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How the Brain Generates Rhythmic Behavior – Neuroscience News

Summary: A new study in rodents reveals a whipping oscillator that consists of a population of inhibitory neurons in the brainstem that fire in rhythmic bursts during whipping behaviors.

Source: MIT

Many of our bodily functions, such as walking, breathing, and chewing, are controlled by brain circuits called central oscillators, which generate rhythmic trigger patterns that regulate these behaviors.

MIT neuroscientists have now uncovered the neural identity and mechanism behind one such circuit: an oscillator that controls the rhythmic back-and-forth sweep of tactile whiskers, or whipping, in mice. This is the first time that such an oscillator has been fully characterized in mammals.

The MIT team found that the whipping oscillator consists of a population of inhibitory neurons in the brainstem that fire rhythmic bursts during whipping. When each neuron fires, it also inhibits some of the other neurons in the network, allowing the overall population to generate a synchronous rhythm that retracts the whiskers from their extended positions.

“We have defined a mammalian oscillator at molecular, electrophysiological, functional, and mechanical levels,” says Fan Wang, professor of brain and cognitive science at MIT and a member of MIT’s McGovern Institute for Brain Research.

“It’s very exciting to see a clearly defined circuit and mechanism of how rhythm is generated in a mammal.”

Wang is the lead author of the study, which appears today in Nature. The lead authors of the paper are MIT researchers Jun Takatoh and Vincent Prevosto.

Rhythmic behavior

Most of the research that has clearly identified the circuits of the central oscillator has been done on invertebrates. For example, Eve Marder’s lab at Brandeis University found cells in the stomatogastric ganglion in lobsters and crabs that generate oscillatory activity to control the rhythmic movement of the digestive tract.

The characterization of oscillators in mammals, especially in awake animals, has proven to be very difficult. The oscillator that controls gait is thought to be distributed throughout the spinal cord, making it difficult to precisely identify the neurons and circuits involved.

The oscillator that generates rhythmic breathing is located in a part of the brainstem called the pre-Bötzinger complex, but the exact identity of the oscillator neurons is not fully understood.

“There haven’t been detailed studies in awake animals, where you can record from molecularly identified oscillator cells and manipulate them in a precise way,” says Wang.

Whipping is an important rhythmic exploratory behavior in many mammals, which use their tactile whiskers to detect objects and feel textures. In mice, whiskers extend and retract at a frequency of about 12 cycles per second. Several years ago, Wang’s lab attempted to identify the cells and mechanism that control this oscillation.

To find the location of the whip oscillator, the researchers traced back from the motoneurons that innervate the whisker muscles. Using a modified rabies virus that infects axons, the researchers were able to label a cluster of cells presynaptic to these motoneurons in a part of the brainstem called the vibrissae intermediate reticular nucleus (vIRt). This finding was consistent with previous studies showing that damage to this part of the brain eliminates whipping.

The researchers then discovered that about half of these vIRt neurons express a protein called parvalbumin, and that this subpopulation of cells drives the rhythmic movement of the whiskers. When these neurons are silenced, whipping activity is abolished.

Next, the researchers recorded the electrical activity of these parvalbumin-expressing vIRt neurons in the brainstem of awake mice, a technically difficult task, and found that these neurons indeed only have bursts of activity during the period whisker retraction. Since these neurons provide inhibitory synaptic inputs to the motor neurons of the whiskers, it follows that the rhythmic whip is generated by a constant protraction signal from the motoneurons interrupted by the rhythmic retraction signal from these oscillator cells.

“It was a very satisfying and gratifying moment to see that these cells are indeed the oscillator cells, because they fire in rhythm, they fire in the retraction phase, and they are inhibitory neurons,” says Wang.

“New Principles”

The oscillatory burst pattern of vIRt cells is initiated at the onset of whipping. When the whiskers are not moving, these neurons fire continuously. When the researchers stopped the vIRt neurons from inhibiting, the rhythm disappeared, and instead the oscillator neurons simply increased their continuous firing rate.

A fluorescent image shows traced viral whip oscillator neurons (green) expressing parvalbumin (blue) and the inhibitory neuronal marker vGat (red). Credit: The Researchers

This type of network, called the recurrent inhibitory network, differs from the types of oscillators observed in the stomatogastric neurons of lobsters, in which the neurons intrinsically generate their own rhythm.

“Now we have found a mammalian network oscillator that is formed by all inhibitory neurons,” Wang says.

The MIT scientists also collaborated with a team of theorists led by David Golomb of Ben-Gurion University, Israel, and David Kleinfeld of the University of California, San Diego. The theorists created a detailed computational model describing how the whipping is controlled, which agrees well with all the experimental data. An article describing this model will appear in an upcoming issue of neuron.

Wang’s lab now plans to study other types of oscillatory circuits in mice, including those that control chewing and licking.

See also

This shows the outline of a head

“We’re very excited to find oscillators of these eating behaviors and compare and contrast with the whipping oscillator, because they’re all in the brainstem, and we want to know if there’s a common theme or if there are many different ways to generate oscillators,” she says.

Funding: The research was funded by the National Institutes of Health.

About this Behavioral Neuroscience Research News

Author: Anne Trafton
Source: MIT
Contact: Anne Trafton – MIT
Image: The image is attributed to the researchers

Original research: Free access.
“The Whipping Oscillator Circuit” by Jun Takatoh et al. Nature


Summary

The Whipping Oscillator Circuit

Single-pass cell surface receptors regulate cellular processes by transmitting ligand-encoded signals across the plasma membrane via changes in their extracellular and intracellular conformations. This transmembrane signaling is generally initiated by the binding of ligands to receptors in their monomeric form.

While subsequent receptor-receptor interactions are established as key aspects of transmembrane signaling, the contribution of monomeric receptors has been difficult to isolate due to the complexity and ligand dependence of these interactions.

By combining membrane nanodiscs produced with cell-free expression, single-molecule Förster resonance energy transfer measurements, and molecular dynamics simulations, we report that ligand binding induces intracellular conformational changes within the receptor monomeric full-length epidermal growth factor (EGFR).

Our observations establish the existence of an extracellular/intracellular conformational coupling within the same receptor molecule. We implicate a series of electrostatic interactions in conformational coupling and find that coupling is inhibited by targeted therapies and mutations that also inhibit phosphorylation in cells.

Collectively, these results introduce an easy mechanism for linking extracellular and intracellular regions through the single transmembrane helix of monomeric EGFR, and raise the possibility that intramolecular transmembrane conformational changes upon ligand binding are common to membrane proteins at single pass.

How the Brain Generates Rhythmic Behavior – Neuroscience News

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