Models Of Paraventricular Nucleus (PVN) Sympathetic Neurone Modulation by Glucose and Hypoglycaemia

Abstract

Hypoglycaemia activates much of the sympathetic nervous system (Fagius 2003. Acta Physiol. Scand. 177:337-343) and this is likely to be important to glucose counter-regulation. The PVN is ideally suited to mediate this response since it contains a high density of spinally-projecting sympathetic control neurones. Furthermore, inactivation of the PVN with lignocaine blunts counter-regulation (Evans et al. 2003 Am. J. Physiol. 284:R57-65).Our in vitro data show paradoxical responses of PVN sympathetic control neurones (SPNs) to hypoglycaemia: They express KATP channels and most are inhibited or unaffected by hypoglycaemia, whereas in vivo they appear to be activated by hypoglycaemia. There could be several possible explanations, however, in this study we explored the possibility that the paradox is accounted for by network properties in the PVN, and differential expression of KATP channels.We constructed very simple Neuron (Hines & Carnevale 1997. Neural Comput. 9:1179-1209) models of SPNs with inputs from both excitatory “Netstim” neurones and inhibitory interneurones. The interneurones are also driven by excitatory “Netstim” neurones. Both interneurones and SPNs incorporate identical KATP channels, but the latter with a lower density. We modelled the situation where this network is intact (in vivo) and where the inhibitory interneurones were lost (in vitro).In the in vitro model, SPN KATP conductance was sufficient for the expected (dose-related) decrease in action potential frequency with hypoglycaemia. Interestingly, however, with no changes to the set-up of the SPN neurones, but re-introduction of input from the inhibitory interneurones, the effect of hypoglycaemia was reversed. Hypoglycaemia now activated SPNs. This model also reproduced the common observation that whilst SPNs in brain slice experiments tend to be “spontaneously” active, they tend to be silent in vivo, but activated by GABAA inhibition.