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A Light on Life's Rhythms

Cara Altimus and her dogs Cara Altimus and her dogs, Tuxedo and Zinnia.

August 2011--A dozen bleary-eyed students lay draped across the furniture in a university lounge at dawn. By the flickering light of the movie Ratatouille, each one gently played with one or two lab mice.

It was part of graduate student Cara Altimus' study on the effects of sleep loss on the mice. Altimus couldn't exactly hold 20 mice herself to keep them awake, so she convinced her labmates to help "Pet a Mouse for Science."

Because mice and humans use similar neurological processes to control many behaviors, studies like this promise to help us better understand the effects of insufficient or disrupted sleep on night shift workers, people with sleep disorders and even students who pull all-nighters to cram for exams.

Now a 26-year-old neuroscientist at the Johns Hopkins University School of Medicine in Baltimore, Maryland, Altimus is burrowing deeper into the brain. She uses genetic and behavioral experiments to uncover how networks of cells, proteins and genes control learning, memory, mood and the daily rhythms of our bodies.

"What gets me excited is circuits -- not electrical circuits, but how cells and components interact," says Altimus. "When you think about it, our memories are just cells talking to each other."

Sand Science

Altimus says the first inklings that she might become a scientist came when, as a kid, she "watched sand move around."

She grew up on St. Simons Island, a major shipping port off the coast of Georgia. Every storm that hit the island swept in mounds of sand that clogged the shipping channels. Altimus watched as engineers scrambled to clear the sand without "messing with" its natural movement up the coast.

"We watched experiments in action," she recalls. "As a family, we would try to predict what would happen" to the sand over time if the engineers hauled it out to sea or dumped it on land.

In high school, she did a science fair project on whether the color of sand related to its proximity to sediment-rich rivers or the ocean.

"We took the family boat to every nearby beach," she says. "It took a whole summer. I took it super-seriously."

By the time she went to college at the University of Georgia, she thought she would become a geologist. On a 10-week van trip across the country, she helped a group of geologists map rivers and canyons, filling notebook after notebook with field observations.

But Altimus ultimately found geology "too static." She turned to ecology, then genetics, and that led her into neuroscience. Now she perturbs genes and sleep patterns instead of sand.

In a twist of fate, in 2010 Altimus married a geologist. She and her husband, John, have spirited debates about just how "static" geology is, and compete to identify rocks or find fossils faster.

With a grin, she says, "He's not always the best."

null Our eyes aren't just for seeing. They also help regulate our body's master clock in the suprachiasmatic nucleus, or SCN. When light enters our eyes, it triggers nerve impulses that zip down our optic nerves and relay information about ambient light levels to the SCN.

More than Meets the Eye

When she started graduate school at Hopkins, Altimus joined the biology department and "rotated in every kind of lab I could."

That included studying gonad formation in flies, neural development in zebrafish and light's effect on body temperature in mice.

She decided on the lab of neuroscientist Samer Hattar, where she studied the "master clock" in the brain. This clock, driven by hundreds of genes and proteins, keeps our bodies running on a roughly 24-hour cycle.

Our brains also use ambient light as an external cue to align our daily, or circadian, rhythms with our environment.

Altimus wanted to know more about how light and darkness help set our inner clock and what happens when our clock is out of synch with the world around us.

When she started her research, scientists already knew that light enters the eye, strikes the retina and triggers nerve impulses that travel along the optic nerve to the brain.

Altimus' first discovery in Hattar's lab was that light information actually has two possible paths to follow: "image-forming," which creates a picture of what we see, or "nonimage-forming," which relays information about how light or dark it is out there.

It turns out that the nonimage-forming path has a big impact on us without our conscious control. It helps align our master clock, constricts our pupils when it's bright outside and even affects our mood and alertness.

"This was her first discovery, and it was a major paper and changed the field," says Hattar. "I still get shivers."

But how do cells in the retina work together to sense the amount of light around us and adjust accordingly? Learning about this process, known as photoentrainment, became Altimus' next major project.

null The retina spreads out in this image like flower petals with the optic nerve at the center. Nerve cells containing the light-sensitive protein melanopsin are shown in blue. Photo from David McNeill, Hattar Lab

Responding to the Light

There are three kinds of light-sensitive cells in the eye: rods, which help us see in the dark; cones, which allow us to see in color; and a tiny smattering of another cell type containing a light-sensitive protein called melanopsin.

The team believed that rods and cones were transmitting imageforming information, while the melanopsin cells were responsible for photoentrainment.

But if people (or mice) don't have working melanopsin cells, their brains still sense light and align their circadian rhythms. Clearly, melanopsin cells aren't the only ones contributing to photoentrainment.

That left two options: rods and cones. Because cones are the main players in image formation during daylight hours, most scientists suspected they would also be the ones involved in photoentrainment.

Altimus proved otherwise.

Through genetic engineering of mice, she showed that rods, rather than cones, help with the heavy lifting of photoentrainment.

"This is where she soared," says Hattar.

She went on to discover that light and dark both affect sleep patterns, and that melanopsin plays a role in the process.

mouse running in a wheel Mice are nocturnal. Those in a laboratory spend most of the day asleep and most of the night running on their exercise wheels.

Night Shift

Driven by concern about the health impact of night shift work, Altimus investigated the effects of exposure to light at the wrong time of day.

