June 19, 2005 Unconventional wiring of the brain circuits that govern sleep and waking might explain the prevalence of insomnia and the condition's association with obesity, according to new work published in the April issue of Cell Metabolism. Characterized by a chronic inability to fall asleep or remain sleeping, insomnia is estimated to affect one in every eight Americans.
By finding ways to interfere with that unconventional wiring, scientists may advance on new treatments for insomnia, the researchers said. Natural variation in this brain system might also explain differences among people in their susceptibility to sleep disturbances.
The researchers found that so-called hypocretin neurons--having important roles in both arousal and appetite--lack the ability of most neurons to filter "noise" from signal, reported Tamas Horvath and Xiao-Bing Gao of Yale University School of Medicine. The neurons also rapidly reorganize themselves, becoming even more excitable, in response to stresses such as food deprivation, they found.
"The cell bodies of most neurons act as a filter," sorting through a multitude of signals to eliminate noise and generate an appropriate response, Horvath said. "In contrast, it appears that the basic wiring of hypocretin neurons allows noise to become the major signal."
As obesity has reached epidemic proportions, the incidence of insomnia and sleep deprivation has also risen. Studies of this apparent insomnia-obesity association have suggested a causal link between the two, but the underlying mechanism has remained unclear. The new findings of hypocretin neurons offer some possible clues, Horvath said.
Scientists discovered hypocretin neurons while studying narcolepsy, a condition marked by sudden bouts of deep sleep. Narcolepsy generally stems from a shortage or malfunction of hypocretin neurons. The neurons also induce appetite, an important activity for the control of food intake. Yet the integration of the brain cells' roles in arousal and appetite remains largely unexplored, Horvath said.
In a series of experiments in brain slices and in mice, the researchers examined the organization and stability of inputs to hypocretin cell bodies, which act as filters in other brain cells. They found that hypocretin neurons have an "unorthodox" organization in which excitatory currents exert control on nerve cell bodies with minimal inhibitory inputs to filter them.
Overnight food deprivation promoted the formation of more excitatory inputs. Those new inputs were reversed upon refeeding, they reported, an indication of the extreme plasticity of the hypocretin system to prevailing conditions.
That sensitivity and adaptability makes sense, given the neurons' role as the body's natural alarm, rousing one from slumber in response to external cues, Horvath said. However, the structure of the system might also explain the prevalence of sleep disorders and, perhaps, the associated rise in obesity.
"In an evolutionary sense, the response of the hypocretin system to small stimuli would have been necessary for survival," he said. "But in today's chronically stressful environment, the circuitry may also be an underlying cause of insomnia and associated metabolic disturbances, including obesity."
The researchers included Tamas L. Horvath and Xiao-Bing Gao of Yale University School of Medicine. This work was supported by NIH grants.
Tamas L. Horvath and Xiao-Bing Gao: "Input organization and plasticity of hypocretin neurons: Possible clues to obesity's association with insomnia"
Publishing in Cell Metabolism, Volume 1, Number 4, April 2005, pages 279-286. www.cellmetabolism.org
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