Investigating how serotonin and dopamine shape sensory cue integration in the Drosophila head direction network

PROJECT SUMMARY Several neurophysiological disorders are linked to inappropriate levels of serotonin (5-HT) and dopamine (DA), and treatments for these disorders are typically designed around re-adjusting the levels of their respective neurotransmitter. 5-HT and DA play complex roles in the nervous system, yet the precise functions that they serve across various brain regions and within specific neural circuits is still poorly understood. A deeper understanding of how these two monoamines modulate circuit function will likely improve the development of safer and more effective therapies for 5-HT- and DA-related disorders. This proposal seeks to understand the modulatory roles that both 5-HT and DA serve in a very well-defined and tractable neural circuit, the head direction (HD) network of the fruit fly Drosophila melanogaster. In the fly HD network, heading representation is stored in the activity of E-PG neurons, whose dendrites tile a donut-shaped neuropil region of the brain called the ellipsoid body (EB); this arrangement remarkably mimics a compass needle, wherein a ‘bump’ of E-PG activity swings around the EB as the fly turns. E-PG bump position is updated in part by sensory information transmitted through different classes of ring neurons. Each ring neuron sends projections uniformly throughout the EB, contacting E-PGs at every position of the “compass,” strongly indicating that ring–E-PG connections are plastic: without different synaptic weights between ring and E-PG neurons, sensory inputs would lose spatial information. Prior work by my sponsor demonstrated that ring–E-PG connections are indeed plastic, and that dopaminergic input to the EB, via the ExR2 neurons, enhances plasticity during fly turns, when spatial information is presumably rich. Another set of neurons, called ExR3, are serotonergic and have strong projections to the EB, and RNA sequencing data suggests that E-PGs and at least one class of ring neuron express 5-HT receptors. However, the function of 5-HT in this network remains unexplored. In Aim 1, I will test the hypothesis that ExR3 release of 5-HT is important for ring–E-PG plasticity. I will measure the likelihood that a new angular offset between the E-PG bump position and the visual scene can be established (i.e., if ‘re- mapping’ can occur), using an optogenetic ‘write-in’ protocol, and I will ask whether gain or loss of 5-HT can enhance or inhibit successful re-mapping. Then, I will measure calcium activity of ExR3 neurons while flies fictively navigate in VR to determine the behavioral correlates of ExR3 activity, when 5-HT-mediated plasticity is likely to be evoked. In Aim 2, I will test the hypothesis that DA and 5-HT, via ExR2 and ExR3, modulate the activities of distinct classes of ring neurons and thereby transiently adjust relative sensory cue importance in updating the compass at behaviorally relevant moments. To test this, I will first survey the distribution of both 5- HT and DA receptors among the different classes of ring neurons using in situ hybridization. I will then ask whether activation or inhibition of ExR2 and ExR3 can bias the HD network’s preference toward one of two discordant sensory cues, revealing a 5-HT- or DA-mediated shift in cue preference.