PhD defence Camilla Paraciani
'Lost' to sleep loss
Mechanisms and strategies to reverse sleep deprivation-induced amnesia
Sleep is a conserved biological process essential for physiological homeostasis and cognitive function, particularly memory consolidation. While memory acquisition and retrieval occur during wakefulness, consolidation (the stabilization and integration of newly encoded information) primarily takes place during sleep. Sleep deprivation (SD), increasingly prevalent in modern society, disrupts this process, impairing memory at behavioral, structural, and molecular levels. However, whether SD leads to permanent memory loss or merely impairs access to stored information remains unclear. This thesis investigates the effects of SD on memory, memory engrams and their retrievability. In Chapter 2, pharmacological and optogenetic approaches demonstrate that SD-induced amnesia reflects impaired retrieval rather than erasure of memory traces. Restoration of memory performance via engram reactivation or modulation of the cAMP-PKA-CREB signaling pathway indicates that stored information remains accessible under appropriate conditions. Chapter 3 extends this analysis to the whole-brain level, identifying network-level disruptions associated with SD. Functional connectivity analyses reveal key brain regions involved in memory retrieval deficits, while interventions targeting cGMP-PKG signaling with the FDA-approved drug vardenafil successfully rescue memory function. These improvements correlate with restored reactivation of dentate gyrus engram cells, highlighting their central role in memory accessibility. Finally, Chapter 4 addresses sex differences in sleep and memory, emphasizing the underrepresentation of female subjects in SD research and the modulatory role of ovarian hormones. Together, these findings suggest that SD primarily disrupts memory retrievability, not storage, and identify potential therapeutic strategies to mitigate its cognitive consequences.