Neuromodulatory control of sleep in Drosophila melanogaster: integration of competing and complementary behaviors

Abstract

The transition between wake and sleep states is characterized by rapid and generalized changes in both sensory and motor processing. Sleep is antagonistic to the expression of important behaviors, like feeding, reproduction and learning whose relative importance to an individual will depend on its circumstances at that moment. An understanding of how the decision to sleep is affected by these other drives and how this process is coordinated across the entire brain remains elusive. Neuromodulation is an important regulatory feature of many behavioral circuits and the reconfiguring of these circuits by modulators can have both long-term and short-term consequences. Drosophila melanogaster has become an important model system for understanding the molecular and genetic bases of behaviors and in recent years neuromodulatory systems have been shown to play a major role in regulation of sleep and other behaviors in this organism. The fly, with its increasingly well-defined behavioral circuitry and powerful genetic tools, is a system poised to provide new insight into the complex issue of how neuromodulation can coordinate situation-specific behavioral needs with the brain's arousal state.

Figure 1. Neuromodulation can cause state-dependent changes in neuronal function

When an animal falls asleep, there is an increase in sensory arousal thresholds that is believed in mammals to occur by alterations in thalamic processing. Motor outputs are also suppressed. Arousal, in contrast, reduces sensory thresholds and facilitates motor output. Neuromodulation may have a role in state changes by acting at multiple sites within these circuits. Pro-arousal and pro-sleep neuromodulators in theory may act in antagonistic manners on the same neurons or may act at distinct points in the circuit.

Figure 2. Summary of behaviors and neuromodulators known to regulate sleep in Drosophila

While only a few of the known neuromodulators in Drosophila have been shown to regulate sleep, these agents affect a diverse array of other systems. All of these modulators have important roles in regulating a non-sleep behavior (indicated by small gray arrows), but they all also have a role in sleep (indicated by large arrows). There are a number of neuromodulators in cells of the core clock circuit. To date, only Pigment Dispersing Factor (PDF) has been shown to directly affect sleep, but there is reason to believe that there are also pro-sleep clock cells which could be neuromodulatory. Feeding and metabolism are regulated by peptidergic cells of the pars intercerebralis. This diverse cell group has been shown to both positively and negatively regulate sleep although the transmitters or modulators underlying these effects are unknown. The circuitry underlying memory formation has been extensively studied, and modulators of this process can regulate both the amount and structure of sleep. Dopamine (DA) is a pro-arousal substance released from multiple neurons in the central brain which is also critical for reinforcement in associative learning. The amnesiac (Amn) gene product and serotonin (5HT) are both found in the dorsal paired medial neurons which are necessary for memory consolidation. Olfactory discovery of opportunities for reproductive behavior can acutely decrease sleep. For females, mating can decrease daytime sleep via actions of SP which is transferred from males in ejaculate. It is unknown if mating or reproductive behaviors can increase sleep.