Neuromodulation of memory networks in Drosophila melanogaster

Thesis

Animals dynamically express memory in a state-dependent manner to align their behaviour with their physiological needs. Drosophila melanogaster fruit flies act on learnt food-associated odours when they are hungry. At the core of this behaviour is the Mushroom Body (MB), which is their centre for learning and memory. The MB is innervated by dopaminergic neurons (DANs) that represent the valence of different stimuli to drive behaviour. While the connectome maps the wired synaptic connections, the mechanisms enabling flexible, state-dependent memory expression suggest regulation by a parallel neuromodulatory network. In this thesis, I show that the different DAN subsets are not just anatomically heterogeneous but have diverse transcriptomes, and together, they function as a dynamic network regulating distinct phases of memory. By leveraging the single-cell transcriptome, I explore a functional role of monoamine and neuropeptide receptors that are expressed in distinct reward-encoding protocerebral anterior medial (PAM) DAN subsets. I show that the different PAM DAN subsets are required for distinct phases of memory that are modulated by discrete novel neuromodulatory mechanisms. I uncover a new long-term memory (LTM) role for octopamine receptors, which have previously been thought to only regulate short-term memory (STM), and demonstrate a novel LTM role for the orphan receptors CG32547 and CG13995 in different PAM DANs. Furthermore, I determine that Neuropeptide F receptor - fly homologue of the mammalian Neuropeptide Y receptor - is required specifically in the 𝛂1 PAM DANs for hunger state-dependent LTM expression. Finally, I show how AlphaFold 3 can be used to screen for potential neuropeptide ligands for the two identified orphan receptors. Taken together, my thesis demonstrates how known and novel neuromodulators act on specific subsets of DANs to fine-tune behaviour at distinct timepoints and internal states, revealing how the fixed synaptic network and dynamic neuromodulatory mechanism work in parallel to drive essential behaviours.

Authors: Choi, JTY

• DOI: 10.5287/ora-ppd6rd0bz
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: dopamine; neuromodulation; drosophila melanogaster; learning and memory; g-protein coupled receptors; mushroom body
• Subjects: Memory; Neuroscience; Learning in animals; Animal behavior genetics