Genetic and pharmacological analysis of motivation control - manic-depressive behaviour in Drosophila

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The mushroom body (MB) of insects has been known to be a centre of olfactory associative learning and memory formation for a long time. Detailed analysis of MB function in the fruit fly Drosophila melanogaster has revealed that the behavioural response to rewarded odours (approach) is modulated through signals to the MB, representing additional external cues (sweetness, bitterness, nutritive value, osmolality) and the internal state (thirst, hunger). Moreover, the MB is involved in regulating the sleep/weak cycle and temperature preference of flies. We have recently shown that different subsets of MB neurons promote (α/β-Kenyon cells) or suppress (γ-Kenyon cells) the motivation to initiate voluntary behaviour like locomotion, courtship, or gap climbing, suggesting that the MB of insects fulfils functions like the limbic system in mice and man. To substantiate this interpretation, we have developed a stress protocol by subjecting flies to uncontrollable episodes of vibration stress over days in order to reduce motivation. Recurrent stress results in reduced serotonergic (5-HT) signalling to the α/β-neurons; specifically to the 5-HT1A receptors in the α-lobes of the MB. Treating stressed flies with the serotonin precursor 5-hydroxy-L-tryptophan or the selective serotonin re-uptake inhibitor Fluoxetine, which is widely used in depression therapy, restored motivation. Therefore, our fly model is comparable to those of vertebrates where reduced 5-HT signalling in the hippocampus is regarded as one cause of depression-like behaviour. Moreover, the depressive-like state in flies can be ameliorated by feeding sugars (with and without caloric value) or the mood stabilizer lithium chloride (LiCl). In the proposed project, we aim to extent our analysis on the role of serotonergic signalling in regulating motivation in flies. We will address the questions whether 5-HT plays a general role in modulating motivation and whether signalling of or to the MB is always involved. Based on the finding that the MB influences sleep drive, we also want to investigate the role of sleep homeostasis in modulating motivation. Specifically, we will ask whether chronic sleep deprivation will reduce motivation to perform voluntary behaviours and whether 5-HT signalling is involved. In addition, we want to identify the neuronal network that integrates stress in Drosophila, and the neuronal pathways that convey resilience to and relief from stress provided by sugar and lithium chloride treatment. Notably, high levels of LiCl induce excessive motivation to climb a gap, suggesting a hyper-activation of the α/β-neurons. We will use our fly model of “manic-depressive” behaviour to elucidate the neuronal underpinnings of motivation, with a special focus on neurophysiological processes in the mushroom body.