The project focussed on mechanisms that control the RIS sleep neuron. The genetic dissection of upstream signaling pathways revealed that pathways that are known to control aging control the activation of RIS, Wu et al. . Core activators of RIS were shown by us to be FoxO and AMP activated Kinase. This work is important as it provided a molecular link between pathways that counteract aging and sleep. Sleep neuron activation hence is a part of the anti-aging action of longevity genes. Transcriptomic analyis of RIS-expressed genes revealed the next upstream pathway that controls RIS: EGFR signaling. We demonstrated that this pathway becomes active upon exogenous stressors such as a heat shock. This insult leads to the release of EGF, which activates EGFR in both RIS direclty as well as in the ALA neuron, which we could demostrate presents an upstream activator neuron for RIS. This work is important as it shows how stress causes tiredness and sleep by activation of an EGFR - responsive circuit, Konietzka et al. Yet another molcular signaling system that we discovered were antimicrobial peptides. We also solved a neuronal circuit that activates RIS . By perforiming translational work in mice we could demonstrate that RIS expressed genes have homologs in mammals that fullfil also sleep functions. Specifically we could show that both TFAP2a and TFAP2b control sleep in mammals, this is important as it validates the C. elegans system, Hu et al.. In the final reporting period we could show that upon wounding epidermal peptides are released and act as neuroendocrine signals to the nervous sytem to activate the sleep neuron RIS, RIS activation in turn promotes the survival and healing of the wound. Hence we could for the first time show that a signaling system exists that couples the sos signal caused by the wound to protective sleep, Sinner et al. .
