Sensory integration and neuromodulatory feedback facilitate Drosophila mechanonociceptive behavior.

Nociception is an evolutionarily conserved mechanism to encode and process harmful environmental stimuli. Like most animals, Drosophila melanogaster larvae respond to a variety of nociceptive stimuli, including noxious touch and temperature, with stereotyped escape responses through activation of multimodal nociceptors. How behavioral responses to these different modalities are processed and integrated by the downstream network remains poorly understood. By combining trans-synaptic labeling, ultrastructural analysis, calcium imaging, optogenetics and behavioral analyses, we uncovered a circuit specific for mechanonociception but not thermonociception. Notably, integration of mechanosensory input from innocuous and nociceptive sensory neurons is required for robust mechanonociceptive responses. We further show that neurons integrating mechanosensory input facilitate primary nociceptive output by releasing short neuropeptide F, the Drosophila neuropeptide Y homolog. Our findings unveil how integration of somatosensory input and neuropeptide-mediated modulation can produce robust modality-specific escape behavior.

Oxytocin modulates proliferation and stress responses of human skin cells: implications for atopic dermatitis.

The neuropeptide hormone oxytocin (OXT) mediates a wide spectrum of tissue-specific actions, ranging from cell growth, cell differentiation, sodium excretion to stress responses, reproduction and complex social behaviour. Recently, OXT expression was detected in keratinocytes, but expression of its receptor and function are still unexplored in human skin. Here, we showed that both OXT and its receptor are expressed in primary human dermal fibroblasts and keratinocytes. OXT-induced dose-dependent calcium fluxes in both cell types demonstrating that the OXT receptor (OXTR) is functionally expressed. We also showed that OXT decreases proliferation of dermal fibroblasts and keratinocytes in a dose-dependent manner. In order to further investigate OXT-mediated functions in skin cells, we performed OXTR knockdown experiments. OXTR knockdown in dermal fibroblasts and keratinocytes led to elevated levels of reactive oxygen species and reduced levels of glutathione (GSH). Moreover, OXTR-depleted keratinocytes exhibited an increased release of the pro-inflammatory cytokines IL6, CCL5 and CXCL10. Our data indicate that the OXT system modulates key processes which are dysregulated in atopic dermatitis (AD) such as proliferation, inflammation and oxidative stress responses. Furthermore, we detected a downregulation of the OXT system in peri-lesional and lesional atopic skin. Taken together, these data suggest that the OXT system is a novel neuroendocrine mediator in human skin homoeostasis and clinically relevant to stressed skin conditions like AD.