Sensing Gravity with Acid: Scientists Discover a Role for Protons in Neurotransmission

While probing how organisms sense gravity and acceleration, scientists at the Marine Biological Laboratory (MBL) and the University of Utah uncovered evidence that acid (proton concentration) plays a key role in communication between neurons. The surprising discovery is reported this week in Proceedings of the National Academy of Sciences.

The team, led by the late MBL senior scientist Stephen M. Highstein, discovered that sensory cells in the inner ear continuously transmit information on orientation of the head relative to gravity and low-frequency motion to the brain using protons as the key synaptic signaling molecule. (The synapse is the structure that allows one neuron to communicate with another by passing a chemical or electrical signal between them.)

“This addresses how we sense gravity and other low-frequency inertial stimuli, like acceleration of an automobile or roll of an airplane,” says co-author Richard Rabbitt, a professor at University of Utah and adjunct faculty member in the MBL’s Program in Sensory Physiology and Behavior. “These are very long-lasting signals requiring a a synapse that does not fatigue or lose sensitivity over time. Use of protons to acidify the space between cells and transmit information from one cell to another could explain how the inner ear is able to sense tonic signals, such as gravity, in a robust and energy efficient way.”

The team found that this novel mode of neurotransmission between the sensory cells (type 1 vestibular hair cells) and their target afferent neurons (calyx nerve terminals), which send signals to the brain, is continuous or nonquantal. This nonquantal transmission is unusual and, for low-frequency stimuli like gravity, is more energy efficient than traditional synapses in which chemical neurotransmitters are packaged in vesicles and released quantally.

The calyx nerve terminal has a ball-in-socket shape that envelopes the sensory hair cell and helps to capture protons exiting the cell. “The inner-ear vestibular system is the only place where this particular type of synapse is present,” Rabbitt says. “But the fact that protons are playing a key role here suggests they are likely to act as important signaling molecules in other synapses as well.”

Previously, Erik Jorgensen of University of Utah (who recently received a Lillie Research Innovation Award from the MBL and the University of Chicago) and colleagues discovered that protons act as signaling molecules between muscle cells in the worm C. elegans and play an important role in muscle contraction. The present paper is the first to demonstrate that protons also act directly as a nonquantal chemical neurotransmitter in concert with classical neurotransmission mechanisms. The discovery suggests that similar intercellular proton signaling mechanisms might be at play in the central nervous system.

Brain scans show what makes us drink water and what makes us stop drinking

Drinking water when you’re thirsty is a pleasurable experience. Continuing to drink when you’re not, however, can be very unpleasant. To understand why your reaction to water drinking changes as your thirst level changes, Pascal Saker of the University of Melbourne and his colleagues performed fMRI scans on people as they drank water. They found that regions of the brain associated with positive feelings became active when the subjects were thirsty, while regions associated with negative feelings and with controlling and coordinating movement became active after the subjects were satiated. The research appears in the Proceedings of the National Academy of Sciences.

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Yale researchers reconstruct facial images locked in a viewer’s mind

Using only data from an fMRI scan, researchers led by a Yale University undergraduate have accurately reconstructed images of human faces as viewed by other people.

“It is a form of mind reading,” said Marvin Chun, professor of psychology, cognitive science and neurobiology and an author of the paper in the journal Neuroimage.

The increased level of sophistication of fMRI scans has already enabled scientists to use data from brain scans taken as individuals view scenes and predict whether a subject was, for instance, viewing a beach or city scene, an animal or a building.

“But they can only tell you they are viewing an animal or a building, not what animal or building,” Chun said. “This is a different level of sophistication.”

One of Chun’s students, Alan S. Cowen, then a Yale junior now pursing an advanced degree at the University of California at Berkeley, wanted to know whether it would be possible to reconstruct a human face from patterns of brain activity. The task was daunting, because faces are more similar to each other than buildings. Also large areas of the brain are recruited in the processing of human faces, a testament to its importance in survival.

“We perceive faces in a much greater level of detail than we perceive other things,” Cowen said.

Working with funding from the Yale Provost’s office, Cowen and post doctoral researcher Brice Kuhl, now an assistant professor at New York University, showed six subjects 300 different “training” faces while undergoing fMRI scans. They used the data to create a sort of statistical library of how those brains responded to individual faces. They then showed the six subjects new sets of faces while they were undergoing scans. Taking that fMRI data alone, researchers used their statistical library to reconstruct the faces their subjects were viewing.

Cowen said the accuracy of these facial reconstructions will increase with time and he envisions they can be used as a research tool, for instance in studying how autistic children respond to faces.

Chun said the study shows the value of funding research ambitions of Yale undergraduates.

“I would never have received external funding for this, it was too novel,” Chun said.

EEG study: Brain infers structure, rules of tasks

A new study documents the brain activity underlying our strong tendency to infer a structure of context and rules when learning new tasks (even when a structure isn’t valid). The findings, which revealed individual differences, shows how we try to apply task knowledge to similar situations and could inform future research on learning disabilities.

