Scientists at the Salk Institute for Biological Studies have identified a gene that regulates sleep and wake rhythms.<\/p>\n
The discovery of the role of this gene, called Lhx1, provides scientists with a potential therapeutic target to help night-shift workers or jet lagged travellers adjust to time differences more quickly. The results can point to treatment strategies for sleep problems caused by a variety of disorders.<\/p>\n
\u201cIt\u2019s possible that the severity of many dementias comes from sleep disturbances,\u201d says Satchidananda Panda, a Salk associate professor who led the research team. \u201cIf we can restore normal sleep, we can address half of the problem.\u201d<\/p>\n
Every cell in the body has a \u201cclock\u201d \u2013 an abundance of proteins that dip or rise rhythmically over approximately 24 hours. The master clock responsible for establishing these cyclic circadian rhythms and keeping all the body\u2019s cells in sync is the suprachiasmatic nucleus (SCN), a small, densely packed region of about 20,000 neurons housed in the brain\u2019s hypothalamus.<\/p>\n
More so than in other areas of the brain, the SCN\u2019s neurons are in close and constant communication with one another. This close interaction, combined with exposure to light and darkness through vision circuits, keeps this master clock in sync and allows people to stay on essentially the same schedule every day. The tight coupling of these cells also helps make them collectively resistant to change. Exposure to light resets less than half of the SCN cells, resulting in long periods of jet lag.<\/p>\n
In the new study, researchers disrupted the light-dark cycles in mice and compared changes in the expression of thousands of genes in the SCN with other mouse tissues. They identified 213 gene expression changes that were unique to the SCN and narrowed in on 13 of these that coded for molecules that turn on and off other genes. Of those, only one was suppressed in response to light: Lhx1.<\/p>\n
\u201cNo one had ever imagined that Lhx1 might be so intricately involved in SCN function,\u201d says Shubhroz Gill, a postdoctoral researcher and co-first author of the paper. Lhx1 is known for its role in neural development: it\u2019s so important, that mice without the gene do not survive. But this is the first time it has been identified as a master regulator of light-dark cycle genes.<\/p>\n
By recording electrical activity in the SCN of animals with reduced amounts of the Lhx1 protein, the researchers saw that the SCN neurons weren\u2019t in sync with one another, despite appearing rhythmic individually.<\/p>\n
\u201cIt was all about communication\u2013the neurons were not talking to each other without this molecule,\u201d says Ludovic Mure, a postdoctoral researcher and an author on the paper. A next step in the work will be to understand exactly how Lhx1 affects the expression of genes that creates this synchronicity.<\/p>\n
Studying a mouse version of jet lag\u2013an 8-hour shift in their day-night cycle\u2013the scientists found that those with little or no Lhx1 readjusted much faster to the shift than normal mice. This suggests that because these neurons are less in sync with one another, they are more easily able to shift to a new schedule, though it is difficult for them to maintain that schedule, Panda says.<\/p>\n
These mice also exhibited reduced activity of certain genes, including one that creates vasoactive intestinal peptide or Vip, a molecule that has important roles in development and as a hormone in the intestine and blood. In the brain, Vip affects cell communication, but nobody had known that Lhx1 regulated it until now, Panda says. Interestingly, the team also found that adding Vip restored cell synchrony in the SCN.<\/p>\n
\u201cThis approach helped us to close that knowledge gap and show that Vip is a very important protein, at least for SCN,\u201d Panda says. \u201cIt can compensate for the loss of Lhx1.\u201d<\/p>\n
On the other hand, cutting back on Vip could be another way to treat jet lag. Vip could be an even easier drug target compared with Lhx1 because Vip is secreted from cells rather than inside cells, Panda says. \u201cIf we find a drug that will block the Vip receptor or somehow break down Vip, then maybe that will help us reset the clock much faster,\u201d he adds.\nSalk Institute for Biological Studies<\/link>\n","protected":false},"excerpt":{"rendered":"
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