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

长期以来，人们一直认为昆虫的蘑菇体是嗅觉联想学习和记忆形成的中心。对黑腹果蝇MB功能的详细分析表明，对奖励气味（接近）的行为反应是通过向MB发送信号来调节的，这些信号代表了额外的外部线索（甜度、苦味、营养价值、渗透压）和内部状态（口渴、饥饿）。此外，MB还参与调节果蝇的睡眠/弱循环和温度偏好。我们最近发现，MB神经元的不同亚群促进（α/β-凯尼恩细胞）或抑制（γ-凯尼恩细胞）发起自发行为的动机，如运动、求偶或爬隙，这表明昆虫的MB实现了与小鼠和人类的边缘系统类似的功能。为了证实这一解释，我们开发了一种压力方案，通过将苍蝇置于无法控制的振动压力下数天，以减少动力。反复应激导致5-羟色胺能（5-HT）信号传导到α/β-神经元的减少；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（广泛用于抑郁症治疗）治疗应激果蝇，可以恢复动机。因此，我们的果蝇模型可与脊椎动物的模型相媲美，其中海马中5-羟色胺信号的减少被认为是抑郁样行为的一个原因。此外，果蝇的抑郁样状态可以通过喂食糖（有或没有热值）或情绪稳定剂氯化锂（LiCl）来改善。在拟议的项目中，我们的目标是扩大我们对血清素能信号在调节果蝇动机中的作用的分析。我们将讨论5-羟色胺是否在调节动机中起一般作用，以及MB的信号是否总是参与其中。在发现MB影响睡眠驱动的基础上，我们还想研究睡眠稳态在调节动机中的作用。具体来说，我们将询问慢性睡眠剥夺是否会降低自愿行为的动机，以及5-HT信号是否参与其中。此外，我们想要确定果蝇中整合压力的神经网络，以及传递对糖和氯化锂治疗提供的压力的恢复力和缓解的神经通路。值得注意的是，高水平的LiCl诱导了过度的攀登间隙的动机，这表明α/β-神经元的过度激活。我们将使用我们的“躁狂抑郁”行为的苍蝇模型来阐明动机的神经元基础，特别关注蘑菇体内的神经生理过程。

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.