Central Command Regulation of Circulatory function Mediated by Descending Pontine Cholinergic Inputs to Sympathoexcitatory Rostral Ventrolateral Medulla Neurons

James R. Padley, Natasha N. Kumar, Qun Li, Thomas B.V. Nguyen, Paul M. Pilowslky, Ann K. Goodchild. Circulation Research (2007)

The rostral ventrolateral medulla (RVLM) is an area in the brainstem that regulates sympathetic nerve activity associated with cardiovascular mechanisms. The RVLM is known to have cholinergic pathways that effect its cardiovascular functions. Muscarinic acetylcholine receptors (mAChR) are the keys to this pathway, but are not yet fully understood. This study examines the activation of mAChR and the cholinergic input to the RVLM.

Two types of injections were used to alter the acetylcholine receptors. Oxotremorine sesquifumarate salt (OXO) is a mAChR agonist and scopolamine hydrobromide (SCOP) is a mAChR antagonist. When OXO was injected, mAChRs became activated and led to an increase in blood pressure, splanchnic sympathetic nerve activity (SSNA), tail blood flow, and heart rate. OXO also caused phrenic nerve activity (PNA) to decrease. When excitatory or inhibitory injections were given after OXO, the results showed that although these excited and inhibited states did still occur, it was at higher blood pressure and SSNA. When SCOP was injected into the RVLM after OXO, blood pressure and SSNA returned to levels very similar to the control. OXO was then injected 30 minutes after SCOP and though it did show excitatory effects, it did not reach the initial OXO injection before SCOP.

Shifting focus to the anatomy, the study shows that the cholinergic terminals synapse directly with sympathetic excitatory neurons in the RVLM. This was done by immunolabeling the vesicular acetylcholine transporters (vAChT), which showed a large buildup next to the RVLM neurons. When the RVLM sections were analyzed, all of the mAChR subtypes were shown to be expressed, but no spinally projecting tyrosine hydroxylase (TH) neurons expressed M2 receptors. TH is a marker for neurons that contain dopamine, norepinephrine, and epinephrine as neurotransmitters. Some non-TH spinally projecting neurons were shown to exhibit M2 receptors. This suggests that it is not one, but many types of receptors that convay information in the RVLM neurons.

The predunculopontine nucleus (PPT) is a group of neurons in the upper pons and is shown, in this study, to be a cholinergic pathway to the RVLM. This was done by injecting cholera toxin B (CTB), which is used as a neuronal tracer, into the RVLM. The tracer CTB was then confirmed to be in a few areas, but only the PPT was shown to exhibit both CTB and VAChT. This suggests that the PPT is the only cholinergic input into the RVLM. The PPT was then stimulated and the results showed increased blood pressure and SSNA, which resembles the activation of mAChRs in the RVLM. 

In conclusion, this study presents the cholinergic pathway from the PPT to the RVLM. In relation to our ongoing work in the lab, I think it’s very interesting to see how the body stimulates the RVLM itself, instead of outside injections. Although we frequently discuss the information coming from the baroreceptors, this study helps complete the picture between baroceptor response and RVLM signaling.

-Paul M