Sedative-hypnotics are administered to about two-third of the patients admitted to the intensive care unit (ICU). Although patients might appear to be ?sleeping,? there are varying effects of sedatives on sleep architecture. The dissociation between the behavioral phenotype of sleep (quiescence, eyes closed) and the restorative effects of sleep can mislead care providers and cause adverse consequences for patients. For example, it is known that certain sedative strategies are associated with a higher incidence of delirium, which is associated with increased mortality. The lack of rational sedation strategies is rooted in a profound gap in our knowledge at the neurobiological level. Two main questions persist and have not been explored: (1) do sedative-hypnotics accomplish the beneficial effects of sleep? and if so, (2) what is the mechanism? The long-term goal of the proposed studies is to identify sedative regimens that can be used more effectively in ICU and perioperative care to achieve homeostatic sleep recovery, and the neurochemical mechanisms through which sedative- hypnotics could provide a sleep-like state with positive functional outcomes. The overall objective of the proposed studies is to examine the effect of sedatives on sleep homeostatic neural circuitry, and to identify the mechanisms of differential effects on slow-wave sleep and rapid eye movement sleep. The central hypothesis, supported by our preliminary data, is that sedatives modulate levels of nitric oxide (NO) and adenosine, the signaling molecules that serve as the ?currency? of sleep debt, in basal forebrain to provide recovery from sleep loss. The rationale for the proposed research is that it will provide the fundamental mechanistic understanding of the interaction between sedatives and sleep homeostasis, which is currently unknown. The study will use four clinically relevant sedative-hypnotics (propofol, dexmedetomidine, midazolam, sevoflurane) and test the hypothesis by pursuing three specific aims that investigate 1) the relationship between sedative- induced changes in sleep homeostasis and the changes in NO and adenosine levels in basal forebrain, 2) the causal influence of NO and adenosine in basal forebrain on sedative-mediated recovery sleep, and 3) the role of NO synthase isoforms in sedative-mediated recovery of distinct sleep phases, i.e., slow-wave sleep vs. rapid eye movement sleep. The approach is innovative because this will be the first study to develop a mechanistic understanding of the processes mediating homeostatic sleep recovery during sedation. In addition, two technical innovations from our laboratory ? high density EEG recordings and mass spectrometric analysis of simultaneous changes in >55 brain analytes in rats ? will be used for mapping changes in rat brain cortical networks as an index of sedative-mediated sleep recovery, and comparison of basal forebrain neurochemistry between sedation and non-sedation states. The proposed research is significant because it is expected to help establish an EEG biomarker for sedation-induced sleep recovery, a framework for rational sedation strategies and, ultimately, facilitate drug design that could be used for sedation and sleep disorders.
Public Health Relevance: This research proposal is relevant to public health and the mission of NIGMS because it aims to understand the neurobiological mechanisms of the effect of sedative-hypnotics on sleep homeostasis, which will have a positive impact on patient care and drug/biomarker development in the field of sedation and sleep medicine.