New wakefulness, anti-anxiety switch found in the brain

August 18, 2004

Researchers have found that a newly discovered protein switch appears to work in the brain to enhance wakefulness and reduce anxiety in laboratory animals. According to Rainer Reinscheid and his colleagues, the protein, which they named neuropeptide S (NPS), could help in the understanding of sleep disorders, anxiety, and depression.

The researchers also discovered that NPS is produced in a previously uncharacterized population of brain cells, perhaps indicating a new and distinct molecular pathway for regulating vigilance.

"Sleep disorders and anxiety affect millions of people," wrote the researchers. "Identifying and understanding the molecular regulators and neurocircuitries that are involved in sleep/wake cycles or arousal and anxious states are keys to the development of therapeutic targets for these diseases."

In their studies, Reinscheid and his colleagues sought to understand the function of a protein receptor and its triggering molecule discovered by other researchers, who had determined their structure but not explored their effects. Many such triggering molecules--short proteins called neuropeptides--exist in the brain and are known to regulate an array of brain functions. The neuropeptides plug into corresponding receptor proteins nestled in the membranes of brain cells, triggering responses in the cells that govern processes from learning to emotional responses.

Studies in rats by Reinscheid and his colleagues revealed that NPS was produced in a few discrete brain regions, particularly in a distinct, previously uncharacterized cluster of cells in the brain region known to regulate arousal and anxiety. The receptor for NPS was widely expressed in many brain regions, found the researchers, including those known to be involved in anxiety. The widespread expression of the receptor suggested that NPS could play a role in a variety of brain functions, concluded the researchers.

When they administered NPS to mice, they found that it produced an increase in locomotor activity; in rats, NPS increased wakefulness and suppressed sleep.

The researchers also tested the effects on anxiety of NPS by administering it to mice placed in environments that could trigger responses indicating their level of stress. For example, in one experiment, animals were given a choice of an anxiety-producing lighted area or a "safer" dark area. The researchers found that the mice treated with NPS showed less fear of being in the lighted area, with the fear reduction corresponding to the dose of NPS. The treated mice also showed reduced fear of an elevated environment in a similar dose-dependent manner.

To distinguish whether the animals' seeming reduced anxiety might just be due to the increased locomotor activity from NPS, the researchers tested the animals' tendency to bury marbles placed in their cages. The level of this natural behavior more directly reflects the level of the animals' anxiety. Reinscheid and his colleagues found that the treated animals buried fewer marbles than untreated animals, again correlating with the dose of NPS.

The researchers concluded that "the discovery of this novel transmitter system that modulates sleep-wake cycles and anxiety might help to further our understanding of sleep disorders, such as insomnia, and pathological states of anxiety. It should be noted that excessive anxiety and disruption of sleep patterns are often observed in patients suffering from depression," they added.
Yan-Ling Xu, Rainer K. Reinscheid, Salvador Huitron-Resendiz, Stewart D. Clark, Zhiwei Wang, Steven H. Lin, Fernando A. Brucher, Joanne Zeng, Nga K. Ly, Steven J. Henriksen, Luis de Lecea, and Olivier Civelli: "Neuropeptide S: A Neuropeptide Promoting Arousal and Anxiolytic-like Effects"

Publishing in Neuron, Volume 43, Issue 4, 19 August 2004, pages 487-497.

Cell Press

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