The Eppendorf Prize is a prestigious international award for scientists. Christopher Zimmerman, a postdoctoral research associate at the Princeton Neuroscience Institute at Princeton University, is the 19th winner of this award. In his work, Zimmerman investigated the neuronal mechanisms associated with thirst and drinking behavior.
Technology Networks recently had the pleasure of speaking with Zimmerman to discover more about his prize-winning research in drinking behavior.
Candice Tolton (CT): What encouraged you to pursue a career within the field of neuroscience?
Christopher Zimmerman (CZ): I want to understand how the brain produces behavior—especially motivated or goal-directed behaviors, in which we are seeking reward or avoiding punishment. Motivated behaviors are important because they represent a huge fraction of our daily actions and are intimately connected to our emotions, and because unfortunately they are frequently dysregulated by disease (obesity and addiction are just two examples). Drinking is a fundamental motivated behavior that’s controlled by the sense of thirst, and I was interested in studying this specific system for two reasons. First, there was so much that we didn’t understand about how the brain controls thirst and drinking behavior, which suggested that there was the potential to make exciting, fundamental discoveries. Second, the brain machinery underlying thirst and drinking appears to be very similar between mice and humans, which meant that we could use cutting edge optical and genetic tools for studying neural circuits in mice to investigate how this system operates during normal behavior, which would be near-impossible in humans or other animals.
CT: Can you elaborate on the concept and background of your research?
CZ: How does the brain control drinking behavior and our feelings of thirst? This seems like a simple question but has actually been a huge challenge for neuroscience to address. Historically, the brain’s thirst centers were thought to simply detect when we are dehydrated (for example, by sensing increases in our blood osmolarity) and then use this information to motivate drinking. This model has been written into neuroscience textbooks for decades. However, these blood signals fluctuate very slowly, while drinking behavior is regulated on a fast, moment-by-moment basis. For example, drinking water quenches our thirst immediately even though the ingested water isn’t absorbed into the bloodstream for many minutes. Similarly, eating stimulates drinking long before the ingested food is absorbed. How does the brain accomplish this? Something must be missing from our model of thirst.
We answered this question by recording the activity of the brain’s thirst neurons for the first time. This revealed that thirst neurons do not only detect signals about our current hydration status from the blood as was historically thought — instead, these cells also receive a second class of signals that arise from elsewhere in the body, including the mouth, throat and gut. This was completely unexpected! This new class of signals predict in real-time the changes in blood hydration that will occur many minutes in the future as a result of eating and drinking. For the first time, this provides a mechanism to explain how the brain adjusts our feelings of thirst on a moment-by-moment basis: combining these two classes of signals — one class that encodes our current hydration level (blood osmolarity signal) and another class that predicts impending changes in hydration (the mouth, throat and gut signals) — enables thirst neurons too estimate the body’s need for water in real-time and, as a result, adjust our feelings of thirst preemptively. We then used a wide array of techniques to specifically pinpoint where in the body these signals originate, how they get to the brain, what information they encode and how they influence our behavior.
CT: Can you explain the technologies you used to establish how thirst triggers a neuronal response in the brain?
CZ: We used technologies that allow us to record the activity of the brain’s thirst-controlling neurons in awake, behaving mice. First, we used genetic techniques to express a protein, called a calcium indicator, which glows green when neurons are active, specifically in thirst neurons. Then, we placed a fiberoptic cable into the brain area that contains the thirst neurons and measured these flashes of light using a photodetector or camera. This gave us ability to record the activity of the brain’s thirst neurons for the first time. We recorded their activity when we triggered thirst (for example, by increasing the blood osmolarity), during normal behaviors like eating and drinking and while we infused different liquids into the mice’s stomachs. This revealed that a single group of cells appears to receive most of the signals that control our thirst – including dehydration signals from the blood, as well as drinking and food intake-related signals from the mouth and throat and salt intake-related signals from the GI tract. A similar set of tools, called optogenetics, allowed us to turn the activity of these neurons “on” or “off” using light, which helped us to show that the new signals revealed by our recordings are essential for normal drinking behavior. For example, artificially activating these cells in a completely hydrated mouse drives immediate and voracious drinking, while artificially inactivating them in a dehydrated, thirsty animal completely quenches thirst.
CT: Can you elaborate on the brain and body functions involved in the ‘osmosensor’ theory?
CZ: The ‘osmosensor’ theory was initially developed in the 1950s, at a time when it was challenging to manipulate small brain areas and nearly impossible to record from specific neurons in the brain. In a pioneering series of experiments, the Swedish scientist Bengt Andersson infused salt into the brains of goats in order to locate the brain’s osmosensor region, which he hypothesized was crucial for the control of thirst. He ultimately discovered a small area within the hypothalamus where even minute amounts of salt triggered immediate, voracious drinking. Subsequent work showed that this area of the brain actually lies outside the blood–brain barrier, which explains its unique ability to detect dehydration signals in the blood. These early experiments established the textbook osmosensor model for thirst.
Here’s a brief summary of the osmosensor model. It begins with a set of neurons in the brain (collectively called the ‘osmosensor’) that sense when we are dehydrated by directly monitoring the osmolarity of our blood. When we are dehydrated, these neurons become activated and trigger the feeling of thirst to motivate us to find and drink water. These also cells influence physiological processes throughout the body to help maintain fluid balance until we can find water. For example, they trigger the release of the hormone vasopressin, which acts on the kidneys to help minimize excretion of water in the urine when we are dehydrated. They also impact our blood pressure to make sure that blood continues to flow properly when the volume of our blood decreases.
My research added a new layer to this theory – we found that the brain’s ‘osmosensor’ neurons do not only monitor dehydration signals in blood, but that they also receive a second class of signals that arises from elsewhere in the body during behavior.
CT: Is there a connection between the digestive system and neurons, in terms of thirst satiation, or is this process reliant on brain response alone?
CZ: Yes! A key finding from our work is that a signal is sent from the gastrointestinal tract to the brain to help regulate thirst. Specifically, this signal rapidly tells the brain how salty the fluids we drink are, before they even enter the bloodstream, so that we can adjust our drinking behavior in advance. This signal is important for satiating thirst when we drink water. This is one example that shows that thirst is not a brain response alone. We discovered two other signals from the body’s periphery that are also important for controlling thirst. These signals are generated in the mouth and throat — one tells the brain the volume of the fluids we drink to help quench thirst, while the other tracks the amount of food we eat to generate thirst during meals. A general principle emerging from our work is that the sense of thirst does not arise exclusively within the brain as previously thought, but rather from layers of signals that originate throughout the body and converge in the brain to generate a real-time estimate of the need for water and adjust thirst preemptively.
CT: Have you considered comparing how water and alcohol consumption are processed in the brain? Are the same neurons involved?
CZ: We have never tested this, but it is a very interesting question. Our current perspective is that these neurons have a very specific role in thirst and fluid homeostasis, and that their primary purpose is to monitor our need for water. For example, activating these neurons drives preferential consumption of water over other fluids. This suggests that separate brain networks control water consumption (thirst) and drinking alcohol – but it would be exciting to see where in the brain these networks overlap and interact, since they both produce the same final ‘output’ (drinking).
Christopher Zimmerman was speaking to Candice Tolton, Editorial Assistant for Technology Networks.