Why Do We Feel Thirst? An Interview with Yuki Oka

Credit: Lance Hayashida/Caltech Marketing and Communications

To fight dehydration on a hot summer day, you instinctively crave the relief provided by a tall glass of water. But how does your brain sense the need for water, generate the sensation of thirst, and then ultimately turn that signal into a behavioral trigger that leads you to drink water? That's what Yuki Oka, a new assistant professor of biology at Caltech, wants to find out.

Oka's research focuses on the study of how the brain and body work together to maintain a healthy ratio of salt to water as part of a delicate form of biological balance called homeostasis.

Recently, Oka came to Caltech from Columbia University. We spoke with him about his work, his interests outside of the lab, and why he's excited to be joining the faculty at Caltech.

Can you tell us a bit more about your research?

The goal of my research is to understand the mechanisms by which the brain and body cooperate to maintain our internal environment's stability, which is called homeostasis. I'm especially focusing on fluid homeostasis, the fundamental mechanism that regulates the balance of water and salt. When water or salt are depleted in the body, the brain generates a signal that causes either a thirst or a salt craving. And that craving then drives animals to either drink water or eat something salty.

I'd like to know how our brain generates such a specific motivation simply by sensing internal state, and then how that motivation—which is really just neural activity in the brain—goes on to control the behavior.

Why did you choose to study thirst?

After finishing my Ph.D. in Japan, I came to Columbia University where I worked on salt sensing mechanisms in the mammalian taste system. We found that the peripheral taste system has a key function for salt homeostasis in the body by regulating our salt intake behavior. But of course, the peripheral sensor does not work by itself.  It requires a controller, the brain, which uses information from the sensor. So I decided to move on to explore the function of the brain; the real driver of our behaviors.

I was fascinated by thirst because the behavior it generates is very robust and stereotyped across various species. If an animal feels thirst, the behavioral output is simply to drink water. On the other hand, if the brain triggers salt appetite, then the animal specifically looks for salt—nothing else. These direct causal relations make it an ideal system to study the link between the neural circuit and the behavior.

You recently published a paper on this work in the journal Nature. Could you tell us about those findings?

In the paper, we linked specific neural populations in the brain to water drinking behavior. Previous work from other labs suggested that thirst may stem from a part of the brain called the hypothalamus, so we wanted to identify which groups of neurons in the hypothalamus control thirst. Using a technique called optogenetics that can manipulate neural activities with light, we found two distinct populations of neurons that control thirst in two opposite directions. When we activated one of those two populations, it evoked an intense drinking behavior even in fully water-satiated animals. In contrast, activation of a second population drastically suppressed drinking, even in highly water-deprived thirsty animals.  In other words, we could artificially create or erase the desire for drinking water.

Our findings suggest that there is an innate brain circuit that can turn an animal's water-drinking behavior on and off, and that this circuit likely functions as a center for thirst control in the mammalian brain. This work was performed with support from Howard Hughes Medical Institute and National Institutes of Health [for Charles S. Zuker at Columbia University, Oka's former advisor].

You use a mouse model to study thirst, but does this work have applications for humans?

There are many fluid homeostasis-associated conditions; one example is dehydration. We cannot specifically say a direct application for humans since our studies are focused on basic research. But if the same mechanisms and circuits exist in mice and humans, our studies will provide important insights into human physiologies and conditions.

Where did you grow up—and what started your initial interest in science?

I grew up in Japan, close to Tokyo, but not really in the center of the city. It was a nice combination between the big city and nature. There was a big park close to my house and when I was a child, I went there every day and observed plants and animals. That's pretty much how I spent my childhood. My parents are not scientists—neither of them, actually. It was just my innate interest in nature that made me want to be a scientist.

What drew you to Caltech?

I'm really excited about the environment here and the great climate. That's actually not trivial; I think the climate really does affect the people. For example, if you compare Southern California to New York, it's just a totally different character. I came here for a visit last January, and although it was my first time at Caltech I kind of felt a bond. I hadn't even received an offer yet, but I just intuitively thought, "This is probably the place for me."

