Rieger, S. | Search bioRxiv

bioRxiv2019

Short-wavelength violet light (420nm) stimulates melanopsin-dependent acute alertness responses in zebrafish

Sunlight throughout the day and seasons strongly influences our biological rhythms and activity. In recent years, it has become evident that night-time overexposure to bright light in urban environments can profoundly affect physiology and behaviour in humans and animals. In particular, the artificial emission of short-wavelength light has been shown to stimulate alertness in humans, but the mechanisms remain largely unknown. Utilising a diurnal larval zebrafish model, we identified instant, non-image-forming (NIF) responses to short-wavelength violet light (~420nm), which are activated only during light exposure, and are reminiscent of alertness, including increased heart rate, enhanced locomotor activity, and pectoral fin beating (for increased oxygen supply). We further determined that these responses are driven by sympathetic neuronal circuits and depend on the zebrafish melanopsin homologue Opn4a. We also found that these responses can be modulated by the sleep-regulatory hormone melatonin, but that melatonin is not essential. Our findings reveal a previously unknown mechanism for violet light-dependent acute alertness.

animal behavior and cognition↗

bioRxiv2019

Paclitaxel-induced peripheral neuropathy is caused by epidermal ROS and mitochondrial damage through conserved MMP-13 activation

Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy (PIPN) as a side effect of cancer treatment. Severely affected patients need to terminate chemotherapy, diminishing their chance of survival. The underlying causes of PIPN are unclear, but epidermal, unmyelinated axons have been shown to be the first to degenerate. We previously utilized a zebrafish in vivo model to show that the epidermal matrix-metalloproteinase 13 (MMP-13) induces degeneration of unmyelinated axons, whereas pharmacological inhibition of MMP-13 prevented axon degeneration. The precise functions by which MMP-13 is regulated and affects axons, however, remained elusive. In this study, we assessed mitochondrial damage and reactive oxygen species (ROS) formation as possible inducers of MMP-13, and we analyzed MMP-13-dependent damage. We show that the small ROS, H2O2, is increased in keratinocytes following treatment with paclitaxel. Epidermal mitochondrial damage appears to be a source of ROS leading to cytoplasmic H2O2 elevation, upregulation of MMP-13, and increased matrix degradation. Intriguingly, although axonal mitochondria also show aberrant morphologies and are vacuolized, as shown in other neuropathies, these axonal mitochondria do not produce increased H2O2 levels. We suggest that mitochondrial vacuolization occurs independently of axonal damage given that MMP-13 inhibition prevents axon degeneration, though vacuoles persist. We further show that MMP-13 dysregulation also underlies PIPN in rodent paclitaxel models, and that this function appears to be DRG neuron-extrinsic. These findings suggest that vacuolization is not a cause of paclitaxel-induced neuropathy, and that epidermal MMP-13 is a strong candidate for therapeutic interventions in cancer patients with neuropathy.

pathology↗