Dietary ketosis improves circadian dysfunction as well as motor symptoms in the BACHD mouse model of Huntington’s disease

Abstract

Disturbances in sleep/wake cycles are common among patients with neurodegenerative diseases including Huntington’s disease (HD) and represent an appealing target for chrono-nutrition-based interventions. In the present work, we sought to determine whether a low-carbohydrate, high-fat diet would ameliorate the symptoms and delay disease progression in the BACHD mouse model of HD. Adult WT and BACHD male mice were fed a normal or a ketogenic diet (KD) for 3 months. The KD evoked a robust rhythm in serum levels of β-hydroxybutyrate and dramatic changes in the microbiome of male WT and BACHD mice. NanoString analysis revealed transcriptional changes driven by the KD in the striatum of both WT and BACHD mice. Disturbances in sleep/wake cycles have been reported in mouse models of HD and are common among HD patients. Having established that the KD had effects on both the WT and mutant mice, we examined its impact on sleep/wake cycles. KD increased daytime sleep and improved the timing of sleep onset, while other sleep parameters were not altered. In addition, KD improved activity rhythms, including rhythmic power, and reduced inappropriate daytime activity and onset variability. Importantly, KD improved motor performance on the rotarod and challenging beam tests. It is worth emphasizing that HD is a genetically caused disease with no known cure. Life-style changes that not only improve the quality of life but also delay disease progression for HD patients are greatly needed. Our study demonstrates the therapeutic potential of diet-based treatment strategies in a pre-clinical model of HD.

Scheduled feeding improves sleep in a mouse model of Huntington’s disease

“…The mechanisms underlying these benefits of TRF on central nervous system function are not known although there are several possibilities (Longo and Panda, 2016; Jensen et al, 2020; Bass, 2024). In recent work, we reported that a ketogenic diet (KD) ameliorates the symptoms and delays disease progression in the BACHD model (Whittaker et al, 2022). Mutant mice fed a KD for three months displayed increased daytime sleep and improved timing of sleep onset.…”

Sleep and Circadian Rhythm Dysfunction in Animal Models of Huntington’s Disease

“…A subsequent study showed that peripheral clocks were also dysregulated [32]. At a molecular level, alterations in the amplitude or phase of the rhythms in core circadian clock gene expression were seen in several brain regions beyond the SCN, including striatum, hippocampus, and motor cortex [19] and peripheral tissues, particularly the liver [32,33]. Notably, pathophysiology is also described in HD mouse SCN [34].…”

“…Mice on this restricted feeding regime showed improvements in their locomotor activity and sleep behavioral rhythms and heart rate variability, with motor improvements correlated with improved circadian output. The mechanisms underlying these benefits of time restricted feeding are not known, although improvements in metabolism that occur in HD would seem to be a logical line of investigation, since metabolism is dysregulated in HD models [32,33,45,54].…”

The Unconventional Effects of the Ketogenic Diet (KD) in Preclinical Epilepsy

“…32,34 Of note, preclinical studies have found KD treatment also improves sleep and sleep architecture in models of Alzheimer’s disease and Huntington’s disease. 35,36…”

“…32,34 Of note, preclinical studies have found KD treatment also improves sleep and sleep architecture in models of Alzheimer's disease and Huntington's disease. 35,36 Cognitive Deficits Preclinical treatment with KD improves cognitive processes in epilepsy models. In vivo, preclinical experiments assess memory acquisition by measuring how quickly and efficiently a task is learned.…”