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An axis between brain and fat body regulates pathogen avoidance behavior in Drosophila

Year: 2025
Type: dissertation
Abstract: Animals must balance the nutritional benefits of food with the potential risks of infection. While sensory cues are crucial to detect external threats, internal immune responses to ingested pathogens can drive long-lasting changes in feeding behavior, such as learned food aversion, a conserved adaptive strategy. However, the mechanisms by which how pathogen detection via the peripheral immune system is signal to the brain to influence behavior remains unclear. To shed light on this question, this thesis investigates how Drosophila melanogaster integrate immune signals with neuromodulation to shape feeding decisions. Our lab previously showed that flies can distinguish between pathogenic and non-pathogenic bacteria using the immune deficiency (IMD) pathway (Kobler, 2020; Kobler et al., 2020). This pathway is activated by peptidoglycan recognition proteins (PGRPs), particularly PGRP-LC, in both the fat body (a liver-like organ) and a set of neurons called octopaminergic neurons (OANs) that release octopamine (OA), the insect analog of adrenaline (Kobler, 2020; Kobler et al., 2020). Building on these findings, I examined the mechanisms underlying learned food aversion via activation of the immune system. Using the flyPAD feeding choice behavioral assay, I found that flies prefer harmless over pathogenic Pseudomonas entomophila (Pe). This aversion was lost in flies lacking antimicrobial peptides, particularly Diptericin B (DptB) and tissue-specific knockdown experiments showed that DptB is required in both the fat body and OANs, but not in the gut. Interestingly, confocal imaging revealed direct projections from OANs to fat body cells. To interrogate their physiological function, I used the GRASP technique to confirm close spatial proximity of OAN terminals and fat body cells indicating potential synaptic contacts. Finally, calcium imaging of fat body explants showed that OAN activation, via OA application or optogenetic stimulation, elicits neuromodulatory responses in the fat body. To further dissect the molecular mechanism underlying this pathogen-induced changes in feeding behaviopr, I performed tissue-specific RNA sequencing to uncover transcriptional changes following bacterial ingestion. Interestingly, I found that DptB was upregulated in the head and a similar, yet not significant, trend was observed in the fat body, consistent with behavioral findings. Notably, tyrosine hydroxylase (ple), the rate-limiting enzyme for dopamine (DA) synthesis, was also upregulated in the fat body. Although canonical dopamine neurons were not required for the aversive response, targeted knockdown of ple in the fat body disrupted this behavior indicating a non-canonical role of dopamine in this pathway. Using a dopamine specific sensor (GRAB-DA), I uncovered that dopamine is released from fat body explants upon OAN stimulation. To reveal the downstream targets of this fat body dopamine release, I performed a dopamine receptor screening, which revealed that Dop1R1 in mushroom body output neurons is required for feeding aversion to pathogenic bacteria. The mushroom body, a central brain structure for learning and memory in flies, thus emerges as the site where peripherally derived dopamine alters behavior. Together, these results uncover a novel neuroimmune pathway in which pathogen detection activates PGRP-LC in OANs, which relay signals to the fat body, triggering dopamine release. This fat-derived dopamine then acts on the mushroom body to drive learned avoidance of harmful food.
DOI: 10.48565/bonndoc-683
Author: Wang, Yujie
Institution: University of Bonn
Language: English
Open Access status: green
OpenAlex ID: W7086868171
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