I'm also looking forward to talking to my colleagues here who use fMRI for human behavioral research. One great advantage about using human subjects in behavioral studies is that they can report back to you about how they feel. There are certainly advantages of using an animal model, like mice. But they cannot report back. We just observe their behavior and say, "They are drinking water, so they must be thirsty." But that is totally different than someone telling you, "I feel thirsty." I believe that combining advantages of animal and human studies should allow us to address important questions about brain functions.

Do you have any hobbies?

I play basketball in my spare time, but my major hobby is collecting fossils. I have some trilobites and, actually, I have a complete set of bones from a type of herbivorous dinosaur. It is being shipped from New York right now and I may put it in my new office.

Written by Jessica Stoller-Conrad


Source: California Institute of Technology

Existing drug, riluzole, may prevent foggy 'old age' brain, research shows

Better memory makers: When researchers looked at certain neurons (similar to the one shown on top) in rats treated with riluzole, they found an important change in one brain region, the hippocampus: more clusters of so-called spines, receiving connections that extend from the branches of a neuron (bottom). Credit: Image courtesy of Rockefeller University

Forgetfulness, it turns out, is all in the head. Scientists have shown that fading memory and clouding judgment, the type that comes with advancing age, show up as lost and altered connections between neurons in the brain. But new experiments suggest an existing drug, known as riluzole and already on the market as a treatment for ALS, may help prevent these changes.

Researchers at The Rockefeller University and The Icahn School of Medicine at Mount Sinai found they could stop normal, age-related memory loss in rats by treating them with riluzole. This treatment, they found, prompted changes known to improve connections, and as a result, communication, between certain neurons within the brain's hippocampus.

"By examining the neurological changes that occurred after riluzole treatment, we discovered one way in which the brain's ability to reorganize itself -- its neuroplasticity -- can be marshaled to protect it against some of the deterioration that can accompany old age, at least in rodents," says co-senior study author Alfred E. Mirsky Professor Bruce McEwen, head of the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology. The research is published this week in Proceedings of the National Academy of Sciences.

Neurons connect to one another to form circuits connecting certain parts of the brain, and they communicate using a chemical signal known as glutamate. But too much glutamate can cause damage; excess can spill out and excite connecting neurons in the wrong spot. In the case of age-related cognitive decline, this process damages neurons at the points where they connect -- their synapses. In neurodegenerative disorders, such as Alzheimer's disease, this contributes to the death of neurons.

Used to slow the progress of another neurodegenerative condition, ALS (also known as Lou Gehrig's disease), riluzole was an obvious choice as a potential treatment, because it works by helping to control glutamate release and uptake, preventing harmful spillover. The researchers began giving riluzole to rats once they reached 10 months old, the rat equivalent of middle age, when their cognitive decline typically begins.

After 17 weeks of treatment, the researchers tested the rats' spatial memory -- the type of memory most readily studied in animals -- and found they performed better than their untreated peers, and almost as well as young rats. For instance, when placed in a maze they had already explored, the treated rats recognized an unfamiliar arm as such and spent more time investigating it.

When the researchers looked inside the brains of riluzole-treated rats, they found telling changes to the vulnerable glutamate sensing circuitry within the hippocampus, a brain region implicated in memory and emotion.

"We have found that in many cases, aging involves synaptic changes that decrease synaptic strength, the plasticity of synapses, or both," said John Morrison, professor of neuroscience and the Friedman Brain Institute and dean of basic sciences and the Graduate School of Biomedical Sciences at Mount Sinai. "The fact that riluzole increased the clustering of only the thin, most plastic spines, suggests that its enhancement of memory results from both an increase in synaptic strength and synaptic plasticity, which might explain its therapeutic effectiveness."

In this case, the clusters involved thin spines, a rapidly adaptable type of spine. The riluzole-treated animals had more clustering than the young animals and their untreated peers, who had the least. This discovery led the researchers to speculate that, in general, the aged brain may compensate by increasing clustering. Riluzole appears to enhance this mechanism.

