Hyped up about the hypothalamus.

Recent work supports the view that the paraventricular nucleus (PVN) of the hypothalamus plays an important role in mediating an increase in sympathetic nerve activity during water deprivation, hypertension and heart failure. There is little information available regarding the PVN neuronal types involved in this sympathoexcitation or the properties of such neurones that are altered under these conditions. Work by Chen & Toney in this issue of The Journal of Physiology shows that small-conductance Ca2+-activated K+ (SK) channels suppress the excitability of PVN neurones that project to the rostral ventrolateral medulla. This is one possible neuronal population altered in pathophysiological states. For many years now, the paraventricular nucleus (PVN) of the hypothalamus has received attention as a supramedullary component of autonomic pathways, in large part because of its role as an integrator of autonomic and neuroendocrine functions (Ferguson et al. 2008). The afferent and efferent connections of the PVN make it easy to envision it having such a role. There are direct projections from PVN to autonomic sites including the rostral ventrolateral medulla (RVLM), the nucleus of the tractus solitarius and the spinal intermediolateral nucleus (IML); and PVN neurones receive information from peripheral and central osmoreceptors, sodium receptors and volume receptors (Dampney et al. 2005; Coote, 2007). Despite a long history of being considered an autonomic nucleus, the PVN has received considerably less attention than medullary sites such as the RVLM when seeking answers to how basal levels of sympathetic nerve activity (SNA) are generated. This ‘neglect’ of the PVN probably stems from the fact that supramedullary structures tend to be suppressed by anaesthesia used in most in vivo animal studies (see Coote, 2007). Also, because a powerful GABAergic inhibitory input to PVN neurones keeps their basal activity at a low level, they are not expected to have a major influence on SNA. Indeed, as discussed by Dampney et al. (2005), there is not a great deal of support for the view that PVN neurones contribute significantly to resting sympathetic vasomotor tone in normotensive animals. However, over the past decade or so evidence has accumulated to encourage researchers to get hyped up about the role of the hypothalamus, especially the PVN, during water deprivation and in pathophysiological states such as hypertension and heart failure (see Dampney et al. 2005; Guyenet, 2006). There is data linking altered PVN neuronal activity to the heightened level of SNA, especially renal SNA, under these conditions. In order to gain a greater appreciation of the pathophysiology associated with these states, it is important to identify which PVN neurones are the key players in causing the increase in vasomotor tone, to identify what happens to these neurones to promote sympathoexcitation, and to identify synaptic and intrinsic membrane factors that regulate their excitability and firing rate under physiological and pathophysiological conditions. There are several logical choices for the PVN neuronal group that mediates sympathoexcitation: those projecting to the RVLM, those projecting to the IML, and those projecting to both the RVLM and IML. Although there are many more PVN neurones that project to the IML than to the RVLM (Coote, 2007), there is indirect evidence from in vivo studies that implicate a PVN-RVLM pathway for the elevation of SNA in water deprivation, hypertension and heart failure (Dampney et al. 2005; Guyenet, 2006; Ferguson et al. 2008). However, still lacking is direct electrophysiological evidence for dysfunction of these PVN-RVLM-projecting neurones under these conditions. As to which chemicals within the PVN are possibly changed with water deprivation, hypertension and heart failure, the list includes GABA, nitric oxide, angiotensin, atrial natriuretic peptide, aldosterone and pro-inflammatory cytokines (Dampney et al. 2005; Guyenet, 2006; Ferguson et al. 2008). In this issue of The Journal of Physiology, Chen & Toney (2009) report the results of a well-designed study using in vitro hypothalamic slices from Sprague–Dawley rats to test the hypothesis that small-conductance Ca2+-activated K+ (SK) channels suppress the excitability of PVN-RVLM-projecting neurones. PVN-RVLM-projecting neurones were labelled by microinjection of rhodamine-containing microspheres in the RVLM 5 to 7 days before making whole-cell patch-clamp recordings. In voltage-clamp recordings, step depolarization revealed a calcium-dependent outward tail current that reversed near EK and was nearly abolished by SK channel blockers, suggesting the current was mediated by SK channels. In current-clamp recordings, depolarizing step current injections elicited action potentials that underwent spike-frequency adaptation (SFA). When the current injection was terminated, a prominent medium after-hyperpolarization potential (mAHP) appeared. SK channel blockade increased spike frequency but did not affect SFA; it also abolished the mAHP and unmasked an after-depolarization potential (ADP). On the basis of these and additional data, the authors concluded that activation of SK channels in PVN-RVLM-projecting neurones suppresses their excitability by a mechanism that probably involves generation of a mAHP that opposes an ADP that would otherwise facilitate firing. Although the authors were careful not to assume that they were studying specifically PVN neurones involved in control of SNA, they offered the tantalizing and novel idea that dysfunction of SK channels in PVN-RVLM neurones could lead to changes in RVLM-IML-projecting neurones and thus SNA. The study by Chen & Toney (2009) provides important information on the role of ion channels in regulating PVN neuronal excitability, but at the same time their data lead to some unanswered questions. Did this study target the right population of PVN neurones that cause sympathoexcitation or might PVN-IML-projecting neurones be the major player? Is there anything unique about SK channels regulating membrane properties of PVN-RVLM neurones, or is this a common mechanism to regulate excitability of PVN neurones? Is activation of SK channels in PVN neurones altered in water deprivation, hypertension or heart failure – conditions in which altered PVN neuronal activity is thought to contribute to elevations in SNA? In many ways, the field of investigating the role of the PVN in control of SNA is in its infancy. Hopefully future in vitro as well as in vivo studies using animal models of various disease states will be conducted to keep pushing us forward.