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Valeo, Tom

doi: 10.1097/01.NT.0000424081.51426.14
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Investigators describe their inroads in understanding the pathophysiology of sleep disorders and potential therapeutic targets through experiments with optogenetics.

Optogenetics provides a precise and powerful tool for studying both arousal and deep REM sleep, presenters at the recent Society for Neuroscience meeting demonstrated.

As the name implies, optogenetics employs genetic engineering to add an “opsin” gene, which generates photosensitive proteins, to neurons in the mouse brain, causing them to turn on or off in response to specifically colored light delivered through a fiber-optic wire that runs from the light source directly into the brain. This provides exquisite control over individual cells, causing them to fire on command without altering the function of surrounding cells. In contrast, electrical stimulation affects all cells in the vicinity of the electrode, and drugs flood the brain, producing widespread changes that disguise alterations in individual cells.

Antoine Adamantidis, PhD, an assistant professor in the department of psychiatry at McGill University in Montreal, has used optogenetics both to wake animals up and to put them to sleep as part of his ongoing research into the neural circuits involved in the sleep-wake cycle of the mammalian brain.

“If you lack the hypocretin gene [a peptide produced by the hypothalamus that promotes arousal and wakefulness] — or have dysfunctional hypocretin system, you become narcoleptic,” he told Neurology Today. “We found when we excite hypocretin neurons with blue light pulses we wake animals up.”

In his most recent work, Dr. Adamantidis has been investigating melanin-concentrating hormone (MCH), produced by neurons in the hypothalamus. The peptide appears to promote sleep.

“The current hypothesis is that hypocretin wakes the animal up, but we didn't know what makes animals fall asleep,” he said. “What is interesting about the MCH neurons in the hypothalamus is that they're not actually involved in non-REM sleep — the first sleep stage that produces light sleep. They're more involved in REM sleep — the deep sleep. We found with optogenetics that if we selectively activated MCH neurons in non-REM sleep, the animal goes into really deep REM sleep. When we stimulate them in REM sleep, we can extend REM sleep by 40–50 percent. We're really excited about this.”

Such work could not have been done, according to Dr. Adamantidis, without the optogenetic method developed by Karl Deisseroth, MD, PhD, at Stanford University, where Adamantidis obtained his PhD. “With optogenetics you can mimic what is really happening in brain,” he said. “With genetic or pharmacological approaches you must be careful about your conclusions because the temporal resolution of those techniques is so low. If you suppress a gene, compensatory mechanisms in the body can occur. When you inject drugs you flood brain. With optogenetics we can selectively manipulate a few cells in the living animal.”

Thomas E. Scammell, MD, who studies sleep circuitry and the neurobiology of narcolepsy at Harvard Medical School, praised Dr. Adamantidis' work on MCH neurons.

“We don't know a lot about how the brain controls REM sleep, but he found a population of cells in the hypothalamus that makes melanin concentrating hormone, and he now can drive REM sleep with that,” said Dr. Scammell, an associate professor of neurology at both Harvard and Beth Israel Deaconess Medical Center. “That has not been possible previously, and it leads to the question, what does REM sleep do? It may provide a method for manipulating REM sleep.”

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Angela Kim, a graduate of the Korea Institute of Science and Technology in Seoul who is studying for her master's degree at the University of Science and Technology in Daejeon, Republic of South Korea, presented a poster of her recent work in which she used optogenetics to demonstrate that sleep spindles — a type of EEG rhythm produced during non-REM sleep — maintain the stability of sleep.

By using optogenetic techniques on mice, Kim demonstrated that sleep spindles play a critical role in protecting sleep. Narcolepsy patients, for example, show abnormally high numbers of sleep spindles, while people with major depression, schizophrenia, and other psychiatric disorders that involve sleep disturbances, often display impaired sleep spindle activity.

Kim demonstrated this by using optogenetics to modulate the activity of the thalamic reticular nucleus (TRN), a known to be the source of sleep spindles. After developing a technique to induce sleep spindles in the mice, Kim and her colleagues increased the total duration of non-REM sleep through optogenetic stimulation, and induced more transitions from non-REM to REM sleep.

These results provide a valuable insight into the TRN region as a novel therapeutic and diagnostic target for the treatment of sleep disorders, Kim noted in the abstract for the study at the Society for Neuroscience meeting. “Modulation of sleep spindles may prove to be an effective treatment for restoring normal sleep architecture in patients suffering from disrupted sleep.”

By generating sleep spindles Kim managed to determine what they actually do, said George Augustine, PhD, a professor of neuroscience and behavioral disorders at the Duke-NUS Graduate Medical School in Singapore, and director of the Center for Functional Connectomics at the Korea Institute of Science and Technology.

“Angela's results were consistent with the idea that spindles protect the sleep state to enable transitions between various sleep states but not the awake state,” said Dr. Augustine.

Kim's work would have been impossible without optogenetics, a “very enabling technology,” according to Dr. Augustine. “For the first time, by using power of this new optogenetic technology, she established the cause-and-effect relationship between neurons in the thalamus and sleep spindles. It wasn't a complete surprise, but the difference between thinking you know something and showing that you know it is quite significant.”

Using a similar technique, Michael Halassa, MD, PhD, also generated sleep spindles by delivering a single pulse to the TRN optogenetically, as he and his colleagues described in a 2011 paper in Nature Neuroscience.

“Jump-starting the TRN precisely can generate a full-blown spindle,” said Dr. Halassa, an instructor in psychiatry at Harvard Medical School, a resident in Psychiatry at Massachusetts General Hospital, and a Neuroscience research fellow at Massachusetts Institute of Technology. “Using a 20 ms pulse into TRN can generate a 1-second spindle.”

Kim contends that an authentic spindle could not be generated by such stimuli, and that her work clearly distinguishes spindles that occur spontaneously from those caused by photostimulation. In addition, she said her work shows that the spindles caused by her optogenetic photostimulation actually change sleep patterns, thereby establishing a causal relationship between spindles and sleep.

All the researchers hope their work will point the way toward better methods of treating sleep disorders or, as Karl Deisseroth discussed in a recent issue of Biological Psychiatry, of providing relief for the sleep problems that often accompany psychiatric disorders such as schizophrenia, anxiety, and depression.

“We believe that by identifying the dynamics of a circuit you can define new targets for pharmacological use,” said Dr. Adamantidis. “That's certainly one of these outcomes of what we would like to see.”

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• de Lecea L, Carter MD, and Adamantidis A. Shining light on wakefulness and arousal. Biol Psychiatry 2012;71(12):1046–1052.
    • Halassa MM, Siegle JH, Moore CI, et al. Selective optical drive of thalamic reticular nucleus generates thalamic bursts and cortical spindles. Nature Neurosci 2011;14(9):1118–1120.
      • Deisseroth K. Optogenetics and psychiatry: Applications, challenges, and opportunities. Biol Psychiatry 2012;71:1030–1032.
        Neurology Today archive on optogenetics:
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