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

长期以来，昆虫的蘑菇体一直被认为是嗅觉联想学习和记忆形成的中心。对果蝇黑腹果蝇MB功能的详细分析表明，对奖励气味的行为反应(方法)是通过向MB发出信号来调节的，这些信号代表额外的外部提示(甜味、苦味、营养价值、渗透压)和内部状态(口渴、饥饿)。此外，MB还参与调节苍蝇的睡眠/弱周期和温度偏好。我们最近发现，MB神经元的不同亚群促进(α/β-Kenyon细胞)或抑制(γ-Kenyon细胞)发起运动、求偶或攀登缺口等自愿行为的动机，这表明昆虫的MB履行类似于小鼠和人类的边缘系统的功能。为了证实这一解释，我们开发了一种应激方案，让苍蝇在几天内经历不可控的振动应激，以减少动机。反复应激导致对α/β神经元的5-羟色胺能(5-HT)信号的减少，特别是MB的α叶中的5-HT1a受体。用5-羟色胺前体5-羟基-L-色氨酸或选择性5-羟色胺再摄取抑制剂氟西汀治疗应激果蝇，可以恢复动力。氟西汀广泛用于抑郁症治疗。因此，我们的苍蝇模型与脊椎动物的模型相当，在脊椎动物的模型中，海马体中5-羟色胺信号的减少被认为是抑郁症样行为的一个原因。此外，果蝇的抑郁状态可以通过喂食糖(有没有卡路里的价值)或情绪稳定剂氯化锂(LiCl)来改善。在拟议的项目中，我们的目标是扩展我们对5-羟色胺能信号在调节果蝇动机中的作用的分析。我们将解决以下问题：5-羟色胺是否在调节动机中起着普遍作用，是否总是涉及MB的信号传递或信号传递。基于MB影响睡眠驱动力的发现，我们还想调查睡眠稳态在调节动机中的作用。具体地说，我们将询问长期睡眠剥夺是否会降低执行自愿行为的动机，以及是否涉及5-羟色胺信号传递。此外，我们想要确定整合果蝇应激的神经网络，以及传递糖和氯化锂治疗所提供的应激的弹性和缓解的神经通路。值得注意的是，高水平的氯化锂诱导了攀登缺口的过度动机，表明α/β神经元过度激活。我们将使用“躁狂抑郁”行为的苍蝇模型来阐明动机的神经基础，特别关注蘑菇体中的神经生理过程。

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.