Modulation of Reproductive Behaviour by Neuropeptides in Drosophila

在黑腹果蝇中，神经系统的性别由性别决定层次的两个末端基因指定：fruitless（fru）和doubletex（dsx）。在发育过程中，Fru和Dsx蛋白协同作用，建立了专门用于产生性别特异性行为的性二态性神经回路。虽然这些生殖行为本身是遗传“硬连线”神经回路的产物，但这些行为的显著灵活性在两性中都很明显。这使得男性和女性能够改变他们的行为，并在竞争行为之间切换，以应对他们的环境和内部状态。这种能力是由许多调节机制的存在产生的，这些调节机制能够检测和整合内部和外部感觉线索，并相应地改变神经回路功能，从而在回路输出中产生适当的变化。在许多物种中，神经肽是神经网络活动和行为的关键调节剂。在黑腹果蝇中，神经肽SifAMIDE已被证明在调节包括生殖在内的几种行为中发挥重要作用。例如，在雄性中敲除肽导致它们不仅向雌性而且向其他雄性展示求爱。此外，敲低由fru基因指定的雄性特异性神经回路中的西夫酰胺受体同样会导致对两性的不加选择的求爱。根据这些发现，有人认为，西夫酰胺可以调节雄性求爱的神经回路，以确保行为仅在适当的环境下产生，即有接受性雌性存在。然而，虽然西福酰胺似乎对调节雄性求偶很重要，但其作用机制仍然难以捉摸。首先，尚不清楚西夫酰胺在相关电路中的作用。它可以调节通常促进或抑制求偶的感觉线索的早期检测和处理。或者，西夫酰胺可以作用于高阶决策中心，这些决策中心整合多感官外部和内部信息，并选择适当的行为输出。西夫酰胺还可以调节产生求偶序列的运动神经元的活动。其次，虽然已知该肽通过G蛋白偶联受体发出信号，但该受体下游的细胞途径尚未被表征。因此，尚不清楚西夫酰胺对神经元活动的影响。最后，对西夫酰胺释放的上游事件仍然知之甚少。例如，尚不清楚是什么触发肽的释放以及其释放是组成性的还是由特定事件/感觉线索调节。这项工作的最初目的是研究SIFAMIDE调节雄性求偶行为的机制。这将涉及使用复杂的遗传工具来靶向和操纵定义的神经元子集。将这些工具与行为、解剖学和生理学技术相结合，将使SifAMIDE神经元和求偶回路之间的物理和功能连接得以表征，并将阐明肽调节回路功能以调节行为的机制。在这样做的过程中，这项研究将阐明许多物种行为灵活性的关键过程。

In Drosophila melanogaster, the sex of the nervous system is specified by two terminal genes of the sex determination hierarchy: fruitless (fru) and doublesex (dsx). During development, Fru and Dsx proteins act in concert to establish sexually dimorphic neural circuits dedicated to the production of the sex-specific behaviours. While these reproductive behaviours are, as such, the product of genetically 'hardwired' neural circuitry, a capacity for significant flexibility in these behaviours is evident in both sexes. This allows males and females to alter their behaviour, and switch between competing behaviours, in response to their environment and internal state. This capacity is engendered by the existence of numerous modulatory mechanisms able to detect and integrate internal and external sensory cues and alter neural circuit function accordingly, producing appropriate changes in circuit output. In many species, Neuropeptides are key modulators of neural network activity and thus behaviour. In D.melanogaster, the Neuropeptide SifAMIDE has been shown to play an important role in regulating several behaviours including reproduction. For instance, knockdown of the peptide in males causes them to display courtship not only towards females but also towards other males. Moreover, knockdown of the SifAMIDE receptor in male specific neural circuitry specified by the fru gene similarly results in indiscriminate courtship toward both sexes. In light of these findings, it has been suggested that SifAMIDE may modulate the neural circuits underlying male courtship to ensure that behaviour is produced only in the appropriate context, I.e. the presence of a receptive female. However, while SifAMIDE appears to be important for regulating male courtship, the mechanisms by which it does so remain elusive. Firstly, it is unclear where SifAMIDE acts within the relevant circuitry. It could modulate the early detection and processing of sensory cues that normally promote or inhibit courtship. Alternatively, SifAMIDE could act on higher order decision making centres that integrate multisensory external and internal information and select appropriate behavioural outputs. SifAMIDE could also modulate the activity of the motor neurons that produce the courtship sequence. Secondly, while the peptide is known to signal through a G protein coupled receptor, the cellular pathways downstream of the receptor are, as yet, uncharacterised. Therefore, it is unclear what affect SifAMIDE has on neuronal activity. Finally, the events upstream of SifAMIDE release remain poorly understood. For example, it is not clear what triggers the release of the peptide and whether its release is constitutive or is regulated by specific events/sensory cues. The initial aim of this work will be to investigate the mechanisms by which SIFAMIDE modulates male courtship behaviour. This will involve the use of sophisticated genetic tools to target and manipulate defined sub sets of neurons. Combining these tools with behavioural, anatomical and physiological techniques will allow physical and functional connectivity between SifAMIDE neurons and courtship circuitry to be characterised, and will elucidate the mechanisms by which the peptide modulates circuit function to regulate behaviour. In so doing, this study will shed light upon a process crucial for behavioural flexibility in many species.