Octopamine mediates sugar relief from a chronic- stress-induced depression-like state in Drosophila

Chronic, uncontrollable stress can result in psychiatric syndromes, including anxiety and major depressive disorder, in humans and mammalian disease models.1,2 Similarly, several days of chronic stress can induce depression-associated behavioral alteration in Drosophila accompanied by changes in biogenic amine levels in the adult brain.3-6 In our chronic stress paradigm, flies are subjected to 3 days of repetitive phases of 300 Hz vibrations combined with overcrowding and food deprivation. This treatment reduces voluntary behavioral activity, including the motivation to climb wide gaps (risk taking) and to stop for sweets (anhe-donia), suggesting a depression-like state (DLS). These behavioral changes correlate with decreased sero-tonin release to the mushroom body (MB), a major behavioral control center in the central brain of the fly.7,8 Stressed flies are relieved from the DLS by feeding the anti-depressant serotonin precursor 5-HTP or the selective serotonin reuptake inhibitor fluoxetine. Notably, feeding sucrose to stressed flies results in elevated serotonin levels in the brain and ameliorates the DLS.3 Here, we show that this sugar relief is medi-ated by the neurotransmitter octopamine signaled from ventral unpaired medial neurons located in the sub -esophageal ganglion. The octopamine signaling of sweet sensation is transmitted to the MB via the dopami-nergic PAM neurons. In addition, neuronal-silencing experiments reveal that the serotonergic dorsal paired medial (DPM) neurons innervating the MB are essential for sugar relief. Conversely, thermogenetic or opto-genetic activation of DPMs can replace sweet sensation, elucidating that serotonergic signaling from DPMs takes part in positively modulating DLS-related behavioral changes.