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Zenodo
2025
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| Online Access: | https://doi.org/10.5281/zenodo.15584369 |
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Table of Contents:
- <p><span lang="EN-US">Sleep is an evolutionarily conserved biological drive essential for brain function, yet sleep deprivation (SD) is increasingly prevalent in modern society. Notably, many major neurological and psychiatric disorders, which emerge across different stages of life, are frequently accompanied by comorbid sleep disturbances. Understanding the brain’s homeostatic response to SD, and how it may be altered in disease states, is therefore of critical importance. Previous studies have shown that acute SD (5–6 hours) induces widespread, cell-type-specific molecular changes across brain regions. The hippocampus, a region critical for learning and memory, is especially sensitive to SD; however, the affected cell types, their gene expression changes, and the underlying regulatory mechanisms remain poorly understood.</span></p> <p><span lang="EN-US">In this thesis, I investigated the homeostatic response to acute SD by examining the interplay between 3D chromatin reorganization, transcriptional regulation, and chromatin accessibility in the murine hippocampus. Focusing on pyramidal glutamatergic neurons in the dorsal CA1 region, I uncovered widespread SD-induced changes across all layers of gene regulation. I observed widespread changes in the expression of neuronal genes involved in maintaining excitation–inhibition (E/I) balance, suggesting that SD may disrupt this equilibrium. Many of these genes are also enriched for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD) and schizophrenia (SCZ). Changes in chromatin accessibility pointed to a central role for Mef-family transcription factors (TFs), neuronal activity-related TFs and CTCF in the SD response. For the first time, I characterized changes in 3D genome architecture as part of the brain’s adaptive response to sleep loss, revealing extensive structural rearrangements beyond gene expression alone. To identify the strongest changes upon SD across all studied molecular layers, I developed HITs & SWINGs method, which detect the pronounced gene-gene interactions shifts, affecting predominantly synaptic genes. </span></p> <p><span lang="EN-US">Given that E/I imbalance is a hallmark of many NDDs, often comorbid with chronic insomnia, I examined the effects of SD in both wild-type mice and homozygous Shank3∆C mutant animals, a model of ASD characterized by chronic sleep problems. My work shows that the Shank3∆C mutation leads to an attenuated SD response in major excitatory neurons, while amplifying it in inhibitory types. These results support the idea that extended wakefulness might induce an E/I imbalance that may underlie, or exacerbate, the molecular basis of ASD.</span></p>