Consequences of Altered Dopamine Signaling on the Serotonin Circuitry in Drosophila

神经元具有共同的特征，如电兴奋性和神经元间的突触通讯。然而，神经元网络中的个体实体在发育过程中表现出广泛的多样性，这是由内在的细胞程序和复杂的顺序机制形成的，从而确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在不发生细胞分裂的情况下稳定地将细胞从一个谱系重编程到另一个谱系。这就提出了一个问题，即神经元的同一性和多样性是否可以在大脑发育的背景之外进行修改。并且，重编程是否可能发生在神经退行性变后的神经元回路的神经元实体中，例如帕金森病（PD），从而补偿退行性神经元回路中相互作用伙伴的神经元损失。PD源于多巴胺能黑质纹状体系统的进行性退化，最终导致运动控制能力下降。此外，6-羟多巴胺处理的大鼠缺乏DA信号可以促进纹状体中5 -羟色胺神经元的生长。最近，我们在果蝇中观察到，在完全发育的果蝇大脑中，多巴胺信号的改变导致血清素神经元投射到目标神经粒的改变。此外，我们发现多巴胺信号的缺失导致少量产生多巴胺的神经元中血清素免疫反应性增加。这一观察结果可以推测，神经元实体的身份不仅依赖于发育过程中的内在细胞程序，还可能依赖于其完全发育的神经元网络中的环境线索。该研究项目旨在了解当多巴胺信号被操纵时，这些多巴胺/血清素共免疫反应神经元中观察到的变化的分子机制。因此，我们将首先结合免疫组织化学、光生理学、热生神经元激活以及单细胞转录组学方法，在野生型条件下在单细胞水平上识别和表征相关神经元，并将其与DA信号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变化的神经元回路，将有助于更好地理解由于神经退行性疾病引起的神经元间通信失调，以及神经退行性疾病（如帕金森病）的药物治疗。

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.