Dataset Information

Chronic alcohol exposure reduces acetylated histones in the sleep-wake regulatory brain regions to cause insomnia during withdrawal.

ABSTRACT:

Background

Alcohol use disorder (AUD) develops after chronic and heavy use of alcohol. Insomnia, a hallmark of AUD, plays a crucial role in the development of AUD. However, the causal mechanisms are unknown. Since chronic alcohol reduces acetylated histones and disrupts the epigenome, we hypothesized that chronic alcohol exposure will reduce acetylated histones in wake-promoting regions of the brain to cause insomnia during alcohol withdrawal.

Methods

Adult male C57BL/6J mice, surgically instrumented for electrophysiological monitoring of sleep-wakefulness, were exposed to chronic alcohol (6.8%) consumption using Lieber-DeCarli liquid diet. Three experiments were performed. First, the effect of chronic alcohol consumption was examined on sleep-wakefulness during 7 days of withdrawal. Second, the expression of acetylated histones, H3 lysine 14 (AcH3K14), was examined in two major sleep-wake regulatory brain regions: basal forebrain (BF) and lateral hypothalamus (LH) of the brain by using western blotting. Next, blockade of histone deacetylase, via systemic administration of TSA was examined on alcohol-induced changes in sleep-wakefulness.

Results

Alcoholic mice displayed a significant reduction in the quality and quantity of NREM sleep coupled with a significant increase in wakefulness that lasted for several days during alcohol withdrawal. In addition, alcoholic mice displayed a significant reduction in the expression of AcH3K14 in both BF and LH. Systemic administration of TSA significantly attenuated insomnia and improved the quality and quantity of sleep during alcohol withdrawal.

Conclusions

Based on our results, we suggest that a causal relationship exists between reduced histone acetylation and insomnia during alcohol withdrawal.

SUBMITTER: Sharma R

PROVIDER: S-EPMC7722632 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In alcohol use disorder, drinking cessation is frequently associated with an alcohol withdrawal syndrome. Early in abstinence (within the first 2 months after drinking cessation), when patients do not exhibit physical signs of alcohol withdrawal syndrome anymore (such as nausea, tremor or anxiety), studies report various brain, sleep and cognitive alterations, highly heterogeneous from one patient to another. While the acute neurotoxicity of alcohol withdrawal syndrome is well-known, its contribution to structural brain alterations, sleep disturbances and neuropsychological deficits observed early in abstinence has never been investigated and is addressed in this study. We included 54 alcohol use disorder patients early in abstinence (from 4 to 21 days of sobriety) and 50 healthy controls. When acute physical signs of alcohol withdrawal syndrome were no longer present, patients performed a detailed neuropsychological assessment, a T1-weighted MRI and a polysomnography for a subgroup of patients. According to the severity of the clinical symptoms collected during the acute withdrawal period, patients were subsequently classified as mild alcohol withdrawal syndrome (mild-AWS) patients (Cushman score ≤ 4, no benzodiazepine prescription, N = 17) or moderate alcohol withdrawal syndrome (moderate-AWS) patients (Cushman score > 4, benzodiazepine prescription, N = 37). Patients with severe withdrawal complications (delirium tremens or seizures) were not included. Mild-AWS patients presented similar grey matter volume and sleep quality as healthy controls, but lower processing speed and episodic memory performance. Compared to healthy controls, moderate-AWS patients presented non-rapid eye movement sleep alterations, widespread grey matter shrinkage and lower performance for all the cognitive domains assessed (processing speed, short-term memory, executive functions and episodic memory). Moderate-AWS patients presented a lower percentage of slow-wave sleep, grey matter atrophy in fronto-insular and thalamus/hypothalamus regions, and lower short-term memory and executive performance than mild-AWS patients. Mediation analyses revealed both direct and indirect (via fronto-insular and thalamus/hypothalamus atrophy) relationships between poor sleep quality and cognitive performance. Alcohol withdrawal syndrome severity, which reflects neurotoxic hyperglutamatergic activity, should be considered as a critical factor for the development of non-rapid eye movement sleep alterations, fronto-insular atrophy and executive impairments in recently detoxified alcohol use disorder patients. The glutamatergic activity is involved in sleep-wake circuits and may thus contribute to molecular mechanisms underlying alcohol-related brain damage, resulting in cognitive deficits. Alcohol withdrawal syndrome severity and sleep quality deserve special attention for a better understanding and treatment of brain and cognitive alterations observed early in abstinence, and ultimately for more efficient relapse prevention strategies.