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This study combines detailed synapse resolution connectivity analysis with mapping of serotonin receptor expression to reveal an inhibitory subnetwork that is the target of serotonergic neurons within the olfactory system of Drosophila. Using neurophysiology and computational modeling, the differential effects of serotonin on this inhibitory subnetwork are posited to provide a mechanism for noise reduction in odor representations. 

<bold>Abstract</bold> Across the animal kingdom, olfactory dysfunction and anosmia have been associated with disruptions in sleep. In the fruit flyDrosophila melanogaster, various studies have demonstrated that broadly inhibiting olfactory receptor neurons (ORNs) similarly disrupts sleep/wake cycles, suggesting that baseline ORN signaling is an integral component of olfactory modulation of sleep. However, due to the diversity of ORNs and combinatorial nature of olfactory processing, many of the cellular and molecular mechanisms by which ORNs modulate sleep remain unclear. In this study, we addressed this gap of knowledge by characterizing the contributions of different ensembles of ORNs, individual ORN types, and a known modulator of ORNs on baseline sleep architecture. We find that the activity of distinct ORN types are important for day and nighttime sleep and heterogeneously shape parameters of sleep architecture. Importantly, the effects of ORN signaling on sleep are adjusted across mating status, suggesting that distinct ORN types are recruited within the context of sleep depending on the demands of the animal. Furthermore, the effects of ORN signaling on sleep are in part shaped by heterogeneous serotonin (5-HT) receptor expression. Together, this work identifies cellular and molecular pathways bridging olfaction and sleep, and helps establish a circuit model that can be used to further characterize the behavioral consequences of sensory dysfunction. 

ABSTRACT Animals are driven to maximize food rewards and adjust their behavior to seek high-quality food and avoid low-quality options. This holds true for Drosophila melanogaster, which approaches food-associated odors and tastes while avoiding aversive ones. Despite its importance for understanding motivation, how voluntary olfactory and gustatory experiences shape fly interactions with these stimuli over time remains unclear. Here, we investigate how stimuli shape volitional behavior using our novel operant learning assay (Open-LA), which tracks individual flies as they enter/exit a region of stimuli self-administration. We analyzed the behaviors flies demonstrated when they control access to an aversive or appetitive odor or taste and analyzed how these behaviors were shaped by experience. As predicted, flies pursued apple cider vinegar and avoided benzaldehyde and showed rapid operant learning for both odors. Flies also self-administered both simulated sweet and bitter taste, which slightly altered aversive odor responses, but did not strongly enhance odor-based operant learning. These data suggest olfaction is the primary sense guiding volitional behaviors and provides a behavioral framework for examining how animals pursue positive and avoid negative stimuli. 

Natural behaviors are a coordinated symphony of motor acts that drive reafferent (self-induced) sensory activation. Individual sensors cannot disambiguate exafferent (externally induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to carry out adaptive behaviors through corollary discharge circuits (CDCs), which provide predictive motor signals from motor pathways to sensory processing and other motor pathways. Yet, how CDCs comprehensively integrate into the nervous system remains unexplored. Here, we use connectomics, neuroanatomical, physiological, and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs) in Drosophila, which function as a predictive CDC in other insects. Both AHN pairs receive input primarily from a partially overlapping population of descending neurons, especially from DNg02, which controls wing motor output. Using Ca2+ imaging and behavioral recordings, we show that AHN activation is correlated to flight behavior and precedes wing motion. Optogenetic activation of DNg02 is sufficient to activate AHNs, indicating that AHNs are activated by descending commands in advance of behavior and not as a consequence of sensory input. Downstream, each AHN pair targets predominantly non-overlapping networks, including those that process visual, auditory, and mechanosensory information, as well as networks controlling wing, haltere, and leg sensorimotor control. These results support the conclusion that the AHNs provide a predictive motor signal about wing motor state to mostly non-overlapping sensory and motor networks. Future work will determine how AHN signaling is driven by other descending neurons and interpreted by AHN downstream targets to maintain adaptive sensorimotor performance. 

The serotonergic system has been widely studied across animal taxa and different functional networks. This modulatory system is therefore well positioned to compare the consequences of neuromodulation for sensory processing across species and modalities at multiple levels of sensory organization. Serotonergic neurons that innervate sensory networks often bidirectionally exchange information with these networks but also receive input representative of motor events or motivational state. This convergence of information supports serotonin’s capacity for contextualizing sensory information according to the animal’s physiological state and external events. At the level of sensory circuitry, serotonin can have variable effects due to differential projections across specific sensory subregions, as well as differential serotonin receptor type expression within those subregions. Functionally, this infrastructure may gate or filter sensory inputs to emphasize specific stimulus features or select among different streams of information. The near-ubiquitous presence of serotonin and other neuromodulators within sensory regions, coupled with their strong effects on stimulus representation, suggests that these signaling pathways should be considered integral components of sensory systems.