Caudal medullary and cervical spinal cord neurons in cardiovascular regulation

Increased sympathetic activity contributes to the pathogenesis of several forms of arterial hypertension, chronic heart failure and chronic kidney disease. Device-based therapeutic measures such as arterial baroreceptor activation and renal denervation have been introduced in recent years to target sympathetic overactivity in patients suffering from these diseases [1–3]. Clinical trials are currently under way to develop the efficacy of these device-based treatments further that includes the introduction of technical innovations and the identification of patient characteristics associated with a high likelihood of a therapeutic benefit. The application of these nonpharmacological treatments to modify autonomic nervous system function in patients and recent advances in experimental biomedical methodology are currently driving preclinical research on the regulation of the sympathetic nervous system and its effects on organ function under physiological and pathological conditions. The rostral ventrolateral medulla (RVLM) is a central nervous system (CNS) region that importantly contributes to the control of sympathetic activity. It contains excitatory presympathetic neurons that project to preganglionic sympathetic neurons in the intermediolateral column of the thoracolumbar spinal cord [4]. RVLM neuronal activity depends on supramedullary and on somatic as well as visceral afferent input. Many of the visceral afferents that modify RVLM activity synapse in the nucleus of the solitary tract (NTS), including arterial baroreceptor afferents [4]. It is well established that NTS neurons activated by baroreceptor afferents synapse with inhibitory neurons of the caudal ventrolateral medulla (CVLM) which in turn inhibit RVLM neurons, thereby reducing sympathetic activity [4]. In addition, medullary neurons localized caudally from the CVLM and in the upper cervical spinal cord contribute to the regulation of sympathetic activity, including the so-called caudal pressor area (CPA) and the medullocervical pressor area (MCPA) [4,5]. CPA and MCPA are involved in the maintenance and activation of sympathetic tone but differ with regard to the RVLM-dependence of these effects [4,6]. In this issue of the Journal of Hypertension, the current knowledge on structure and function of the CPA and MCPA obtained in experimental animals is summarized [6]. The review reveals that the CPA and MCPA have been investigated less than other brain stem regions involved in cardiovascular and respiratory control and that progress in the understanding of their functions has been slow in the last decade. The available knowledge on CPA and MCPA function is to a great extent based on pharmacological interventions in these brain regions performed in unconscious animals [6]. The contribution of the CPA and MCPA to the regulation of sympathetic tone in conscious freely behaving animals is currently unknown. Optogenetic and pharmacogenetic techniques developed during the last years allow experimental manipulations of CNS neuronal activity in genetically modified animals. Animals carrying light-sensitive ion channels or synthetic G protein-coupled receptors in specific populations of neurons can be studied in the conscious state with neuronal activity in CNS regions of interest acutely modified by illumination or administration of a synthetic ligand for artificial G protein-coupled receptors [7,8]. In the future, such manipulations of CPA or MCPA neuronal activity combined with sympathetic nerve recordings in conscious animals may reveal the contribution of these regions to sympathetic tone under physiological conditions. The role of CPA and MCPA neurons for the pathogenesis of cardiovascular diseases has hardly been investigated. So far, it has been shown that CPA inhibition is accompanied by greater arterial pressure reductions in spontaneously hypertensive rats (SHR) than in normotensive Wistar–Kyoto rats (WKY) [9], which suggests but does not prove that CPA-dependence of sympathetic tone is higher in SHR than in WKY. Another study transduced rat RVLM and MCPA neurons with a human, inwardly rectifying potassium channel (hKir2.1) via lentivirus-mediated gene transfer to reduce their activity [10]. Chronic arterial pressure reductions were observed in SHR expressing hKir2.1 in the RVLM but not in SHR expressing hKir2.1 in the MCPA suggesting that MCPA neurons do not contribute to the maintenance of hypertension in SHR [10]. The CPA is involved in the processing of afferent input from peripheral arterial chemoreceptors [6]. Peripheral chemoreceptor reflex sensitivity is enhanced and contributes to sympathetic overactivity in chronic heart failure [11]. Future studies may test if altered CPA-dependent processing of chemoreceptor input is part of the chemoreceptor reflex-dependent sympathetic activation in chronic heart failure. Another potential area of research on the role of CPA and MCPA neurons under pathological conditions may be sympathetic overactivity in chronic kidney disease and renovascular hypertension that is at least in part due to signals that arise in the damaged kidneys and activate renal afferent nerve fibers [3,12,13]. Translation of the detailed knowledge on the localization and function of CNS neurons controlling sympathetic activity obtained in experimental animal-based research to humans is important for its clinical application but a major challenge. The development of sophisticated techniques that allow simultaneous functional magnetic resonance imaging of the brain and sympathetic nerve recordings in humans is an important methodological achievement to facilitate this translation [14]. Functional magnetic resonance imaging of the brain stem revealed positive correlations between sympathetic nerve activity and the activity of RVLM as well as CPA neurons in humans [14,15]. The detailed review by Ghali [6] on the physiology and pharmacology of CPA and MCPA neurons identifies many open questions regarding their function under physiological and pathological conditions. It will stimulate future research in this area of neuroscience which will benefit from refined methods now available to study neuronal circuits in animals and humans with great accuracy and under experimental conditions that allow drawing conclusions on the role of CNS neurons for the regulation of sympathetic activity in the conscious state. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.