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. 2019 Oct 9;42(10):zsz135.
doi: 10.1093/sleep/zsz135.

NMDAR Activation Regulates the Daily Rhythms of Sleep and Mood

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Free PMC article

NMDAR Activation Regulates the Daily Rhythms of Sleep and Mood

Jeffrey S Burgdorf et al. Sleep. .
Free PMC article

Abstract

Study objectives: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion.

Methods: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day-night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings.

Results: NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1-4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm.

Discussion: These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.

Keywords: EEG; NMDA receptors; ketamine; sleep; sleep deprivation; ultrasonic vocalizations.

Figures

Figure 1.
Figure 1.
NYX-2925 facilitates NREM sleep during the light phase, whereas the NMDAR antagonist ketamine inhibits NREM. Non-deprived or sleep-deprived (ZT0-6) rats received either NYX-2925 (1 mg/kg PO), ketamine (10 mg/kg IV; non-deprived only) or vehicle at ZT5 and sleep EEG and EMG was recorded for 24 hours post-dosing. (A) NREM and (D) REM sleep diurnal rhythm before (baseline) and after NYX-2925 or vehicle administration. NYX-2925 increased (B) NREM sleep but did not alter (E) REM sleep during the light phase in both non-deprived and sleep-deprived rats. In contrast, ketamine acutely reduced both (C) NREM and (F) REM sleep in non-deprived rats followed by rebound increase in both sleep states. *p < .05 Fisher’s PLSD post hoc test vs. vehicle. Data are reported as mean ± SEM. Sleep deprived (vehicle n = 7, NYX-2925 n = 9, non-deprived controls n = 14), non-sleep deprived (vehicle n = 8, NYX-2925 n = 11), ketamine (vehicle n = 11, ketamine n = 4).
Figure 2.
Figure 2.
Dose response and time course for NYX-2925 facilitation of NREM in sleep-deprived rats. Sleep-deprived (ZT0-6; day 1–2) rats received either NYX-2925 (0.1, 1, 10 mg/kg PO) or vehicle at ZT5 and sleep EEG and EMG were recorded for 3 days post-dosing. (A) NYX-2925 (0.1, 1, 10 mg/kg PO) increased NREM sleep during the light phase as compared to vehicle during the first 24 hours after dosing, whereas (B) only the 10 mg/kg PO dose facilitated NREM across all 3 days. (C) NYX-2925 (10 mg/kg PO) across all 3 days significantly increased the duration of individual sleep bouts, the amount of time spent in NREM before transitioning to REM in a sleep bout, delta power during NREM, and theta power during REM. NYX-2925 also decreased delta power during wake. p < .05 Fisher’s PLSD post hoc test vs. vehicle for all doses and timepoints. Data are reported as mean ± SEM. (A) Vehicle n = 15, NYX-2925 0.1 mg/kg n = 9, 1 mg/kg n = 17, 10 mg/kg n = 8; (B) vehicle N = 15 (d1), 8 (d2), 7 (d1), NYX-2925 n = 8; (C) n = 8 per group.
Figure 3.
Figure 3.
Sleep deprivation inhibits NMDAR-dependent positive emotional learning which is rescued with pretreatment with NYX-2925. (A) NYX-2925 (1 mg/kg PO) increased the rates of hedonic 50-kHz USVs in response to a temporal conditioned stimulus (CS) that predicated heterospecific rough-and-tumble play in rats that had received 23 hours of sleep deprivation as well as non-dosed/non-deprived naive controls. (B) Rates of hedonic 50-kHz USVs or aversive 20-kHz USVs in response to unconditioned heterospecific rough-and-tumble play. (C) Approach latency (cm/second) for the rats to approach the experimenter’s hand in order to self-administer heterospecific rough and tumble play. *p < .05 NYX-2925 vs. vehicle, #p < .05 naive vs. vehicle Fisher’s PLSD post hoc test. Data are reported as mean ± SEM. N = 6 per group.
Figure 4.
Figure 4.
NYX-2925 facilitates the amplitude and phase transition timing of diurnal rhythm of both activity and emotional expression whereas ketamine does the opposite. Non-deprived rats received either NYX-2925 (10 mg/kg PO), ketamine (10 mg/kg IV) or vehicle at ZT5 and both sound levels (activity) and USVs (hedonic and aversive calls) were recorded in sound-attenuated chambers housing three rats per cage. (A–C) Diurnal rhythm of locomotor activity as well as positive and negative affect. (D) Acutely, ketamine suppressed hedonic and aversive USVs for the first 4 hours post-dosing. *p < .05 ANOVA NYX-2925 vs. vehicle. Data are reported as mean ± SEM. Vehicle n = 6, NYX-2925 n = 6, ketamine n = 4.
Figure 5.
Figure 5.
Sleep-affect model. (top panel) NYX-2925 treatment synchronized day–night activity patterns results in limited wake/affect during the day and robust positive affect during the night. (bottom panel) NMDAR antagonists or sleep deprivation disrupts the rhythm. Desynchronized activity patterns lead to increased wake and negative affect during the day and mixed affect during the night. The synchronization of activity and affect appear to be a form of NMDAR-dependent behavioral plasticity which is regulated by the lights-on and lights-off stimuli.

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