"In our study, this phenomenon of clustering proved to be the core underlying mechanism that prevented age-related cognitive decline. By compensating the deleterious changes in glutamate levels with aging and Alzheimer's disease and promoting important neuroplastic changes in the brain, such as clustering of spines, riluzole may prevent cognitive decline," says first author Ana Pereira, an instructor in clinical investigation in McEwen's laboratory.

Taking advantage of the overlap of neural circuits vulnerable to age-related cognitive decline and Alzheimer's disease, Pereira is currently conducting a clinical trial to test the effectiveness of riluzole for patients with mild Alzheimer's.

Source: Rockefeller University

First contracting human muscle grown in laboratory

This is a microscopic view of lab-grown human muscle bundles stained to show patterns made by basic muscle units and their associated proteins (red), which are a hallmark of human muscle.
Credit: Nenad Bursac, Duke University

In a laboratory first, Duke researchers have grown human skeletal muscle that contracts and responds just like native tissue to external stimuli such as electrical pulses, biochemical signals and pharmaceuticals.

The lab-grown tissue should soon allow researchers to test new drugs and study diseases in functioning human muscle outside of the human body.

The study was led by Nenad Bursac, associate professor of biomedical engineering at Duke University, and Lauran Madden, a postdoctoral researcher in Bursac's laboratory. It appears January 13 in the open-access journal eLife

"The beauty of this work is that it can serve as a test bed for clinical trials in a dish," said Bursac. "We are working to test drugs' efficacy and safety without jeopardizing a patient's health and also to reproduce the functional and biochemical signals of diseases -- especially rare ones and those that make taking muscle biopsies difficult."

Bursac and Madden started with a small sample of human cells that had already progressed beyond stem cells but hadn't yet become muscle tissue. They expanded these "myogenic precursors" by more than a 1000-fold, and then put them into a supportive, 3D scaffolding filled with a nourishing gel that allowed them to form aligned and functioning muscle fibers.

"We have a lot of experience making bioartifical muscles from animal cells in the laboratory, and it still took us a year of adjusting variables like cell and gel density and optimizing the culture matrix and media to make this work with human muscle cells," said Madden.

Madden subjected the new muscle to a barrage of tests to determine how closely it resembled native tissue inside a human body. She found that the muscles robustly contracted in response to electrical stimuli -- a first for human muscle grown in a laboratory. She also showed that the signaling pathways allowing nerves to activate the muscle were intact and functional.

To see if the muscle could be used as a proxy for medical tests, Bursac and Madden studied its response to a variety of drugs, including statins used to lower cholesterol and clenbuterol, a drug known to be used off-label as a performance enhancer for athletes.

The effects of the drugs matched those seen in human patients. The statins had a dose-dependent response, causing abnormal fat accumulation at high concentrations. Clenbuterol showed a narrow beneficial window for increased contraction. Both of these effects have been documented in humans. Clenbuterol does not harm muscle tissue in rodents at those doses, showing the lab-grown muscle was giving a truly human response.

"One of our goals is to use this method to provide personalized medicine to patients," said Bursac. "We can take a biopsy from each patient, grow many new muscles to use as test samples and experiment to see which drugs would work best for each person."

This goal may not be far away; Bursac is already working on a study with clinicians at Duke Medicine -- including Dwight Koeberl, associate professor of pediatrics -- to try to correlate efficacy of drugs in patients with the effects on lab-grown muscles. Bursac's group is also trying to grow contracting human muscles using induced pluripotent stem cells instead of biopsied cells.

"There are a some diseases, like Duchenne Muscular Dystrophy for example, that make taking muscle biopsies difficult," said Bursac. "If we could grow working, testable muscles from induced pluripotent stem cells, we could take one skin or blood sample and never have to bother the patient again."

Other investigators involved in this study include George Truskey, the R. Eugene and Susie E. Goodson Professor of Biomedical Engineering and senior associate dean for research for the Pratt School of Engineering, and William Krauss, professor of biomedical engineering, medicine and nursing at Duke University.

The research was supported by NIH Grants R01AR055226 and R01AR065873 from the National Institute of Arthritis and Musculoskeletal and Skin Disease and UH2TR000505 from the NIH Common Fund for the Microphysiological Systems Initiative.

Source: Duke University