Compartment specific regulation of sleep by mushroom body requires GABA and dopaminergic signaling

Abstract

Sleep is a fundamental behavioral state important for survival and is universal in animals with sufficiently complex nervous systems. As a highly conserved neurobehavioral state, sleep has been described in species ranging from jellyfish to humans. Biogenic amines like dopamine, serotonin and norepinephrine have been shown to be critical for sleep regulation across species but the precise circuit mechanisms underlying how amines control persistence of sleep, arousal and wakefulness remain unclear. The fruit fly, Drosophila melanogaster, provides a powerful model system for the study of sleep and circuit mechanisms underlying state transitions and persistence of states to meet the organisms motivational and cognitive needs. In Drosophila, two neuropils in the central brain, the mushroom body (MB) and the central complex (CX) have been shown to influence sleep homeostasis and receive aminergic neuromodulator input critical to sleep–wake switch. Dopamine neurons (DANs) are prevalent neuromodulator inputs to the MB but the mechanisms by which they interact with and regulate sleep- and wake-promoting neurons within MB are unknown. Here we investigate the role of subsets of PAM-DANs that signal wakefulness and project to wake-promoting compartments of the MB. We find that PAM-DANs are GABA responsive and require GABAA-Rdl receptor in regulating sleep. In mapping the pathways downstream of PAM neurons innervating γ5 and β′2 MB compartments we find that wakefulness is regulated by both DopR1 and DopR2 receptors in downstream Kenyon cells (KCs) and mushroom body output neurons (MBONs). Taken together, we have identified and characterized a dopamine modulated sleep microcircuit within the mushroom body that has previously been shown to convey information about positive and negative valence critical for memory formation. These studies will pave way for understanding how flies balance sleep, wakefulness and arousal.

Neurofibromin 1 mediates sleep depth in Drosophila

“…While Nf1 is broadly expressed throughout the brain, its function has been linked to the modulation of GABA signaling during the formation of associative memories (Georganta et al, 2021). In Drosophila, the GABAA receptor Resistant to dieldrin (Rdl) is expressed in numerous populations of sleep-regulating neurons (Fig 4A; Chung et al, 2009;Driscoll et al, 2021;Parisky et al, 2008).…”

“…While Nf1 is broadly expressed throughout the brain, its function has been linked to the modulation of GABA signaling during the formation of associative memories (Georganta et al, 2021). In Drosophila , the GABA A receptor Resistant to dieldrin (Rdl) is expressed in numerous populations of sleep-regulating neurons (Fig 4A; Chung et al, 2009; Driscoll et al, 2021; Parisky et al, 2008). To examine whether Nf1 functions in GABA A receptor neurons, we selectively knocked down Nf1 by expressing Nf1 RNAi under the control of Rdl -GAL4 and then measured its effect on sleep.…”

Mutation of theDrosophilaserotonin transporter dSERT disrupts courtship and feeding and increases both daytime and nighttime sleep

“…For over two decades, Drosophila has been utilized as a model system to study sleep (14,15) and both serotonin (16)(17)(18)(19)(20) and dopamine (21)(22)(23)(24)(25) have been shown to play significant roles in regulating sleep duration and quality. A role for serotonin in promoting sleep in Drosophila has been demonstrated in part by feeding the precursor 5-hydroxytryptophan (5-HTP) (16) or by utilizing mutants for the serotonin rate-limiting synthetic enzyme tryptophan hydroxylase (TRH) (20).…”

Circadian clock disruption promotes the degeneration of dopaminergic neurons

“…The PAM cluster comprises ~130 neurons per hemisphere, accounting for approximately 80% of fly brain DA neurons. PAM neurons are highly heterogeneous in their projection patterns and functions and play critical roles in behavioral processes such as olfactory associative learning, foraging, sleep, and locomotion [14][15][16][17][18] . We and others showed that loss of a subclass of PAM neurons leads to defective startle-induced climbing behavior in several PD models 13,19,20 , suggesting a partial analogy between the PAM cluster and the substantia nigra pars compacta.…”