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bioRxiv · 10.64898/2026.06.05.730457

Activity-Dependent Postsynaptic Mitochondrial ROS Signaling Drives Avoidance Plasticity in C. elegans

Knight, K. M.·Lenninger, Z.·Deihl, E. W.·Doser, R. L.·Hoerndli, F. J.
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Abstract

Reactive oxygen species (ROS) are signaling molecules involved in neuronal excitatory function, with mitochondrial ROS (mitoROS) playing key roles in metabolic regulation and stress responses. Studies have shown that neuronal activity upregulates mitoROS production through oxidative phosphorylation, but it remains unclear if and how acute elevations in mitoROS influence synaptic plasticity. Here, we develop an avoidance sensitization paradigm in C. elegans using optogenetic excitation and training of nociceptive ASH neurons to initiate avoidance reversals by downstream activation of the AVA command interneurons. Using this paradigm, we show that the probability of reversal to light stimulation increases 4-hours after optogenetic training, indicating behavioral sensitization. This avoidance sensitization is accompanied by an increase of surface glutamate receptor (GLR-1) levels at ASH-AVA synapses which is dependent on postsynaptic expression of GLR-1 and active transcription. Interestingly, we find that somatic and nerve ring mitochondria produce ROS after optogenetic training. We show that this mitochondrial ROS (mitoROS) peak is dependent on postsynaptic GLR-1 and MCU-1 function during optogenetic training and is necessary for avoidance sensitization. Finally, we demonstrate that postsynaptic signaling by mitoROS in AVA is sufficient to induce avoidance sensitization. Postsynaptic photoactivation of mitochondria-targeted Killer Red in AVA, calibrated to produce the mitoROS peak observed during training, induces avoidance sensitization bypassing optogenetic training and MCU-1 requirement. Our results indicate that activity-dependent mitoROS signaling can instruct synaptic strengthening and directly modulate circuit function and behavior. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/730457v2_ufig1.gif" ALT="Figure 1"> View larger version (113K): org.highwire.dtl.DTLVardef@91f9bborg.highwire.dtl.DTLVardef@1a274b1org.highwire.dtl.DTLVardef@9b394forg.highwire.dtl.DTLVardef@cf8b7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Knight, K. M., Lenninger, Z., Deihl, E. W., Doser, R. L., Hoerndli, F. J.. 2026-06-09. Activity-Dependent Postsynaptic Mitochondrial ROS Signaling Drives Avoidance Plasticity in C. elegans. https://doi.org/10.64898/2026.06.05.730457

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