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Circadian disruptions and time-of-day-dependent memory deficiency with long noncoding RNA expression profiling changes in Presenilin1/2 conditional knockout mice

ABSTRACT: Alzheimer’s disease (AD) patients exhibit sleep and circadian disturbances before cognitive decline, and these disruptions worsen with disease severity. However, the molecular mechanisms of sleep and circadian disruptions in AD patients are poorly understood. In this study, we investigated the sleep pattern and circadian rhythms in Presenilin-1/2 conditional knockout mice (DKO mice). Assessment of EEG and EMG recording showed that DKO mice exhibit sleep disorders from 2 months of age that worsen at the age of 6 months. The actogram of wheel running activity of DKO mice manifested movement splitting both in Dark and Light phases during the 24-hour light/dark cycle compared to WT mice. Notably, DKO mice also displayed increased NREM sleep time during the dark phase compared to WT mice at the age of two months; however, REM sleep showed no change in either WT or DKO littermates in the dark phase. When sleep and wakefulness were examined at the age of 6 months, the DKO mice showed increased wakefulness time and decreased total time spent in NREM and REM sleep. Analysis of the circadian modulation of memory revealed that the recall for contextual fear memory trained at ZT2 in WT mice was greater at ZT2 than at ZT14; however, the DKO mice had the same freezing responses with respect to both ZT2 and ZT14. Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides, and they have rhythmic expression in mammals. However, no study has investigated rhythmic lncRNA expression in Alzheimer’s disease so we applied RNA-seq technology to profile the expression of lncRNAs in the hippocampus of DKO mice in the light (resting) phase and dark (active) phase. Furthermore, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the biological process, cell component and molecular function of these differentially expressed lncRNAs (DE-lncRNAs). These results provide a useful resource for studying lncRNAs in circadian disruptions in Alzheimer’s disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE211860 | GEO | 2023/07/29

REPOSITORIES: GEO

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Project description:Sleep has been strongly implicated in learning and especially in the reprocessing of recently acquired memory. Children with intellectual disability (ID) tend to have sleep-wake disturbances, which may contribute to the pathophysiology of the disease. As far as sleep is, in part, a circadian process, we decided to study rhythmic gene expression in hippocampus, a brain structure, which plays a key role in memory in human and rodents. By investigating the transcriptome of mouse adult hippocampus, we report here the identification of 663 circadian rhythm (CR)-regulated genes, which have been clustered in four categories, based on their temporal pattern of expression. In addition to the standard core-clock genes, enrichment analysis of the hippocampal CR-regulated genes revealed the presence of several transcription factors, underlying the existence of an inter-regulation of genes' expression between clusters. Interestingly, these hippocampal circadian rhythm-regulated genes are very enriched in sleep/wakefulness related genes. We show here that glucocorticoid signaling, already shown to be involved in memory regulation, is a circadian regulated pathway in hippocampus. Furthermore, we identified a list of 30 CR-regulated ID genes. Our results demonstrate that hippocampus can be considered as a peripheral oscillator and illustrate the link between circadian rhythm, sleep, intellectual disability and memory consolidation. In order to identify circadian rhythm-regulated genes in mouse hippocampus, we realized a study in dark-dark conditions, thus allowing to overcome the effects induced by light changes. To systematically identify genes with circadian regulated expression, RNA samples from the hippocampus of three mice at four Circadian Time (CT) points were used for expression profiling using Agilent microarray technology. The dark/dark period started at 7 p.m. The Circadian Time (CT) 18 samples were taken after 30 h of continuous dark; the other circadian times followed at 6-h intervals: CT0, CT6 and CT12 after 36, 42 and 48 h of continuous darkness, respectively.

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Circadian disruptions and time-of-day-dependent memory deficiency with long noncoding RNA expression profiling changes in Presenilin1/2 conditional knockout mice

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