Consequences of Altered Dopamine Signaling on the Serotonin Circuitry in Drosophila

果蝇血清素回路多巴胺信号改变的后果

• 批准号: 432219264
• 负责人: Dr. Thomas Riemensperger
• 金额: --
• 依托单位: Institut für Zoologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432219264?language=en
• 关键词: Consequences; Altered; Dopamine; Signaling; Serotonin

Neurons share common features, such as electrical excitability and synaptic inter neuron communication. However, the individual entities within a neuronal network exhibit extensive diversity shaped by intrinsic cellular programs and elaborate sequential mechanisms during development, specifying their neuronal identity. Recently, it was shown that transient overexpression of transcription factors can stably reprogram cells from one lineage to another without cell division. This raises the question whether neuronal identity and diversity may be modified outside the context of development of the brain. And, whether reprogramming may occur in neuronal entities of neuronal circuits subsequently to neuro-degeneration, e.g. Parkinson’s disease (PD), allowing for compensation of neuronal loss of their interaction partners within the degenerating neuronal circuit. PD results from a progressive degeneration of the dopaminergic nigrostriatal system, ultimately leading to a decline in movement control. Moreover, lack of DA signaling in 6-hydroxydopamine treated rats promotes the growth of serotonin neurons in the striatum.Recently, we observed in flies that altered dopamine signaling leads to modifications of serotonin neuron projections onto their target neuropils in the fully developed Drosophila brain. In addition, we found that absent dopamine signaling leads to increased serotonin immunoreactivity in a small number of dopamine producing neurons. This observation allows for speculations that the identity of a neuronal entity does not solely dependent on intrinsic cellular programs during development but may also depend on environmental cues within its fully developed neuronal network. The proposed research project aims at understanding the molecular mechanisms that underly these observed alterations in these dopamine / serotonin co-immunoreactive neurons when dopamine signaling is manipulated. Therefore, we will first employ a combination of immunohistochemistry, optophysiology, thermogenetic neuron activation, as well as single cell transcriptomics methods to identify and characterize the implicated neurons at a single cell level under wild type conditions and compare them to animals with altered DA signaling. Studying the neuronal circuits that compensate for alterations in signaling among different neuro-transmitters within the same circuit will help a better understanding maladaptive interneuron communication due to neuro-degeneration, as well as pharmacological treatment of neurodegenerative diseases, such as Parkinson’s disease.

神经元具有共同的特征，如电兴奋性和突触间神经元通信。然而，神经元网络中的个体实体表现出广泛的多样性，这些多样性是由内在的细胞程序和发育过程中的复杂顺序机制形成的，从而指定了它们的神经元身份。最近，研究表明转录因子的瞬时过表达可以稳定地将细胞从一个谱系重编程为另一个谱系，而无需细胞分裂。这就提出了一个问题，即神经元的身份和多样性是否可以在大脑发育的背景下进行修改。并且，重编程是否可以发生在神经元回路的神经元实体中，随后发生神经元变性，例如帕金森病（PD），从而允许在变性的神经元回路内补偿其相互作用伴侣的神经元损失。PD是由多巴胺能黑质纹状体系统的进行性变性引起的，最终导致运动控制能力下降。此外，在6-hydroxydopamine处理的大鼠中缺乏DA信号促进了纹状体中5-羟色胺神经元的生长。最近，我们在果蝇中观察到，在完全发育的果蝇脑中，改变的多巴胺信号导致5-羟色胺神经元投射到其靶神经元上的修改。此外，我们发现，缺乏多巴胺信号导致增加血清素免疫反应在少数多巴胺产生神经元。 这一观察结果允许推测，神经元实体的身份不仅取决于内在的细胞程序在发展过程中，但也可能取决于其充分发展的神经元网络内的环境线索。拟议的研究项目旨在了解当多巴胺信号被操纵时，这些多巴胺/5-羟色胺共免疫反应神经元中观察到的变化的分子机制。因此，我们将首先采用免疫组织化学，光生理学，热神经元激活，以及单细胞转录组学方法的组合，以确定和表征野生型条件下在单细胞水平上的牵连神经元，并将它们与DA信号转导改变的动物进行比较。研究补偿同一回路内不同神经递质之间信号改变的神经元回路将有助于更好地理解由于神经变性引起的适应不良的神经元间通信，以及神经退行性疾病（如帕金森病）的药物治疗。