The John B. Pierce Laboratory


Dr. Pieribone awarded multi-million-dollar DARPA contract to explore ways to create systems where the brain transforms digital images into the equivalent of eyesight

Published in YALE NEWS on November 14, 2017
Written by Sonya Collins

A research team led by Vincent Pieribone (left) is exploring ways to create systems where the brain transforms digital images into the equivalent of eyesight. Jason Crawford is investigating genes that may be integral to achieving that result.

The process by which the brain decodes and recognizes a visual image is mostly unknown. Solving its mysteries is the essential first step toward the goal of restoring vision to people who are blind.

An international, multidisciplinary team of researchers led by Vincent A. Pieribone, professor of cellular and molecular physiology and of neuroscience at Yale School of Medicine, has received a four-year, multi-million-dollar contract from the Pentagon’s Defense Advanced Research Projects Agency (DARPA) to take that step.

DARPA’s Neural Engineering System Design (NESD) program aims to develop a portable neural interface system capable of providing precise communication between the brain and the digital world. Such an interface could allow individuals to operate a computer with their minds rather than their fingers, say the researchers. For people who lack sight, it also could bypass the eyes and transmit visual images directly to the brain, they add, noting that the implications for people with sensory disabilities would be immense, while the technology could also benefit other areas of society.

Pieribone’s is one of six teams based at institutions across the country that DARPA has enlisted to generate the basic knowledge necessary to develop this interface and create non-invasive technology potentially applicable to sensory restoration. Each team will take a different approach to learning how the brain processes sensory information.

“The big problem is our inability to monitor the activity of nerve cells through the entire pathway from hearing or seeing to processing that sound or image,” says Pieribone, who is also director and fellow in the John B. Pierce Laboratory. His team of neuroscientists, engineers, computational scientists, chemists, a neurosurgeon, and a marine biologist will approach the problem in two ways.

First, they will attempt to modify neurons that process visual stimuli, says Pieribone, “so that every time they fire, they produce a burst of light.” Next, chemical biologist Jason M. Crawford, associate professor of chemistry and of microbial pathogenesis, in collaboration with a marine biologist and a biochemist, will seek to identify the gene best suited to accomplish that result.  By studying bioluminescent sharks, jellyfish, and a glowing variety of small insect-like sea creatures called copepods, they plan to learn how luminescent molecules called luciferin are genetically encoded. Among the various forms of luciferin the team will study, the one that now appears most likely to produce the best result, says Crawford, is coelenterazine, which consists of simple amino acids found in human metabolism.

“Some luciferins are from weird animals, and they use substrates not found in humans,” says Crawford. “We’ve identified candidate enzymes in comb jellies that we think are involved in coelenterazine production.”

When the investigators find a promising combination of genes and luciferin, they will begin observations of neurons in which those components have been implanted.

Meanwhile, engineers will develop a tiny, lens-less imaging system — about one centimeter square and the thickness of two sheets of paper — that will fit under the skull and, it is hoped, document the work of brain cells to record the means by which the brain processes images. “It’s ambitious,” says Pieribone. “Some of these pieces have been done before, but independently, never in a way that would allow them all to work together in one package.”

For Pieribone, even partial success would be a huge step forward. “If we don’t get to the goal line in four years, but we get pretty close, the whole field is going to be advanced as a result,” he says. If all ultimately works as hoped, Pieribone envisions a commercially available system — probably still decades away, he notes — where tiny cameras built into eyeglasses would create images that travel to a device implanted in the user, which then would convert them into data that the brain could transform into the equivalent of eyesight.

The researchers are funded by an initial infusion of $6 million. They will continue to receive annual multi-million-dollar installments as long as they reach scheduled milestones.


More Than Half Full: Our Bodies, Water, and Balance

Dr. Nina Stachenfeld credits WHRY for helping launch her lab’s pioneering research on the role of female sex hormones in regulating body fluids.

written by Rick Harrison, Communications Officer, Women’s Health Research at Yale

There is a reason NASA scientists have been looking for water on Mars, and that’s because, at least on Earth, water is life.

Blood is mostly water, delivering oxygen from heart to head to toes to fingertips and everywhere in between. Water, through urine and perspiration, rids the body of waste. We also lose water through sweating to cool our bodies down when hot. Water in saliva aids digestion. It keeps mucous membranes moist to stop germs from getting in. Water lubricates joints. Water cushions the brain and spinal cord from shocks. Most of our water is in our cells, which they need to survive, grow, and reproduce. It’s most of everything inside of us.

Water makes up about 50-60 percent of all human body weight, and we need to consume enough every day to remain healthy through drinking and eating.

“The body always wants equilibrium,” said Dr. Nina Stachenfeld, a Fellow at the John B. Pierce Laboratory and a Senior Research Scientist in Obstetrics, Gynecology, and Reproductive Sciences at Yale School of Medicine. “If you stop drinking, you start to dehydrate cells, which will inhibit their function and lead to bad outcomes.”

But beyond drinking, the ways in which our bodies regulate water content remain a subject of ongoing investigation. With the help of Women’s Health Research at Yale, Stachenfeld’s lab has helped pioneer research to understand the role of female sex hormones in the regulation of body fluids.

“Estrogen and progesterone fluctuate widely in women of reproductive age,” she said. “So isolating the effects of each hormone is difficult.”

