Biological Clocks Discovery Overturns Long-held Theory

University of Michigan mathematicians and their British colleagues say they have identified the signal that the brain sends to the rest of the body to control biological rhythms, a finding that overturns a long-held theory about our internal clock.

Understanding how the human biological clock works is an essential step toward correcting sleep problems like insomnia and jet lag. New insights about the body's central pacemaker might also, someday, advance efforts to treat diseases influenced by the internal clock, including cancer, Alzheimer's disease and mood disorders, said University of Michigan mathematician Daniel Forger.

"Knowing what the signal is will help us learn how to adjust it, in order to help people," said Forger, an associate professor of mathematics and a member of the U-M's Center for Computational Medicine and Bioinformatics. "We have cracked the code, and the information could have a tremendous impact on all sorts of diseases that are affected by the clock."

The body's main time-keeper resides in a region of the central brain called the suprachiasmatic nuclei, or SCN. For decades, researchers have believed that it is the rate at which SCN cells fire electrical pulses---fast during the day and slow at night---that controls time-keeping throughout the body.

Imagine a metronome in the brain that ticks quickly throughout the day, then slows its pace at night. The rest of the body hears the ticking and adjusts its daily rhythms, also known as circadian rhythms, accordingly.

That's the idea that has prevailed for more than two decades. But new evidence compiled by Forger and his colleagues shows that "the old model is, frankly, wrong," Forger said.

The true signaling mechanism is very different: The timing signal sent from the SCN is encoded in a complex firing pattern that had previously been overlooked, the researchers concluded. Forger and U-M graduate student Casey Diekman, along with Dr. Mino Belle and Hugh Piggins of the University of Manchester in England, report their findings in the Oct. 9 edition of Science.

To test predictions made by Forger and Diekman's mathematical model, the British scientists collected data on firing patterns from more than 400 mouse SCN cells. The U-M scientists then plugged the experimental results into their model and found that "the experimental data were almost exactly what the model had predicted," Forger said.

Though the experiments were done with mice, Forger said it's likely that the same mechanism is at work in humans, since timekeeping systems are similar in all mammals.

The SCN contains both clock cells (which express a gene call per1) and non-clock cells. For years, circadian-biology researchers have been recording electrical signals from a mix of both types of cells. That led to a misleading picture of the clock's inner workings.

But Forger's British colleagues were able to separate clock cells from non-clock cells by zeroing in on the ones that expressed the per1 gene. Then they recorded electrical signals produced exclusively by those clock cells. The pattern that emerged bolstered the audacious new theory.

"This is a perfect example of how a mathematical model can make predictions that are completely at odds with the prevailing views yet, upon further experimentation, turn out to be dead-on," Forger said.

The researchers found that during the day, SCN cells expressing per1 sustain an electrically excited state but do not fire. They fire for a brief period around dusk, then remain quiet throughout the night before releasing another burst of activity around dawn. This firing pattern is the signal, or code, the brain sends to the rest of the body so it can keep time.

"The old theory was that the cells in the SCN which contain the clock are firing fast during the day but slow at night. But now we've shown that the cells that actually contain the clock mechanism are silent during the day, when everybody thought they were firing fast," Diekman said.

Piggins said the findings "force us to completely reassess what we thought we knew about electrical activity in the brain's circadian clock." In addition, the results demonstrate the importance of interdisciplinary collaborative research, he said.

"This work also raises important questions about whether the brain acts in an analog or a digital way," Belle said.

Learning To Talk Changes How Speech Is Heard: 'Sound Of Learning' Unlocked By Linking Sensory And Motor Systems

Learning to talk also changes the way speech sounds are heard, according to a new study published in Proceedings of the National Academy of Sciences by scientists at Haskins Laboratories, a Yale-affiliated research laboratory. The findings could have a major impact on improving speech disorders.

"We've found that learning is a two-way street; motor function affects sensory processing and vice-versa," said David J. Ostry, a senior scientist at Haskins Laboratories and professor of psychology at McGill University. "Our results suggest that learning to talk makes it easier to understand the speech of others."

As a child learns to talk, or an adult learns a new language, Ostry explained, a growing mastery of oral fluency is matched by an increase in the ability to distinguish different speech sounds. While these abilities may develop in isolation, it is possible that learning to talk also changes the way we hear speech sounds.

