Tae Kim

Consumption of a high-fat diet (HFD) has been associated with reduced wakefulness and various behavioral deficits, including anxiety, depression, and anhedonia. The dopaminergic system, which plays a crucial role in sleep and ADHD, is known to be vulnerable to chronic HFD. However, the association between HFD-induced behavioral and molecular changes remains unclear. Therefore, we investigated the effects of a HFD on the dopaminergic system and its association with behavioral deficits in male mice. The mice were divided into normal diet and HFD groups and were analyzed for sleep patterns, behavior tests, and transcription levels of dopamine-related genes in the brain. The HFD group showed decreased wakefulness, increased REM sleep with fragmented patterns, decreased time spent in the center zone of the open field test, shorter immobile time in the tail suspension test, impaired visuospatial memory, and reduced sucrose preference. Additionally, the HFD group had decreased mRNA levels of D1R, COMT, and DAT in the nucleus accumbens, which negatively correlated with REM sleep proportion and REM sleep bout count. The results suggest that HFD-induced behavioral deficits were resemblance to ADHD-like behavioral phenotypes and disturbs REM sleep by dysregulating the dopaminergic system.

Abstract Introduction Energy homeostasis and sleep have a bidirectional relationship. Cereblon (CRBN), a substrate receptor of the CRL4 E3 ubiquitin ligase complex, regulates energy levels by ubiquitinating AMP-activated protein kinase (AMPK), a master energy sensor. While CRBN’s role in energy regulation is established, its involvement in sleep remains unclear. Thalidomide, a pharmacological modulator of CRBN, has shown to improve sleep quality, particularly by increasing slow-wave sleep (SWS) and overall sleep efficiency. This study explores the impact of CRBN deletion on sleep-wake patterns and examines parallels to thalidomide’s effects. Methods Sleep-wake patterns were analyzed in Crbn+/+ and Crbn-/- mice under three conditions: 24-hour baseline, 6-hour sleep deprivation (SD), and 6-hour recovery sleep (RS). EEG/EMG recordings quantified sleep architecture, with a focus on slow-wave activity as an indicator of homeostatic sleep drive. Stress-associated proteins, including phospho-Tau, phospho-α-Synuclein, DNAJA1 (DJ2), DNAJB1 (DJ1), and Heat Shock Protein 70 (HSP70), were measured via immunoblotting. Results At baseline, sleep architecture was similar between Crbn+/+ and Crbn-/- mice. Sleep deprivation reduced CRBN expression in Crbn+/+ mice and elevated stress markers such as phospho-Tau, phospho-α-Synuclein, DJ2, and DJ1 in both genotypes. Crbn-/- mice showed a blunted increase in phospho-Tau and phospho-α-Synuclein but higher levels of HSP70, DJ2, and DJ1. During recovery sleep, Crbn-/- mice exhibited significantly increased slow-wave activity, suggesting heightened homeostatic sleep pressure, likely due to AMPK hyperactivation in the absence of CRBN. Conclusion CRBN plays a critical role in regulating sleep homeostasis and recovery sleep, likely through its modulation of AMPK activity and stress protein responses. Interestingly, thalidomide, a CRBN modulator, has been shown to enhance slow-wave sleep and overall sleep quality in clinical studies. This improvement in slow-wave activity parallels the increased SWA observed in Crbn-/- mice during recovery sleep. However, while thalidomide’s effects appear beneficial, the heightened sleep drive in CRBN-deficient mice likely reflects underlying AMPK hyperactivation. This highlights a dual role for CRBN in both promoting energy balance and regulating sleep architecture. Thalidomide or related CRBN modulators could offer therapeutic benefits for improving sleep quality and mitigating neurodegeneration associated with disrupted sleep, while careful attention is needed to avoid unintended effects related to CRBN deficiency. Support (if any)