In life, many tasks have a context that dictates the right actions, so when people learn to do something new, they’ll often infer cues of context and rules. In a new study, Brown University brain scientists took advantage of that tendency to track the emergence of such rule structures in the frontal cortex — even when such structure was not necessary or even helpful to learn — and to predict from EEG readings how people would apply them to learn new tasks speedily.

Context and rule structures are everywhere. They allow an iPhone user who switches to an Android phone, for example, to reason that dimming the screen would involve finding a “settings” icon that will probably lead to a slider control for “brightness.” But when the context changes, inflexible generalization can lead a person temporarily astray — like a small-town tourist who greets strangers on the streets of New York City. In some developmental learning disabilities, the whole process of inferring abstract structures may be impaired.

“The world tends to be organized, and so we probably develop prior [notions] over time that there is going to be a structure,” said Anne Collins, a postdoctoral scholar in the Department of Cognitive, Linguistic, and Psychological Sciences at Brown and lead author of the study published March 25 in the Journal of Neuroscience. “When the world is organized, you just reduce the size of what you have to learn about by being able to generalize across situations in which the same things usually happen together. It is efficient to generalize if there is structure, and there usually is structure.”

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MRI reveals genetic activity

New MIT technique could help decipher genes’ roles in learning and memory

Doctors commonly use magnetic resonance imaging (MRI) to diagnose tumors, damage from stroke, and many other medical conditions. Neuroscientists also rely on it as a research tool for identifying parts of the brain that carry out different cognitive functions.

Now, a team of biological engineers at MIT is trying to adapt MRI to a much smaller scale, allowing researchers to visualize gene activity inside the brains of living animals. Tracking these genes with MRI would enable scientists to learn more about how the genes control processes such as forming memories and learning new skills, says Alan Jasanoff, an MIT associate professor of biological engineering and leader of the research team.

“The dream of molecular imaging is to provide information about the biology of intact organisms, at the molecule level,” says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research. “The goal is to not have to chop up the brain, but instead to actually see things that are happening inside.”

To help reach that goal, Jasanoff and colleagues have developed a new way to image a “reporter gene” — an artificial gene that turns on or off to signal events in the body, much like an indicator light on a car’s dashboard. In the new study, the reporter gene encodes an enzyme that interacts with a magnetic contrast agent injected into the brain, making the agent visible with MRI. This approach, described in a recent issue of the journal Chemical Biology, allows researchers to determine when and where that reporter gene is turned on.

An on/off switch

MRI uses magnetic fields and radio waves that interact with protons in the body to produce detailed images of the body’s interior. In brain studies, neuroscientists commonly use functional MRI to measure blood flow, which reveals which parts of the brain are active during a particular task. When scanning other organs, doctors sometimes use magnetic “contrast agents” to boost the visibility of certain tissues.

The new MIT approach includes a contrast agent called a manganese porphyrin and the new reporter gene, which codes for a genetically engineered enzyme that alters the electric charge on the contrast agent. Jasanoff and colleagues designed the contrast agent so that it is soluble in water and readily eliminated from the body, making it difficult to detect by MRI. However, when the engineered enzyme, known as SEAP, slices phosphate molecules from the manganese porphyrin, the contrast agent becomes insoluble and starts to accumulate in brain tissues, allowing it to be seen.

The natural version of SEAP is found in the placenta, but not in other tissues. By injecting a virus carrying the SEAP gene into the brain cells of mice, the researchers were able to incorporate the gene into the cells’ own genome. Brain cells then started producing the SEAP protein, which is secreted from the cells and can be anchored to their outer surfaces. That’s important, Jasanoff says, because it means that the contrast agent doesn’t have to penetrate the cells to interact with the enzyme.

Researchers can then find out where SEAP is active by injecting the MRI contrast agent, which spreads throughout the brain but accumulates only near cells producing the SEAP protein.

Exploring brain function

In this study, which was designed to test this general approach, the detection system revealed only whether the SEAP gene had been successfully incorporated into brain cells. However, in future studies, the researchers intend to engineer the SEAP gene so it is only active when a particular gene of interest is turned on.

Jasanoff first plans to link the SEAP gene with so-called “early immediate genes,” which are necessary for brain plasticity — the weakening and strengthening of connections between neurons, which is essential to learning and memory.

“As people who are interested in brain function, the top questions we want to address are about how brain function changes patterns of gene expression in the brain,” Jasanoff says. “We also imagine a future where we might turn the reporter enzyme on and off when it binds to neurotransmitters, so we can detect changes in neurotransmitter levels as well.”

Assaf Gilad, an assistant professor of radiology at Johns Hopkins University, says the MIT team has taken a “very creative approach” to developing noninvasive, real-time imaging of gene activity. “These kinds of genetically engineered reporters have the potential to revolutionize our understanding of many biological processes,” says Gilad, who was not involved in the study.