Renewed Excitement for Paraventricular Neurons and Sympathetic Nerve Activity.

As first speculated by Phillip Bard in the 1920s, the hypothalamus is referred to as a chief coordinator of autonomic function (see Dampney, 2011; Pyner, 2014). Yet autonomic physiologists seem to have placed greater emphasis on the role of the lower brainstem, in particular the rostral ventrolateral medulla (RVLM), than on the role of the hypothalamus in the control of sympathetic nerve activity (SNA) and blood pressure (see Wenker et al. 2017). Interest in the RVLM was justifiably spurred by the findings in the 1970s that neurons in the RVLM formed a prominent projection to the intermediolateral (IML) nucleus in the thoracolumbar spinal cord, the location of preganglionic sympathetic neurons, and by the subsequent discovery of a profound rise or fall in blood pressure with chemical activation or inactivation, respectively, of these neurons as demonstrated primarily in anaesthetized animals. The results of a recent study by Wenker et al. (2017) challenged the often-expressed view that RVLM neuronal activity is a major determinant of basal levels of SNA and blood pressure. They used loss-of-function optogenetics (photoinhibition) to explore the contribution of RVLM neuronal activity in conscious rats and found that the activity of these neurons accounts minimally for resting blood pressure under normoxia, but RVLM neurons become activated and contribute to blood pressure regulation during hypoxia and anaesthesia and after baroreceptor denervation. This offers a compelling rationale for more research aimed at determining how RVLM neuronal activity is controlled under physiological states and how it is altered under pathophysiological conditions. Looking at the potential role of inputs to the RVLM in establishing RVLM neuronal activity under different conditions would be a reasonable target. Anatomical and physiological evidence shows that the paraventricular nucleus (PVN) of the hypothalamus projects to the RVLM (PVN-RVLM projecting neurons) and that inhibition of PVN neurons reduces SNA and blood pressure in hypertensive and heart failure models (see Dampney 2011; Pyner 2014). Coupled to the fact that the PVN is thought to integrate information that allows the body to respond to both external and internal challenges to maintain cardiovascular homeostasis (Ferguson et al, 2008), there is a strong rationale for work like that described in this issue of The Journal of Physiology by Koba et al. (2018) to understand the characteristics of PVN neurons that contribute to the control of SNA and blood pressure. Koba et al. (2018) report the results of a well-designed series of experiments that addressed the question of whether glutamatergic PVN-RVLM neurons contribute to the sympathoexcitatory effects mediated by activation of the PVN. As described by the authors, there were considerable data implicating a role for PVN-RVLM projecting neurons in mediating sympathetic hyperactivity in cardiovascular diseases such as heart failure and during acute stressors. Nonetheless, no study had yet established evidence that PVN neurons directly excite RVLM neurons to induce sympathoexcitation and an increase in blood pressure. Koba and colleagues used neural tract tracing techniques to identify a projection of glutamatergic PVN neurons that directly targeted RVLM C1 neurons, and they used state-of-the-art optogenetic stimulation to control the excitability of this select pool of PVN-RVLM neurons. They showed that photostimulation of the nerve terminals of ChIEF-tdTomato-expressing PVN-RVLM neurons induced an increase in renal SNA and an accompanying pressor response. Immunofluorescence confocal microscopy showed that these PVN-RVLM neuronal axons containing VGLUT2 immunoreactivity were closely associated with tyrosine hydroxylase-positive cells in the RVLM, supporting the view that PVN-RVLM glutamatergic neurons make synaptic contacts with RVLM C1 neurons. Photostimulation of the cell bodies of PVN neurons transduced with ChR2-GFP by retrograde infection of adeno-associated virus (AAV) injected into the RVLM induced an increase in renal SNA that was reversibly prevented by blockade of ionotropic glutamate receptors in the RVLM. This study by Koba et al. (2018) used urethane-anaesthetized animals, which, of course, is a limitation. It will be interesting to see how these glutamatergic PVN-RVLM neurons function in conscious animals. This integrative set of experiments provided compelling new evidence that the activity within the glutamatergic PVN-RVLM pathway is a worthwhile target for studies designed to assess the role of the PVN in cardiovascular homeostasis. Technologies today are far superior to those available to Phillip Bard in the early 1900s, so whereas he could only hypothesize that the hypothalamus was a major integrator of autonomic function, we can now formulate testable hypotheses to characterize its role in the most fundamental aspect of physiology, i.e. homeostasis. This study by Koba et al. (2018) should stimulate continued interest in the role of the PVN in mediating control of SNA and blood pressure in both health and disease. A PubMed search indicates a rise in interest in this field in recent years. Using ‘paraventricular nucleus’ AND ‘sympathetic nerve activity’ as search terms, only 24 papers were listed between 1975 and 1999. Between 2000 and 2009, the number grew to 162, and between 2010 and 2018 the number increased to 234. The PVN contains far more than simply glutamatergic PVN-RVLM neurons; it is a very heterogeneous nucleus in terms of anatomical projections, chemical nature of neurons, synaptic inputs and of course function. As stated by Ferguson et al. (2008), the PVN ‘has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune, and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular).’ It is time now to find out exactly how it does this. None declared. Sole author. None.