Pokaleva, N. | 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

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↗