Contribution of non‐catecholaminergic rostral ventrolateral medulla neurons to blood pressure control

Abstract

Previous work identified the rostral ventrolateral medulla (RVLM) as a critical location for the sympathetic regulation of circulation. C1 neurons are a group of catecholaminergic neurons that are co‐extensive with this region, contain VGLUT2 and release glutamate, project to the intermediolateral cell column of the spinal cord, increase renal sympathetic tone, are barosensitive, and are activated by psychological and physiological stress. Despite these findings, selective stimulation of C1 neurons produced complex cardiovascular responses with no distinct increase in BP in conscious mice. C1 neurons are likely made up of several sub‐groups with unique roles, and stimulation of C1 neurons en masse may mask the cardiovascular effect of a pressor subgroup. In rats, selective stimulation of the rostral C1 neurons—the bulbospinal subgroup—increases BP, and selective inhibition of this subgroup decreases BP under hypoxia and anesthesia. Due to differences in the distribution of C1 subgroups in mouse and rat, selective stimulation of bulbospinal C1 neurons in mouse using previous techniques is not possible. Therefore, we sought to determine whether the RVLM BP regulatory neurons in mouse were a bulbospinal subgroup of C1 neurons or a separate non‐catecholaminergic group. All experiments were carried out using dopamine β‐hydoxylase Cre mice, which, in the rostral ventrolateral medulla, exclusively express Cre in C1 neurons. For selective stimulation, we injected an AAV to express the light‐driven ChR2 protein in either C1 or non‐C1 neurons. C1 neurons were targeted using a Cre‐dependent AAV to deliver ChR2, while non‐C1 RVLM neurons were targeted using an AAV where ChR2 was driven by the CaMKIIα promoter. First, we verified that our CaMKIIα‐ChR2 AAV injections labeled few C1 neurons using immunohistochemistry. We then tested whether stimulation of C1 or non‐C1 RVLM neurons increased BP in conscious and anesthetized mice. Next, we asked whether stimulation of the spinally projecting axons of either C1 or non‐C1 RVLM neurons increased BP or sympathetic nerve activity (SNA) in anesthetized mice. We conclude that in dopamine β‐hydoxylase Cre mice, non‐C1 RVLM neurons contribute to BP regulation, while we found no physiological evidence to support the role of bulbospinal C1 neurons in BP control. Our conclusions are based on the following results: (1.) Our CaMKIIα‐ChR2 AAV injections were selective for non‐C1 neurons in the RVLM. (2.) Stimulation of CaMKIIα RVLM neurons in conscious mice increases BP while stimulation of C1 does not. (3.) Stimulation of CaMKIIα bulbospinal axons from RVLM neurons increases BP in anesthetized mice while stimulation of C1 axons does not. (4.) Continued high‐frequency stimulation of CaMKIIα RVLM neurons causes robust and sustained increases in BP, while continued high‐frequency stimulation of C1 causes a depressor effect.Support or Funding InformationAmerican Heart Association National Institutes of HealthThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.