GENETIC UNDERPINNINGS OF THE EFFECTS OF SLEEP LOSS ON NEUROBEHAVIORAL PERFORMANCE

Lillian Skeiky

doi:10.7273/000006502

Total sleep deprivation (TSD) degrades cognition, including associative memory and vigilant attention. However, the mechanisms underlying this degradation in cognition are poorly understood. There are large individual differences in the magnitude of cognitive deficits resulting from sleep loss, with some individuals being particularly vulnerable to the effects of TSD on cognition, while others are relatively resilient. Moreso, these individual differences are remarkably stable and robust, constituting a human phenotype. This phenotype prompts the exploration of genetic variation as potential mediators of this vulnerability. This dissertation makes use of TSD, a powerful systems perturbation, and various genetic methodologies, to investigate novel mechanisms underlying sleep loss-induced performance impairment. Understanding these mechanisms has the potential to help inform possible interventions that may mitigate sleep loss-induced cognitive deficits. In Chapter 2 of this dissertation, we utilized caffeine as a pharmacologic intervention, in combination with TSD to help elucidate the mechanisms involving the TNFα G308A polymorphism’s association with resilience to sleep loss. We confirmed our previous work, which found that the A allele of this phenotype is associated with resilience to sleep loss, but found no interactions with caffeine dose. This finding suggests that the mechanism of this polymorphism is separate from that of caffeine (adenosine). Our previous work has shown that TSD impacts source memory deficits, above and beyond deficits in item memory. However, whether the effect of TSD on source memory is dissociable from its effect on item memory is still up for debate. In Chapter 3, we investigated whether 5-HTTLPR, a functional serotonin transporter gene, is related to item and source memory deficits during TSD. We showed that the 5-HTTLPR polymorphism affects source memory, but not item memory during TSD. This finding helps confirm that the effect of TSD on item and source memory are dissociable and distinct, and also implicates a serotonergic mechanism in the latter. In recent years, it has been suggested that individual differences in glymphatic flow are related to cognition in clinical populations, but it is unclear how these differences play out in young, healthy adults undergoing sleep deprivation. Aquaporins are thought to help facilitate the transport of glymphatic flow. In Chapter 4, we investigated whether an Aquaporin4 haplotype is associated with individual differences in vigilant attention deficits during TSD. We showed that genetic variation in Aquaporin4 haplotype is associated with vulnerability to sleep loss. These results may point towards the glymphatic system as a potential mediator of individual differences in sleep loss-related performance impairment. Alzheimer’s disease (AD) is associated with deficits in both sleep and cognition, even before the onset of clinically relevant symptomology. The glymphatic system has also been implicated in the pathogenesis of AD. In Chapter 5, we investigated whether an AD polygenic risk score is associated with individual differences in sleep loss-induced vigilant attention deficits. We found that greater genetic risk for AD is associated with vulnerability to sleep loss. The AD polygenic risk score implicates immune and glial cells and tau and amyloid-beta protein catabolism in vulnerability to sleep loss. The involvement of glia and tau and amyloid-beta protein catabolism further implicates the glymphatic system in potential mechanisms underlying sleep loss-induced performance impairment. The overall goal of this dissertation project was thus to shed light onto new and existing mechanisms underlying individual differences in vulnerability to TSD.

GENETIC UNDERPINNINGS OF THE EFFECTS OF SLEEP LOSS ON NEUROBEHAVIORAL PERFORMANCE

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