Regulation of sleep circuits by the Drosophila serotonin transporter

Serotonin regulates a variety of complex behaviors in both mammals and invertebrates including sleep. The extracellular serotonin level available for signaling to post-synaptic receptors determines the activity of most, if not all underlying circuits. The plasma membrane Serotonin Transporter (SERT) is responsible for reuptake of serotonin after exocytotic release and therefore represents the primary mechanism for regulating extracellular serotonin levels. To date, the mechanisms by a which a decrease in SERT activity and the subsequent increase in extracellular serotonin alters circuit function and behavior remain poorly understood. Drosophila represents a powerful model to address this issue, but the requisite genetic tools have remained underdeveloped. We have addressed this issue by generating new tagged and/or mutant alleles of the Drosophila Serotonin Transporter (dSERT) and a subset of serotonin receptors. In Aim 1 we will use these lines to explore potential heterogeneities in the pathways by which dSERT regulates sleep and determine whether loss of dSERT activity during development can influence adult sleep. Both issues have broad translational relevance. In Aim 2 we will map for the first time, the location of serotonergic autoreceptors in the fly. We will then determine whether a serotonergic autoreceptor we have identified regulates sleep. In Aim 3 we will probe specific subsets of post-synaptic neurons in the mushroom bodies for potential changes in gene expression. We will use genetic tools that surpass the level of detail available in mammalian systems. These data will provide fundamental information about the mechanisms by which SERT can influence a translationally relevant behavior. We speculate that the principles we uncover will be relevant to both sleep as well as other complex behaviors regulated by serotonin and SERT. Project Number: 1R01MH139938-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: David Krantz | Institution: UNIVERSITY OF CALIFORNIA LOS ANGELES, LOS ANGELES, CA | Award Amount: $662,437 | Activity Code: R01 | Study Section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298110