Vertebrate Respiratory Rhythm Generation

Breathing is a rhythmic motor behavior that is necessary for life, but the way that brainstem neurons produce this rhythm is not known. We study isolated brainstems from adult red-eared slider turtles because reptiles aspirate air into their lungs similar to mammals. Also, turtle brainstems produce the 3-phase breathing rhythm (inspiratory, post-inspiratory, and expiratory activity) for days under in vitro conditions. Currently, we are testing whether:

(1) Pacemaker neurons play a critical role in rhythm generation using multichannel recordings with silicon microelectrodes.

(2) The pons is required for the normal 3-phase breathing rhythm using novel microfluidic chambers (collaboration with Dr. Justin Williams at UW-Madison).

(3) Hypoxia augments post-inspiratory activity similar to mammals.

(4) Activation of alpha-1 adrenergic receptors switches episodic respiratory motor output (ie, several breaths clustered together) into singlet motor output (ie, single breaths), and induces long-lasting increases in respiratory breath frequency and regularity.

 

EVOLUTION OF VERTEBRATE RESPIRATORY MOTOR NETWORKS

In collaboration with Dr. Michael Hedrick (Cal St-East Bay), we are addressing similar questions in isolated frog brainstems to test whether the properties of respiratory motor networks found in mammals and reptiles are conserved in amphibians.

 

Figure 5 from Johnson et al., 2007 shows that flufenamic acid (FFA) decreases the frequency of respiratory motor bursts in a dose- and time-dependent manner.

These data are consistent with the hypotheses that: (1) pacemaker neurons with calcium-activated cation currents are necessary for rhythm generation, or (2) the group-pacemaker mechanism is responsible for respiratory rhythm generation.

Recent studies on intact turtles and isolated turtle brainstems show that:

(1) Serotonin 5-HT3 receptors and nociceptin/orphanin receptors regulate episodic breathing.

(2) Respiratory rhythm generation can be blocked by flufenamic acid, but not riluzole, suggesting that a certain type of pacemaker neuron may be required for breathing.

(3) Mu-opioid receptor activation produces profound respiratory depression. However, tramadol (common analgesic in veterinary clinics) provides pain relief with minimal or no respiratory depression.

 

Related Articles:

Bartman ME, Wilkerson JER, Johnson SM. 5-HT3 receptor-dependent modulation of respiratory burst frequency, regularity, and episodicity in isolated adult turtle brainstems. Respir Physiol Neurobiol 172:42-52, 2010.

Johnson SM, Moris CM, Michelle E. Bartman, Wiegel LM. Excitatory and inhibitory effects of opioid agonists on respiratory motor output produced by isolated brainstems from adult turtles (Trachemys). Respir Physiol Neurobiol 170:5-15, 2010.

Johnson SM, Kinney ME, Wiegel LM. Inhibitory and excitatory effects of mu (MOR), delta (DOR), and kappa (KOR) opioid receptor activation on breathing in awake turtles (Trachemys scripta). Am J Physiol Regul Integr Comp Physiol 295: R1599-R1612, 2008.

Majewski DM, Wiegel LM, Johnson SM. Respiratory pattern in midline-lesioned brainstems and hemibrainstems from adult turtles. Respir Physiol Neurobiol 164: 338-349, 2008.

Johnson SM, Wiegel LM, Majewski DM. Are pacemaker properties required for respiratory rhythm generation in adult turtle brainstems in vitro? Am J Physiol Regul Integr Comp Physiol 293: R901-R910, 2007.