Ferry, F. S. | bioRxiv Science

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

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↗