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Scientists Discover ‘Reset’ Button For Our Biological Clock

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For the first time, scientists have discovered a “reset” button for our brain’s master biological clock — the ‘command center’ of the brain that maintains rhythms of sleeping and waking. The groundbreaking findings, reported in the Feb. 2 issue of the journal Nature Neuroscience, could eventually lead to new treatments for conditions like seasonal affective disorder, reduce the adverse health effects of working the night shift, and possibly even cure jet lag.

The biological clock is located in the suprachiasmatic nucleus (SCN) — a tiny region within the hypothalamus, a section of the brain that controls hormone production. The SCN maintains a 24-hour cycle of rest and activity that helps us know when we should be eating and sleeping (it’s also what determines if we are a ‘morning’ person or an ‘evening’ person). The cycle is also linked to critical biological activities like hormone and metabolic regulation, brain wave activity, and cell regeneration.

While these mechanisms are regulated in the brain, they’re affected by external cues like light and temperature. If an external factor throws this clock out of rhythm — be it through lack of exposure to sunlight, working late shifts, or binge-watching Netflix all night — it can induce mood changes, weight gain, and conditions such as depression and seasonal affective disorder. Over time, these effects can lead to major health problems including obesity, diabetes, heart disease, stroke, and possibly even cancer .

Over the years, various research efforts have been directed at pinning down the mechanism that keeps this clock ticking, and how it might be manipulated to counter the negative health impacts. This has resulted in solutions such as LED light glasses, purpose-built glass houses and glowing pillows.

Now, a team at Vanderbilt University say they have discovered a switch that controls our body’s master biological clock. The researchers, led by Dr. Douglas McMahon of the Department of Biological Sciences, found that they were able to artificially stimulate mouse brains with a specific technique to modify when the mice naturally woke up and went to sleep, without needing to change the light. They did this by stimulating or suppressing neurons in the SCN, effectively “resetting” the biological clock.

Optogenetics used to reset internal clock without altering environment

To reach their conclusions, the team genetically engineered two strains of mice. They chose the animal because mice have a biological clock that’s nearly identical to the ones humans have, except that mice are nocturnal. The neurons in the brains of one strain of mice contained an optically sensitive protein that triggers neuronal activity when exposed to light. The neurons in the brain of the other strain had a similar protein that suppressed neuronal activity when exposed to light. In other words, one of the strains of mice was wired to be nocturnal, while the other was wired to be diurnal, or awake in the day.

Then, the researchers stimulated neurons in the biological clocks of both strains of mice using a laser and an optical fiber, through a technique called optogenetics — a method that allows researchers to stimulate or suppress neurons with just a beam of light. First, light-sensitive genes are inserted into the neurons in order to make those neurons “turn on” when stimulated with the laser. By assessing how the neurons responded to the light, the researchers were able to both measure and control the rate at which neurons fired in the SCN.

The researchers discovered that, by altering the firing of neurons in the SCN, they could actually “reset” the mice’s circadian rhythms — shifting their internal schedules for sleeping and waking. The firing rate of these neurons had previously been thought to be only an output of the biological clock’s activity, but these findings indicate they also play a role in regulating our circadian rhythm.

‘We still have a lot to learn about how our biological clocks work’

According to doctoral student Jeff Jones, one of the study’s authors, scientists have been able to measure how quickly neurons fire within the biological clock, but they’ve never been able to control and alter the neural activity that happens there. Now, the optogenetic technique has given them the ability to do that. “This puts clock neurons under our control for the first time,” Jones said. Notably, the team was able to use optogenetics to directly activate the SCN in the absence of light, thereby resetting the clock without actually changing anything external about the mice’s environment.

While this approach isn’t yet ready for human use, the Vanderbilt team and other researchers are making progress towards the eventual creation of targeted pharmaceuticals that could turn on and off neurons that are implicated in circadian-related health problems. They hope to eventually see optogenics put to use in therapeutic contexts. This would involve an experimental technique that uses viruses to insert new genes into cells, which is considered a promising potential treatment for a number of diseases. This could be used to implant optically sensitive proteins in SCN neurons that could be activated by an implanted LED. The Vanderbilt team is currently testing whether strains of mice that suffer from seasonal affective disorder respond to this new approach.

“The fact that the SCN firing rate is a key component of circadian rhythmicity, rather than solely an output as we had thought, shows that we still have a lot to learn about how our biological clocks work,” added Dr. McMahon.



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