions while coupling cardiac rhythms to central computation. Our findings reveal how evolution transforms nutrient sensing into divergent neural dynamics, establishing a mechanistic framework for understanding how ecological pressures sculpt the biophysical architecture of interoceptive circuits to coordinate adaptive brain-body interactions.

neuroscience↗

bioRxiv2026

Neuronal microscale biophysical instability mediates macroscale network dynamics shaping pathological manifestations

Subtle changes in membrane excitability may contribute to neurological disease, but disease-relevant dynamical signatures that generalize across models remain poorly defined. Here, we quantified variability in action potential initiation in Drosophila neurons expressing tauopathy- or epilepsy-associated mutations and in human iPSC-derived neurons from patients with Alzheimers disease or epilepsy. Across these models, disease-associated neurons exhibited increased instability in spike timing relative to controls. In Drosophila neurons, this phenotype was accompanied by increased variability in voltage-gated sodium currents during non-stationary inactivation, identifying a candidate biophysical contributor to altered spike initiation. Antiepileptic drugs reduced sodium-current variability and stabilized spike initiation in fly neurons, and similarly improved spike-timing instability in patient-derived human neurons. In the fly models, neuronal instability was also associated with altered circuit- and brain-state readouts. Together, these findings identify unstable spike initiation as a conserved electrophysiological phenotype across distinct neurological disease models and suggest that sodium-channel-dependent variability may contribute to this phenotype. Rather than establishing a complete multiscale causal framework, our study defines a tractable cellular and dynamical entry point for investigating how subtle perturbations in intrinsic excitability may scale toward circuit dysfunction and disease-relevant phenotypes. Significance StatementLinking microscale neuronal changes to macroscale disease phenotypes remains a key challenge in neuroscience biophysics. Here, we show that neurons from Drosophila models of tauopathy and epilepsy and human iPSC-derived neurons from patients with Alzheimers disease and epilepsy share increased biophysical instability in their local neural activities. In fly neurons, this phenotype is associated with increased variability in voltage-gated sodium currents and is reduced by antiepileptic treatment. These findings define unstable local spike variability as a conserved dynamical signature across distinct disease models and nominate sodium-current variability as a mechanistically testable, pharmacologically reversible contributor to pathological excitability.

neuroscience↗

bioRxiv2024

Neuropeptide-dependent spike time precision and plasticity in circadian output neurons

Circadian rhythms influence various physiological and behavioral processes such as sleep-wake cycles, hormone secretion, and metabolism. In Drosophila, an important set of circadian output neurons are called pars intercerebralis (PI) neurons, which receive input from specific clock neurons called DN1. These DN1 neurons can further be subdivided into functionally and anatomically distinctive anterior (DN1a) and posterior (DN1p) clusters. The neuropeptide diuretic hormones 31 (Dh31) and 44 (Dh44) are the insect neuropeptides known to activate PI neurons to control activity rhythms. However, the neurophysiological basis of how Dh31 and Dh44 affect circadian clock neural coding mechanisms underlying sleep in Drosophila is not well understood. Here, we identify Dh31/Dh44-dependent spike time precision and plasticity in PI neurons. We first find that a mixture of Dh31 and Dh44 enhanced the firing of PI neurons, compared to the application of Dh31 alone and Dh44 alone. We next find that the application of synthesized Dh31 and Dh44 affects membrane potential dynamics of PI neurons in the precise timing of the neuronal firing through their synergistic interaction, possibly mediated by calcium-activated potassium channel conductance. Further, we characterize that Dh31/Dh44 enhances postsynaptic potentials in PI neurons. Together, these results suggest multiplexed neuropeptide-dependent spike time precision and plasticity as circadian clock neural coding mechanisms underlying sleep in Drosophila.

neuroscience↗