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Common transcriptional changes in the brain during hibernation and Alzheimer’s disease

ABSTRACT: Hibernation demands rapid brain adaptations, involving cycles of reduced metabolic rate during torpor, followed by brief periods of arousal. Previous studies show hibernation induces a drastic increase in Tau hyperphosphorylation, but a mechanistic connection to disease remains unclear. Using single-nucleus RNA sequencing on hippocampi of golden hamsters, we unveil large transcriptional shifts across the hibernation cycle in all cell types, especially glia. Common transcriptional changes in mitochondrial and ribosomal genes are observed in all different cell types. In addition, hibernation triggers an inflammatory-like response in microglia that in part resembles cell states observed in Alzheimer’s disease, but here in the absence of Aβ-accumulation and neurodegeneration. These findings reveal brain transformations that might help preserve vital functions under extreme conditions and they suggest that early cellular changes in AD may be a natural adaptive process.

ORGANISM(S): Mesocricetus auratus

PROVIDER: GSE304024 | GEO | 2026/09/02

REPOSITORIES: GEO

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Project description:Hibernators dramatically lower metabolism to save energy while fasting for months. Prolonged fasting challenges metabolic homeostasis, yet small-bodied hibernators emerge each spring ready to resume all aspects of active life, including immediate reproduction. The liver is the body’s metabolic hub, processing and detoxifying macromolecules to provide essential fuels to brain, muscle and other organs throughout the body. Here we quantify changes in liver gene expression across several distinct physiological states of hibernation in 13-lined ground squirrels, using RNA-seq to measure the steady-state transcriptome and GRO-seq to measure transcription for the first time in a hibernator. Our data capture key timepoints in both the seasonal and torpor-arousal cycles of hibernation. Strong positive correlation between transcription and the transcriptome indicates that transcriptional control dominates the known seasonal reprogramming of metabolic gene expression in liver for hibernation. During the torpor-arousal cycle, however, discordance develops between transcription and the steady-state transcriptome by at least two mechanisms: 1) although not transcribed during torpor, some transcripts are unusually stable across the torpor bout; and 2) unexpectedly, on some genes, we document continuing, slow elongation with a failure to terminate transcription across the torpor bout. While the steady-state RNAs corresponding to these readthrough transcripts did not increase during torpor, they did increase shortly after rewarming despite their simultaneously low transcription. Both of these mechanisms would assure the immediate availability of functional transcripts upon rewarming. Integration of transcriptional, post-transcriptional and RNA stability control mechanisms, all demonstrated in these data, likely initiate a serial gene expression program across the short euthermic period that restores the tissue and prepares the animal for the next bout of torpor.

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Common transcriptional changes in the brain during hibernation and Alzheimer’s disease

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