Biology subjects

Didenko, O.

Publications and source records attributed to Didenko, O..

3 recordsLinked to original sources

bioRxiv2026

Suzetrigine-evoked analgesia is potentiated by Nav1.7 null-related opioid mechanisms.

The genetic evidence for an essential role of sodium channel Nav1.7 in human pain conditions is compelling. Unfortunately, potent selective channel blockers of Nav1.7 are not useful analgesics because they have deleterious side effects, particularly on the autonomic nervous system. Here we have evaluated the downstream mechanisms induced by Nav1.7 loss in utero. Nav1.1 compensates for loss of Nav1.7 in sensory neurons and antisense Nav1.1 oligonucleotides diminish excitability in Nav1.7 embryonic null sensory neurons. Enhanced endogenous opioid signalling contributes substantially to analgesia. This is linked to altered gene expression that potentiates opioid signalling through lowered levels of proteins that terminate G-protein signalling (RGS4 and RGS8). There is also enhanced opioid drive through increased enkephalin levels linked to lowered sodium levels in Nav1.7 null neurons. Opioid signalling is the main driver of analgesia, but enhanced potassium channel expression (KCNC4 KCNK2, KCNMB2, KCNAB3) all implicated in pain control, may also contribute to the small level of naloxone-resistant analgesia. These findings suggest a potential new route to analgesia, through mimicking the events at Nav1.7 null sensory neuron terminals. Here we demonstrate potentiation of suzetrigine-evoked analgesia with RGS antagonists alone or in combination with normally inactive doses of morphine in formalin-evoked pain and CFA-induced inflammatory pain. Intriguingly, no analgesia is observed with acute pain. Cancer pain is under investigation. These data are of potential clinical interest.

neuroscience↗

bioRxiv2026

Dorsal striatal dopamine integrates sensory and reward prediction errors to guide perceptual decisions

Perceptual decisions are shaped by expectations about sensory stimuli and rewards, learned through sensory and reward prediction errors. Dopamine is known to convey reward prediction errors that shape perceptual decisions. However, whether dopamine also signals sensory prediction errors during perceptual decision-making remains unknown. We recorded dopamine release in the dorsal striatum of mice performing a visual decision-making task while manipulating sensory and reward expectations. The two manipulations produced similar behavioral biases but elicited opposite dopamine signals, indicating that dopamine within the same striatal region encoded both sensory and reward prediction errors. Sensory prediction error signaling was specific to dopamine as striatal acetylcholine showed no such error signals. Optogenetically stimulating striatal dopamine at stimulus onset biased subsequent perceptual decisions, consistent with updating sensory expectations. A computational model learning from both sensory and reward prediction errors captured behavioral biases and dopamine data, revealing distinct but spatially overlapping dopaminergic teaching signals.

neuroscience↗

bioRxiv2025

Evolution of sensory systems underlies the emergence of predatory feeding behaviours in nematodes

Understanding how animal behaviour evolves remains a major challenge, with few studies linking genetic changes to differences in neural function and behaviour across species. Here, we identify specific sensory adaptations associated with the emergence of predatory feeding behaviours in the nematode Pristionchus pacificus. While Caenorhabditis elegans uses contact-dependent sensing primarily to avoid threats, Pristionchus pacificus has co-opted this modality to support both avoidance and prey detection, enabling context-dependent predatory behaviour. To uncover a potential mechanism underlying the evolution of P. pacificus prey perception, we mutated 27 canonical mechanosensory genes and assessed their function using behavioural assays, automated behavioural tracking, and a machine learning analysis of behavioural states. While several mutants showed mechanosensory defects, Ppa-mec-6 mutants specifically also impaired prey detection, indicating the emergence of a novel mechanosensory module linked to predatory behaviour. Furthermore, disrupting both mechanosensation alongside chemosensation revealed a synergistic influence for these modalities. Crucially, both mechanosensation and chemosensation pathways converge in the same environmentally exposed IL2 neurons, and silencing these cells induced severe predation defects validating their importance for prey sensing. Thus, predation evolved through the co-option of mechanosensory and chemosensory systems that act together to shape the evolution of complex behavioural traits.

neuroscience↗