Genetic basis of individual vulnerability to sleep loss and responsivity to stimulants

Introduction Inadequate sleep is prevalent in modern society. Sleep loss exerts substantial deleterious effects on an individual's cognitive and behavioral function (see Chapters 1 and 2, this volume) and is associated with a number of physical and mental health problems, including cardiometabolic disorders, chronic pain, and major depression. Inadequate sleep played a pivotal role in a number of major catastrophic events in recent history: sleep deprivation was determined by investigators to be an important factor in the nuclear accident at Three Mile Island and the nuclear meltdown at Chernobyl. Results of investigations surrounding the Exxon Valdez oil tanker spill similarly led to the conclusion that sleep debt played a non-trivial role. These events, which might have been averted if those involved had adequate sleep opportunity, resulted in significant ecological, environmental, and economic damage. Inadequate sleep, or sleep loss, is rightfully considered a significant public health and safety concern [1]. Sleep and wakefulness are regulated by (a) an endogenous circadian oscillator that sets the timing of sleep and (b) a sleep homeostatic mechanism that tracks sleep debt [2]. These two systems work interactively to determine sleep timing, duration, and sleep architecture as well as individual variability in neurobehavioral and cognitive responses to sleep loss. As indicated by Landolt [3], the molecular bases of normal human sleep and its physiological regulation is not well understood. It is well known that reliable interindividual differences exist in normal sleep–wake patterns and neurobehavioral responses to different types of sleep loss (e.g., total sleep deprivation and chronic sleep restriction). Yet, within-person (intraindividual) neurobehavioral responses to sleep loss appear to be highly stable (trait-like [4]). While environmental factors (e.g., noisy environments, medical conditions, work schedules, etc.) can impact the duration and depth of sleep, the high degree of heritability of various sleep phenotypes (e.g., [5, 6]) and sleep disorders (e.g., restless legs syndrome and narcolepsy [7]) highlights the fact that genetic control of sleep and wakefulness must be acknowledged. These data suggest that individual differences in sleep need and individual vulnerability to sleep loss are largely determined at the molecular level.