How the brain generates rhythmic behavior

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

source: Massachusetts Institute of Technology

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

Neuroscientists at MIT have now discovered the identity of neurons and the mechanism behind one of these circuits: an oscillator that controls the rhythmic passing back and forth of tactile hairs, or flickering, in mice. This is the first time such an oscillator has been fully characterized in mammals.

The MIT team found that the flickering oscillator consists of a group of inhibitory neurons in the brainstem that fire rhythmic impulses while flapping. When each neuron fires, it also blocks some of the other neurons in the network, allowing the general public to generate a synchronous rhythm that pulls the hairs from their elongated positions.

“We have identified a mammalian oscillator that is molecular, electrophysiological, functional, and mechanistic,” says Van Wang, professor of brain and cognitive sciences at MIT and a member of the McGovern Institute for Brain Research at MIT.

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

Wang is the lead author of the study that appears today in temper nature. The paper’s lead authors are MIT research scientists John Takatoh and Vincent Prevosto.

rhythmic behavior

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

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

The oscillator that generates regular breathing is located in a part of the brain stem called the pre-Poetzinger complex, but the exact identity of the oscillator neurons is not fully understood.

“There have been no detailed studies in awake animals, where one could score from molecularly identified and precisely manipulated oscillator cells,” says Wang.

Flapping is a rhythmic exploratory behavior prominent in many mammals, which use their tactile whiskers to detect objects and sense textures. In mice, bristles dilate and retract at a rate of 12 cycles per second. Several years ago, Wang’s lab began trying to identify the cells and the mechanism that controls this oscillation.

To find the location of the whiskering oscillator, the researchers traced out the motor neurons that innervate the muscles of the whiskers. Using a modified rabies virus that infects axons, the researchers were able to classify a group of presynaptic cells of these motor neurons in a part of the brainstem called the vibratory intermediate reticulum nucleus (vIRt). This finding was consistent with previous studies showing that damage to this part of the brain eliminates palpitations.

The researchers then found that about half of these vIRt neurons express a protein called parvalbumin, and that this population of cells drives the rhythmic movement of the hairs. When these neurons are silenced, their flickering activity is canceled.

Next, the researchers recorded electrical activity from these paravalbumin-expressing vIRt neurons in the brainstem of awake mice, a technically challenging task, and found that these neurons did indeed have bursts of activity only during the period of drinker retraction. As these neurons provide inhibitory synaptic input to the motor neurons, it follows that the rhythmic flickering is generated by a lengthening signal of the stationary motor neurons that is interrupted by the rhythmic retreat signal from these oscillator cells.

“It was a very satisfying and rewarding moment, to see that these cells are really oscillator cells, because they fire rhythmically, they fire in the regression phase, and they are inhibitory neurons,” Wang says.

“new principles”

The oscillatory blast pattern of vIRt cells begins at the onset of flickering. When the hairs are not moving, these neurons fire constantly. When the researchers prevented the vIRt neurons from inhibiting each other, the rhythm disappeared, and instead the oscillating neurons increased their continuous firing rate.

This shows the neurons
Fluorescent image shows viral-trace oscillating neurons (in green) expressing parvalbumin (blue) and the inhibitory neuron marker vGat (red). credit: researchers

This type of network, known as a repetitive inhibitory network, differs from the types of oscillators seen in oropharyngeal neurons in lobsters, in which the neurons generate their own rhythms.

“We have now found a mammalian network oscillator consisting of all inhibitory neurons,” says Wang.

The MIT scientists also collaborated with a team of theorists led by David Golomb at Ben-Gurion University in Israel and David Kleinfeld at the University of California, San Diego. Theorists have devised a detailed computational model outlining how to control the flickering, which fits well with all the experimental data. A paper describing this model will appear in the next issue of neuron.

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

see also

This shows a drawing of a middle-looking mother and a sad teenage girl

“We are very excited to find oscillators for these feeding behaviors and to compare and contrast with the fapping oscillator, because they are all in the brainstem, and we want to see if there is a common theme or if there are many different ways of generating oscillators,” she says.

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

About this behavioral neuroscience research news

author: Anne Trafton
source: Massachusetts Institute of Technology
Contact: Ann Trafton – Massachusetts Institute of Technology
picture: The image is attributed to the researchers

original search: open access.
flickering oscillator circuitWritten by John Takatoh et al. temper nature


flickering oscillator circuit

Single-pass receptors regulate cellular processes by transmitting ligand-encoded signals across the plasma membrane via changes in their extracellular and intracellular conformations. These membrane signals are generally initiated by associating with receptors in their monomeric form.

While subsequent 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 dependence of these interactions on ligands.

By combining transmembrane nanodiscs produced with cell-free expression, single-molecule resonance energy transfer measurements, and molecular dynamics simulations, we report that crosslinking leads to intracellular conformational changes within the monomeric epidermal growth factor receptor (EGFR).

Our observations demonstrate the existence of extracellular/intracellular conformational coupling within a single receptor molecule. We refer to a series of electrostatic interactions in the harmonic coupling and find that the coupling is inhibited by targeted therapies and mutations that also prevent phosphorylation in cells.

Collectively, these findings present a facile mechanism for the binding of extracellular and intracellular regions through the single transmembrane helix of monomeric EGFR, and raise the possibility that intramolecular conformational changes upon ligand binding are common to single-pass transmembrane proteins.

Leave a Comment