She found that when she shifted the sleep patterns of mice by turning on a light when it was supposed to be dark (a regular experience for night workers), the animals had temporary learning problems.

To detect learning, she gave the animals new objects -- typically Christmas ornaments -- and let them sniff, nudge and climb all over them. Sometime later, she would show the mice the ornaments again to see whether they recognized them.

She discovered that, even when the mice got a normal amount of sleep, if their sleep cycles were misaligned with their environment, they didn't seem to remember the objects. This suggests that shift work might cause trouble with learning and remembering, even for those workers who get 8 hours of sleep during the day.

Construction Zone

When Altimus began her research, Hattar's lab didn't have all the equipment she needed.

She lacked the budget and the patience to wait, so she built what she needed herself.

Armed with amateur experience in woodworking and a stubborn determination, she made a water maze -- a setup that can cost $10,000 -- from a $350 cattle tank. Then she built a camera mount on the ceiling to record the mice's movements.

She made boxes to hold the cages where the mice ran on their wheels. She built a crate to house a tool that measured the mice's ability to track a moving pattern. And she put together a contraption shaped like a plus sign to see how much time the mice spent in closed versus open spaces, a measure of their anxiety levels.

It wasn't all perfect -- sometimes she had to build things twice -- but today, the lab staff still uses much of what she built.

Knack for Numbers

Altimus also has another uncommon and useful skill.

"I am slightly obsessed with numbers," she says. "I remember the first phone number I ever dialed and my parents' credit card number from when I was 16."

She loves quantifying things, from tracking gas prices to calculating the perfect speed to drive to work so she makes the most green lights.

This talent helps her out in the lab, where she can look at data and quickly recognize changes in a mouse's wheel-running behavior or sense if a piece of equipment isn't calibrated properly.

Work and Play

Altimus also prizes her ability to stay fully engaged in her work for hours, something she got better at when she took music classes.

"In science, there's a lot of stuff to process. You need to think about things for a lot of time," she says.

As a result, she sometimes finds it hard to stop working at the end of the day. After meeting her husband for dinner, Altimus often finds herself going back to the lab to solve a nagging problem while John reads scientific papers and keeps her company. Or they'll go to his office and she'll catch up on her own paperwork.

Altimus playing guitar In college, Altimus taught classical guitar to underprivileged children.

"We are both really interested and excited by our work," she says. "We get bogged down if something doesn't make sense, and we try to solve it right then."

Spending evenings together in the lab is one way Altimus and her husband make time to see each other while juggling busy schedules. They also carve out 20 minutes each morning to sit and have breakfast.

"We don't really rest. We get antsy if we're not doing something," she says.

Instead of watching TV, they read and debate the news. When they're not at work, they hike, bike and take advantage of Baltimore's cultural events, from museum exhibits to symphony concerts.

Altimus also plays classical guitar and tutors high school students in biology.

In the midst of everything, she still finds time to bake. The latest in a "long line" of bakers, she whips up cookies, cakes and pastries for her labmates and other staff.

Learning About Learning

After 5 years in Hattar's lab, Altimus completed her Ph.D. degree in 2010. Since her subsequent departure, Hattar and others have missed more than her cookies.

"I wanted Cara to stay [in my lab] forever," Hattar says. "She is innovative, doesn't get scared, reads the literature, works hard and gets things done. And she can build stuff."

Altimus is now a postdoctoral researcher in the lab of Hopkins neuroscientist David Foster.

Even though she has been in his lab for just a few months, Foster says Altimus "is not only persistent and works really hard, she is creative. That is a very potent and rare thing, to see both in the same individual."

Altimus is setting up experiments that will give her a front-row seat to a live performance -- watching and recording the brain activity of rats and mice as they navigate their way through mazes in search of food.

She's following up on an intriguing finding Foster made: As rats run through a maze, their neurons fire in a certain order, seemingly taking note of landmarks. Then, when the rats reach the food and stop to eat and groom themselves, the same sequence of neurons fires again -- but in reverse.

It's as if their brains are reviewing the path backwards to remember how they got to their tasty snack.

Foster calls it "reverse replay." He suspects human brains do it, too.

Altimus will conduct similar maze experiments in mice, which are easier to genetically modify than rats. She'll study a range of brain processes, like how certain neurons get "recruited" at different times during memory formation, how reverse replay happens in normal brains and how it may go wrong in diseased brains.

It's complicated work because the brain is intimidatingly complex -- countless genes and proteins are working simultaneously. She can't just study one at a time, then piece them together to get the whole picture.

Foster explains, "It's like trying to make a blueprint of a car by saying where all the atoms should go."

Altimus hopes to improve scientists' basic understanding of what happens in our brains as we go about our daily lives.

That knowledge, in turn, might lead to better treatments for brain disorders like Alzheimer's disease.

"The whole field is feeling its way, but the motivation is very clear: preventing cognitive diseases," says Foster.

In the meantime, Altimus says that, for her, the greatest reward of science is "the day-to-day."

"It's that stereotype of you in a room, seeing something that suddenly makes sense," she continues. "Or thinking about it until it makes sense. Or maybe it doesn't make sense, and then you try something else."

Does she ever worry about running out of ideas or new things to try?

No. "There's always more to be done," she says. "It's science."

--Stephanie Dutchen, originally published in Findings Magazine, a publication for the National Institute of General Medical Sciences

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