Persistent Short-Term Memory Defects Following Sleep Deprivation in a Drosophila Model of Parkinson Disease

PARKINSON DISEASE (PD) RESULTS IN THE PROGRESSIVE LOSS OF DOPAMINERGIC NEURONS AND IS ASSOCIATED WITH MOTOR DEFICITS INCLUDING bradykinesia, rigidity, and loss of postural reflexes. In addition, many PD patients develop cognitive deficits eventually leading to dementia, thus significantly increasing the personal and socioeconomic burden of the disease.1 Cognitive impairments occur both at the early and late stages of the disease, independently of depression and dementia.2 These impairments are well documented and predominantly affect prefrontal cortex and dopamine dependent executive functions including working memory, response inhibition, and behavioral flexibility.3,4 Poorer cognitive performance correlates with increased severity of the motor deficits, indicating that they may share a similar etiology.5 In addition to motor and cognitive deficits, sleep abnormalities are highly prevalent in PD (> 74% of patients).6–9 Sleep disturbances are both a primary feature of the disease and a secondary consequence of medications, tremor, rigidity, and bradykinesia. Primary sleep disturbances include excessive daytime sleepiness and REM sleep behavior disorder (RBD). RBD may predate the motor symptoms by many years,10 can predict cognitive impairment,11 and is associated with dementia.12 In addition, PD patients present narcolepsy-like symptoms that appear to be associated with a substantial loss of hypocretin neurons.13 Secondary sleep disturbances include insomnia, sleep fragmentation, restless legs syndrome, and sleep apnea.14 Multiple lines of evidence in both mammals and flies indicate important interactions between sleep and dopaminergic systems.15–22 For example, in healthy adult wild-type flies, sleep deprivation results in an increase in dopamine levels, a reduction in dopamine D1-receptor (dDA1) mRNA and learning impairments that are recovered following a brief 2-h nap.21 A similar process affecting the D2/D3 receptor has been reported in sleep deprived humans.22 Importantly, dopaminergic transmission plays a critical role in regulating sleep following environmental manipulations associated with brain plasticity.23 Although increased dopamine may facilitate plastic processes in the healthy adult, an acute change in dopamine signaling during critical windows of plasticity in dopaminergic circuits may result in long-lasting decrements in learning and other adaptive behaviors that persist when normal dopamine levels are restored.24 Together, these observations raise the possibility that sleep deprivation, by affecting the function of dopaminergic systems,21 may be particularly deleterious during degenerative processes that alter dopamine signaling such as PD. Drosophila, with the availability of models recapitulating many features of PD, and the ease of manipulating and monitoring sleep, appears well suited to address this question.. Using the GAL4-UAS system25 human α-synuclein can be expressed throughout the nervous system of the adult fly. Flies expressing α-synuclein (αS flies) reproduce key symptoms of human PD: age dependent and progressive disruption of selective dopaminergic neuronal groups, motor dysfunction responsive to dopaminergic treatment, and formation of Lewy body-like protein inclusions.26,27 To evaluate the consequences of sleep deprivation in αS flies, a functional readout of dopaminergic systems that is relevant to the deficits observed in PD is required. Since cognitive impairments appearing early in PD affect executive functioning,3 we chose to evaluate short-term memory and response inhibition in αS flies, using aversive phototaxis suppression (APS).28 Here we show that at an intermediate stage of the pathology, a single sleep deprivation challenge results in persistent short-term memory defects in αS flies. To explore possible mechanisms underlying these impairments, we evaluated dopaminergic neuron numbers using whole brain immunohistochemistry and mRNA levels of genes involved in dopamine signaling. We found that learning impairments are prevented when αS flies are administered a D1 antagonist during sleep deprivation suggesting that the deficits are due to an extended activation of D1-like receptors. Finally, we report that flies fed curcumin, a compound known to protect against the neurotoxic effects of 6-hydroxydopamine in rats29 and inhibit the formation of α-synuclein aggregates,30 prevents sleep deprivation induced impairments in short-term memory in αS flies.