Sleep Function – Mechanisms Lab

Dr. Krueger’s research is focused on the biochemical regulation of sleep.  He has described how many hormones and immune regulators are involved in physiological sleep regulation. These substances, and their corresponding mRNAs and protein levels, vary in brain with the sleep-wake cycle and are affected by sleep deprivation.  If injected into animals, these substances increase sleep.  Conversely, if they are inhibited, sleep is inhibited, and the sleep rebound after sleep deprivation is also blocked.  These substances include cytokines such as interleukin-1 (IL1) and tumor necrosis factor (TNF). Cytokines are a group of small proteins involved in the immune response and inflammation regulation as well as brain plasticity and sleep.  In brain, they are synthesized in neurons in response to neuronal activity.  Collectively, his work led to a description of a molecular sleep homeostat.

Dr. Krueger’s research also is concerned with sleep and infectious diseases.  Although known for millennia, e.g., Hippocrates proposed that sleep benefits recovery from illness, Dr. Krueger and his collaborator, Dr. Linda Toth, provided the first measures of sleep over the course of infections.  Dr. Krueger went on to show that bacterial, protozoan, fungal and viral infectious agents greatly alter sleep.  His work determined how the presence of microbes is translated into sleep responses.  Thus, bacterial cell wall-peptidoglycan is digested by macrophages, releasing somnogenic muramyl peptides (these are the monomeric building blocks of bacterial cell walls).  Muramyl peptides in turn induce enhanced production of cytokines which in turn promote sleep.  With virus infections, viral double-stranded RNA enhances cytokine release and thereby sleep. 

Dr. Krueger has proposed a new view of the brain organization of sleep.  He hypothesized that small neuronal/glial networks are the organizational level at which sleep is initiated and that local sleep is dependent upon prior activity within the local network.  Thus, active glia and neurons increase expression of cytokines that in turn drive increases in sleep locally.  Individual cortical columns (these are the functional units of the cerebral cortex) alternate between sleep- and wake-like states.  The cortical column sleep-like state correlates with organism sleep, and it is induced by cytokines.  In vitro mature co-cultures of neurons/glia have a default sleep-like state.  If electrically stimulated, or stimulated with wake-promoting substances, the cultures wake up.  In contrast, if treated with cytokines the cultures, go into a deeper sleep-like state.  Finally, if cells from mice lacking a key molecule involved in interleukin-1 signaling are cultured, the ontological emergence of sleep-like states is delayed.  These data demonstrate that sleep is an emergent property of any viable network of neurons and glia whether found with a living animal or in a culture dish.  The concept of sleep as a fundamental process of small networks driven by cell activity triggered a paradigm shift within the sleep research community.

James Krueger

Regents Professor
Integrative Physiology & Neuroscience

j.krueger@wsu.edu
509-358-7808
WSU Health Sciences Spokane