Consequences of Altered Dopamine Signaling on the Serotonin Circuitry in Drosophila

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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.