D1 Receptor Activation in the Mushroom Bodies Rescues Sleep-Loss-Induced Learning Impairments in Drosophila

Abstract

Background Extended wakefulness disrupts acquisition of short term memories in mammals. However, the underlying molecular mechanisms triggered by extended waking and restored by sleep are unknown. Moreover, the neuronal circuits that depend on sleep for optimal learning remain unidentified. Results Learning was evaluated using Aversive Phototaxic Suppression (APS). In this task, flies learn to avoid light that is paired with an aversive stimulus (quinine /humidity). We demonstrate extensive homology in sleep deprivation induced learning impairment between flies and humans. Both 6 h and 12 h of sleep deprivation are sufficient to impair learning in Canton-S (Cs) flies. Moreover, learning is impaired at the end of the normal waking-day in direct correlation with time spent awake. Mechanistic studies indicate that this task requires intact mushroom bodies (MBs) and requires the Dopamine D1-like receptor (dDA1). Importantly, sleep deprivation induced learning impairments could be rescued by targeted gene expression of the dDA1 receptor to the MBs. Conclusion These data provide direct evidence that extended wakefulness disrupts learning in Drosophila. These results demonstrate that it is possible to prevent the effects of sleep deprivation by targeting a single neuronal structure and identify cellular and molecular targets adversely affected by extended waking in a genetically tractable model organism.

foraging alters resilience/vulnerability to sleep disruption and starvation in Drosophila

“…The lack of a homeostatic response seen in for R flies may represent either an adaptation that allows animals to better withstand the negative effects of waking, or it may indicate that foraging disrupts regulatory processes, thereby preventing flies from obtaining needed sleep. Because deficits in short-term memory are a robust consequence of sleep loss (13,22,23), we evaluated short-term memory (STM) using aversive phototaxic suppression (APS) in for R , for s , and for s2 flies following 12 h of SD. In the APS, flies are individually placed in a T maze and allowed to choose between a lighted and darkened chamber (13,24).…”

“…Because deficits in short-term memory are a robust consequence of sleep loss (13,22,23), we evaluated short-term memory (STM) using aversive phototaxic suppression (APS) in for R , for s , and for s2 flies following 12 h of SD. In the APS, flies are individually placed in a T maze and allowed to choose between a lighted and darkened chamber (13,24). During 16 trials, flies learn to avoid the lighted chamber, which is paired with an aversive stimulus (quinine/humidity).…”

“…During 16 trials, flies learn to avoid the lighted chamber, which is paired with an aversive stimulus (quinine/humidity). The performance index is calculated as the percentage of times the fly chooses the dark vial during the last 4 trials of the 16-trial test (13,25). As seen in Fig.…”

“…1B, for R flies maintain their ability to learn following SD, whereas for s flies are significantly impaired; for s2 mutants showed impaired performance in the APS both under baseline conditions and following SD. for R , for s , and for s2 flies did not differ in sensory thresholds as measured by either the photosensitivity index (PI; percentage of photopositive choices in 10 trials in the absence of quinine) or the quinine sensitivity index (QSI; time in seconds flies reside on the nonquinine side of a chamber) (Table S1) (13,25). Given that for R flies maintain their ability to learn following 12 h of SD and do not appear to be sleepy, as indicated by the absence of a sleep rebound, for R flies are considered to be resistant to SD.…”

“…SD is known to result in robust cognitive impairments in humans (10), rodents (11), bees (12), and flies (13,14). However, the extent to which prolonged waking will result in cognitive impairments is strongly influenced by the environmental context.…”