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

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 slee..., The work presented in this study followed all the guidelines and regulations of the UCLA Division of Animal Medicine that are consistent with the Animal Welfare Policy Statements and the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association. 
Animals
The BACHD mouse model used in this study expresses the full length of the human mutant HTT gene encoding 97 glutamine repeats under the control of the endogenous regulatory machinery (Gray et al., 2008). BACHD dams, backcrossed on the C57BL/6J background for a minimum of 12 generations, were bred with C57BL/6J (WT) males from The Jackson Laboratory (Bar Harbor, Maine) in our facility at UCLA. Data were collected from male WT and heterozygous for the BACHD transgene littermates. Genotyping was performed at 15 days of age by tail snips, and after weaning at postnatal day 21, littermates were group housed, until otherwise noted. All animals were housed in soundproof chambers with controlled temperature, humi..., Excel