Ostry and co-author Sazzad M. Nasir tested the notion that speech motor learning alters auditory perceptual processing by evaluating how speakers hear speech sounds following motor learning. They simulated speech learning by using a robotic device, which introduced a subtle change in the movement path of the jaw during speech.

To assess speech perception, the participants listened to words one at a time that were taken from a computer-produced continuum between the words "had" and "head." In the speech learning phase of the study, the robot caused the jaw to move in a slightly unusual fashion. The learning is measured by assessing the extent to which participants correct for the unusual movement.

"Its like being handed a two-pound weight for the first time and being asked to make a movement, it's uncomfortable at first, but after a while, the movement becomes natural," said Ostry. "In growing children, the nervous system has to adjust to moving vocal tract structures that are changing in size and weight in order to produce the same words. Participants in our study are learning to return the movement to normal in spite of these changes. Eventually our work could have an impact on deviations to speech caused by disorders such as stroke and Parkinson's disease."

"Our study showed that speech motor learning altered the perception of these speech sounds. After motor learning, the participants heard the words differently than those in the control group," said Ostry. "One of the striking findings is that the more motor learning we observed, the more their speech perceptual function changed."

Ostry said that future research will focus on the notion that sensory remediation may be a way to jumpstart the motor system.

The team previously found that the movement of facial muscles around the mouth plays an important role not only in the way the sounds of speech are made, but also in the way they are heard.

Haskins Laboratories was founded in 1935 by the late Dr. Caryl P. Haskins. This independent research institute has been in New Haven, Connecticut since 1970 when it formalized affiliations with Yale University and the University of Connecticut. The Laboratories' primary research focus is on the science of the spoken and written word.

Short Heels Make Elite Sprinters Super Speedy: Longer Toes, Unique Ankle Structure Aid Sprinters

Longer toes and a unique ankle structure provide sprinters with the burst of acceleration that separates them from other runners, according to biomechanists.

"At the start of a sprint the only way a runner can speed up is through the reaction force that results from the action of leg muscles pushing on the ground," said Stephen Piazza, associate professor of kinesiology, Penn State. "Long toes provide sprinters the advantage of maintaining maximum contact with the ground just a little bit longer than other runners."

Piazza and his colleague Sabrina S. M. Lee, former Penn State graduate student now a post-doctoral fellow at Simon Fraser University, Vancouver, Canada, studied the muscle architecture of the foot and ankle to look at the differences between sprinters and non-sprinters.

They matched 12 collegiate sprinters with 12 non-athletes of the same height. They measured the distance between the heel and the end of the toes and used ultrasound imaging to measure the sliding of the Achilles tendon during ankle motion, from which the leverage of the tendon can be calculated.

"What we found was that the lever arms (distance between the tendon and center of rotation of the ankle) were significantly shorter -- about 25 percent shorter -- in sprinters," said Piazza, whose findings appeared recently in the Journal of Experimental Biology. "This difference might be explained by a tradeoff between leverage and muscle force-generating capacity."

Because the lever arms are shorter, the muscles shorten less for the same joint rotation. If muscles shorten less, they shorten more slowly, which helps them to produce greater force that more than compensates for the reduced leverage.

While there is little published work on foot shapes and sprinting, previous work on animals suggests that ostriches, greyhounds and cheetahs have feet built for sprinting.

To understand the kind of human foot that would produce a similar sprinting advantage, the researchers developed a simple computer model that could analyze the physiological data they had collected earlier.

"We wanted to see how much acceleration we could get out of the model when we changed the tendon lever arm and the length of the toes," said Piazza. "What we found is that when the Achilles tendon lever arm is the shortest and the toes are longest, we get the greatest acceleration."

Piazza cites other recent research suggesting that shorter toes in modern humans could be an evolutionary adaptation for efficient distance running.

"Maybe our ancestors with longer toes were better sprinters. Or maybe longer toes were selected for at a time when navigating in trees was more important and our toes became shorter as endurance running became more important for our survival," he added.

The Penn State researcher cautions that while the study could be a piece of the puzzle in determining who could potentially be a good sprinter, other physiological components such as body type, cardiovascular physiology and muscle fiber types should also be taken into account.

It is also unclear whether sprinting ability is congenital or whether training can influence the shape of bones in the foot.

"It is not too far-fetched to think that training can help accentuate the shape of the bone," said Piazza. "But if sprinters' skeletal characteristics were shown to be immutable, it would support the coaches' adage that sprinters are born and not made."

The National Science Foundation funded this work.