SALT LAKE CITY— When a person is sleeping, what exactly is it that sleeps? And if it is part of the brain, which part? These questions, to the surprise of James M. Krueger, PhD, are ones that sleep researchers do not often ask. Although the answers may lie mainly in the brain, evidence suggests that sleep is not a whole-brain phenomenon.

Dr. Krueger’s interest in exploring how sleep occurs stems from a single finding from numerous studies. That is, "With millions of stroke victims, there’s not a single, at least to my knowledge, description in the literature of a poststroke victim who fails to sleep," he said. "No matter what part of the brain is lesioned, [people] somehow reorganize their brain to start sleeping. Their sleep is probably not normal, but they sleep. They may have a bad rhythm distribution; there may be less of it—but they still sleep. I think this is an important collective finding of the field." Dr. Krueger, a Professor of Neuroscience at Washington State University in Pullman, addressed the 20th Anniversary Meeting of the Associated Professional Sleep Societies.

Sleep is incredibly robust, according to Dr. Krueger. "No specific area is necessary for sleep," he said. "This is a little bit controversial in one sense, because many people have devoted their lives to study sleep regulatory circuits. And they are, in fact, correct; there are sleep regulatory circuits. They are necessary for normal sleep regulation. I’m convinced of that. But they are not necessary for sleep to occur."

Research has shown that bottlenose dolphins, for example, have unilateral sleep and are able to swim while in this state. "Dolphins never have high-amplitude, slow-wave [sleep] simultaneously in both hemispheres," said Dr. Krueger. "That tells you at the very least that sleep is a property of half the brain. You don’t need the whole brain." Clinical observations have also suggested that a patient could be asleep and awake simultaneously, he added. "To a neurologist, this is not so new."

SLEEP REGULATION

Dr. Krueger’s research has dealt with such topics as how viral double-stranded RNA initiates the sleep cascade, as well as the role that cytokines have in physiologic sleep regulation. He and his colleagues have shown that interleukin-1, tumor necrosis factor (TNF), and growth hormone–releasing hormone all increase non-REM sleep. When those substances are inhibited, then sleep is inhibited. "You can make a rat look a little more like a dolphin, sleeping more intensely on one side than on the other, just by sprinkling TNF on [one side of] the cortex," said Dr. Krueger.

Much of the research that Dr. Krueger conducts involves whisker twitching in rats, which induces cortical synaptic reorganization. "Whiskers are very important to a rat," explained Dr. Krueger. "By giving a rat a shave, it’s the equivalent of blinding you, or almost the equivalent, until the whiskers grow back."

CORTICAL COLUMN THEORY

Dr. Krueger and colleagues have hypothesized that sleep is initiated in these cortical columns within larger neuronal groups. When enough of these cortical columns go to sleep, so to speak, then the entire body goes into sleep mode. "If we were right, and the cortical columns were the fundamental unit that sleep is involved in, we ought to be able to demonstrate, at least sometime, that one cortical column could be in a sleep-like state and another cortical column in a wake-like state," noted Dr. Krueger. "And this could interchange regardless of organism state."

A colleague of Dr. Krueger’s, David Rector, PhD, pursued this line of thought by twitching the whiskers of rats and recording amplitudes of surface-evoked response potentials for two separate cortical columns, one on each side of the brain. "When the animal is in quiet sleep, generally the amplitude of these evoked response potentials is higher," noted Dr. Krueger. "Occasionally, you can find periods when they separate. For example, [in] a period of quiet sleep, on the right side of the brain the cortical column is behaving as if it is in a sleep-like state, because it has a higher surface-evoked potential. On the other side of the brain, it is lower, behaving more like it is awake. So it is these areas where they are separated that are important. In essence, the cortex is sort of like a Christmas tree with blinking lights on. Most of the time, those lights are blinking in synchrony. But every now and then you can have an odd light blinking on."

Dr. Rector has also developed a conditioned learning paradigm in which rats were taught to lick after a single whisker was twitched and to not lick when another whisker was twitched. Once the rats were conditioned, one whisker was twitched repeatedly, tiring out the neurons connected to it. Subsequently, when the cortical column went to sleep, the rat’s score on the test decreased. "The bottom line is when that cortical column is in a sleep-like state, when its amplitude of surface-evoked potentials is higher, [the rat] makes mistakes," noted Dr. Krueger. "When it is awake, in a wake-like state, it doesn’t make mistakes…. The state of the column makes a difference in behavior, and the behavior is predicted in the right way. You make more mistakes in your learned behavior when you are sleepy than when you are wide awake."

When these findings are published, "I think it will be one of the more important papers in neuroscience, because it is showing column state predicting of behavior," commented Dr. Krueger.

—Colby Stong

Suggested Reading
Churchill L, Yasuda K, Yasuda T, et al. Unilateral cortical application of tumor necrosis factor alpha induces asymmetry in Fos- and interleukin-1 beta-immunoreactive cells within the corticothalamic projection. Brain Res. 2005;1055:15-24.
Rector DM, Topchiy IA, Carter KM, Rojas MJ. Local functional state differences between rat cortical columns. Brain Res. 2005;1047:45-55.
Traynor TR, Majde JA, Bohnet SG, Krueger JM. Sleep and body temperature responses in an acute viral infection model are altered in interferon type I receptor-deficient mice. Brain Behav Immun. 2006;20:290-299.

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