However, knowledge of how hormones affect fluid regulation carries significant health benefits beyond simple curiosity. For example, these hormones affect sodium balance in the body, which can increase the risk of high blood pressure and carries a risk for developing heart disease. Estrogen and progesterone also have important direct effects on blood vessels themselves.

With one of the first grants from Women’s Health Research at Yale in 1998, Stachenfeld used a synthetic hormone called leuprolide acetate to suppress all estrogen and progesterone production in young, healthy women volunteers and then introduced each of the sex hormones individually to study its effects on body fluid regulation.

Dr. Stachenfeld’s lab investigates orthostatic tolerance, which is the ability to stay in an upright position or move quickly from a seated to an upright position without fainting. This is more difficult for young women than young men.

“This was the first study in which we used this method,” Stachenfeld said, crediting Dr. David Keefe, currently the Chair of Obstetrics and Gynecology at the New York University School of Medicine, for teaching her. “You can start fresh and introduce hormones one at a time. These days we use a different drug, but this is now a standard technique we use in our lab.”

Stachenfeld had hypothesized that estrogen was the main player in the way that a hormone secreted by the heart called atrial natriuretic peptide altered body fluid dynamics. Instead, the researchers discovered that progesterone was driving the process.

“The focus of researchers has mostly been on estrogen, without considering changes in other hormones such as progesterone,” Stachenfeld said. “But we’ve learned that progesterone has important influences on how estrogen affects cardiovascular changes and body fluid and sodium regulation in women.”

Stachenfeld credited the model developed in her WHRY-funded study for the ability to better study progesterone today. And her work has opened avenues of research to minimize the side effects of hormone therapy for menopausal women and oral contraceptives for women of reproductive ages that often lead them to abandon otherwise beneficial treatments.

“Water retention, bloating, and high blood pressure carry serious health risks,” Stachenfeld said. “Our studies on the mechanisms underlying the effects of sex hormones on body water regulation can lead to therapeutic advances for both young and older women.”

Stachenfeld’s current work has also focused on orthostatic tolerance, which is the ability to stay in an upright position or move quickly from a seated to an upright position without fainting. As it turns out, young women possess much poorer orthostatic tolerance compared to men of similar age. And, not surprisingly, the mechanism involves water — the primary ingredient of blood.

“Low blood volume can contribute to poor orthostatic tolerance, but is not the only factor,” Stachenfeld said. “If there’s not the appropriate amount of water at the level of the heart and the brain, this can lessen the amount of blood that reaches the center of the body and brain. Reflexes that control the constriction of blood vessels all the way down to the toes can cause blood to move toward the center of the body and the brain so you can stand up are also key to this process.”

This complex process involved in helping human beings remain upright might not work as well in women, possibly because of the effect of blood volume, reflexes, or the impact of hormones on both, Stachenfeld said. But interestingly, the sex difference doesn’t appear to apply to African American women, who appear to have higher orthostatic tolerance than white women.

“This finding might point to an advantage for black women when they are younger,” she said, adding that these racial differences emphasize how important it is to include women from all ethnicities and races in research. “But it could also be a clue to the higher risk of cardiovascular disease that black populations experience as they grow older. This is something we continue to study.”

Stachenfeld expressed gratitude for WHRY’s grant, which she said showed great confidence in her as a research scientist relatively new to Yale and in the promise of a study unlikely to receive outside financial support without first providing a proof of concept.

With the results of her WHRY-funded study, Stachenfeld applied for and received two grants from the National Institutes of Health to continue her work. “I think there are so many important things to study in the physiology of women and the impact of hormones that have gone understudied for so long,” she said. “We haven’t caught up yet. There’s a lot to be done.”


A study by scientists Ivan de Araujo, Wenfei Han, and team suggests the origin of hunting behavior may come from two set of neurons tucked deep in the forebrain of most vertebrates

(Yale Press Release)

Activating these neurons in living mice prompt them to pursue never seen before prey and to bite everything in their path, even sticks and bottle caps, the researchers report in the January 12, 2017 issue of the journal Cell.

“This area, the central amygdala, seems to allow the animal precise control over the muscles involved in pursuing and capturing prey,’’ said Ivan de Araujo, associate fellow at The John B. Pierce Laboratory, associate professor of psychiatry at Yale School of Medicine, and senior author of the paper.

In their experiments, de Araujo and colleagues used light-based technique called optogenetics to specifically activate neurons of the central amygdala, an almond-shaped structure involved in emotion and motivation. They found that one set of neurons prompted mice to pursue moving objects, while a second set of neurons seemed to activate jaw muscles involved in biting.

Normally behaving lab mice “jump on inanimate objects and bite them” when both sets of neurons are activated, de Araujo said. Activating these neurons also increased the efficiency with which mice hunt and capture live insects, in addition to make them pursue and attack animate toy insects. The two sets of neurons seem to act as relay stations that trigger hunting behavior after the animal detects visual signals of nearby moving prey.

These areas of the amygdala are preserved in almost all vertebrates, attesting to their importance in evolution.  Interestingly, these regions seem to be absent in brains of some species such as lampreys, which have no jaws, de Araujo noted.  His lab studies feeding behaviors of mice in the lab but felt “we needed to truly understand how an animal pursues food in a natural environment.”