0046 Chemogenetic activation of A2AR neurons in Nucleus Accumbens increases sleep, affecting cognition and behavior in mice

Abstract

Abstract Introduction Sleep influences various cognitive and physiologic processes; however, the mechanisms through which sleep affects these different functions are not fully understood. The Nucleus Accumbens (NAc) was recently identified as a sleep regulating center. We hypothesized that manipulation of sleep via chemogenetic activation of sleep active Adenosine-2A receptor (A2aR) neurons in the NAc core could induce restorative sleep and affect memory, anxiety and depression-like states in mice. Methods We transfected A2A neurons in NAc core of A2AR-Cre transgenic mice with an adeno-associated virus (AAV) carrying the gene sequence for hM3Dq. Using Clozapine-N-Oxide (CNO) at varying concentrations (0.1, 0.3, 0.9, 2.7 mg/kg), we activated these neurons and analyzed EEG/EMG traces for rapid eye movement (REM) sleep, non-REM (NREM) sleep and wakefulness. Mice were then divided into three separate conditions: normal sleep, sleep deprivation or increased sleep for 4 hr. Following this sleep intervention mice underwent the following behavioral tests 1) Novel object recognition (NOR) test for memory, 2) the open field test (OFT) for anxiety and 3) the forced swim test (FST) for depression-like states. Results During the first 4 hours of chemogenetic activation of NAc A2AR neurons, we observed a 105% increase of NREM sleep at the highest dose of CNO when compared to saline ­treatment. REM sleep was increased similarly. Analysis of the behavioral tests revealed that mice in the increased sleep condition tended to perform better at the NOR test, suggesting increased memory performance. In the OFT, sleep deprived mice showed a significant increase in %time spent in the center zone and total distance travelled within the arena. They also spent significantly less time immobile. Sleep deprived mice also exhibited a trend towards spending more time swimming in the FST, indicating lower levels of depression-like states. Conclusion Our results suggest that chemogenetic activation of A2AR neurons in the NAc core strongly increases NREM and REM sleep, confirming the importance of these neurons in sleep/wake regulation. Moreover, we observed that increased sleep improves memory performance but does not significantly affect levels of anxiety or depression-like states. Instead, reduced sleep significantly decreases anxiety and tends to reduce depressive-like states. Support (if any)