Bringing a steady supply of fresh air to the lungs can seem like a simple task, but breathing is a careful orchestration of brain and body.

Diseases like Rett syndrome, central sleep apnea and congenital central hypoventilation syndrome are characterized by breathing difficulties that may be caused by dysfunction in the brain’s breathing center. Now, Drexel scientists have introduced a new concept of how the brain is involved in this essential function, providing new insight into how breathing disorders could be treated in the future.

The brainstem, which connects the brain with the spinal cord, generates the breathing rhythm and controls its rate, depending on the body’s demands. While this process normally occurs automatically, we can also control our breathing voluntarily, such as when speaking or eating.

Twenty-five years ago, a cluster of neurons within the brainstem, called the pre-Bötzinger complex (pre-BötC), was identified as the likely source of rhythmic inhalation. Following this breakthrough, researchers have spent years attempting to understand how the pre-BötC operates.

“For any cyclical biologic process, you need some mechanism that generates a rhythm, and then that rhythm is translated to a motor pattern. How exactly the pre-BötC generates that rhythm has remained a mystery,” said Bartholomew Bacak, PhD, a researcher in the School of Biomedical Engineering, Science and Health Systems, and an MD student in the College of Medicine.

Two decades after the discovery of the pre-BötC, scientists hypothesized that two distinct systems in the brain interact to initiate breathing: a “rhythm-generating” layer composed of high- frequency neurons and a “pattern-forming” layer, which signals the diaphragm to contract and the lungs to fill with air.

Using a series of computational models, Drexel researchers in the Laboratory for Theoretical and Computational Neuroscience, under the leadership of Ilya Rybak, PhD, are the first to challenge this paradigm.

Their study, recently published in the journal eLife, suggests that mixed-mode oscillations in the pre-BötC — or regular back-and-forth movements — result from synchronizations of many neurons with different levels of excitability. Neurons with low excitability have low bursting frequencies, but generate strong activity and recruit other neurons, ultimately producing the large amplitude bursts that cause breathing.

Photo of a child blowing bubbles.

The discovery could have important implications for our understanding of the brain’s control of breathing. The findings may ultimately impact how scientists research and clinicians treat respiratory disorders.

Many other parts of the nervous system also contain networks of neurons with diverse excitability. A challenge for future studies is to investigate whether networks similar to those in the pre-BötC complex generate the rhythms that control other repetitive actions, such as walking and chewing.


Funding: Funding provided by NIH/National Institute of Neurological Disorders and Stroke.

Source: Lauren Ingeno – Drexel University
Image Credit: The image is in the public domain.
Original Research: Abstract for “Mixed-mode oscillations and population bursting in the pre-Bӧtzinger complex” by Bartholomew J Bacak, Taegyo Kim, Jeffrey C Smith, Jonathan E Rubin, and Ilya A Rybak in eLife. Published online March 14 2016 doi:10.7554/eLife.13403


Mixed-mode oscillations and population bursting in the pre-Bӧtzinger complex

This study focuses on computational and theoretical investigations of neuronal activity arising in the pre-Bӧtzinger complex (pre-BӧtC), a medullary region generating the inspiratory phase of breathing in mammals. A progressive increase of neuronal excitability in medullary slices containing the pre-BӧtC produces mixed-mode oscillations (MMOs) characterized by large amplitude population bursts alternating with a series of small amplitude bursts. Using two different computational models, we demonstrate that MMOs emerge within a heterogeneous excitatory neural network because of progressive neuronal recruitment and synchronization. The MMO pattern depends on the distributed neuronal excitability, the density and weights of network interconnections, and the cellular properties underlying endogenous bursting. Critically, the latter should provide a reduction of spiking frequency within neuronal bursts with increasing burst frequency and a dependence of the after-burst recovery period on burst amplitude. Our study highlights a novel mechanism by which heterogeneity naturally leads to complex dynamics in rhythmic neuronal populations.

“Mixed-mode oscillations and population bursting in the pre-Bӧtzinger complex” by Bartholomew J Bacak, Taegyo Kim, Jeffrey C Smith, Jonathan E Rubin, and Ilya A Rybak in eLife. Published online March 14 2016 doi:10.7554/eLife.13403