Neural control of inflammation by the greater splanchnic nerves

The brain influences immune function through a powerful neural reflex that suppresses the release of a key pro-inflammatory cytokine, tumor necrosis factor \u3b1, after immune challenge. The efferent motor pathway of this reflex is in the splanchnic nerves, not the vagi. This reflex regulates inflammation but does not suppress fever

Analysis of sympathetic neural discharge in rats and humans

Neural signals convey information through two different modalities: intensity and discharge pattern. The intensity code is based on the number of action potentials per unit time, which is then easily translated into neurotransmitter release. This kind of information may be assessed simply by counting the number of spikes or bursts over a time unit. However, the discharge pattern is a further, efficient means of neural information transfer. Rhythmic patterns (i.e. oscillations) can support highly structured, temporal codes based on correlation and synchronization. It is therefore clear that applying frequency domain analysis to sympathetic activity recorded in animals and humans may provide additional information about the neural control of the circulation. Over the last century, data obtained by the analysis of sympathetic activity in experimental animals, and recently also in humans, have provided fundamental contributions to our understanding of the physiological mechanisms involved in the neural control of circulation, as well as how these are altered in cardiovascular and non-cardiovascular diseases. The aim of this paper is to address some aspects related to the recording, analysis and interpretation of sympathetic activity in rats and humans, with special emphasis on analysis in the frequency domain

The median preoptic nucleus: Front and centre for the regulation of body fluid, sodium, temperature, sleep and cardiovascular homeostasis

Located in the midline anterior wall of the third cerebral ventricle (i.e. the lamina terminalis), the median preoptic nucleus (MnPO) receives a unique set of afferent neural inputs from fore-, mid- and hindbrain. These afferent connections enable it to receive neural signals related to several important aspects of homeostasis. Included in these afferent projections are (i) neural inputs from two adjacent circumventricular organs, the subfornical organ and organum vasculosum laminae terminalis, that respond to hypertonicity, circulating angiotensin II or other humoural factors, (ii) signals from cutaneous warm and cold receptors that are relayed to MnPO, respectively, via different subnuclei in the lateral parabrachial nucleus and (iii) input from the medulla associated with baroreceptor and vagal afferents. These afferent signals reach appropriate neurones within the MnPO that enable relevant neural outputs, both excitatory and inhibitory, to be activated or inhibited. The efferent neural pathways that proceed from the MnPO terminate on (i) neuroendocrine cells in the hypothalamic supraoptic and paraventricular nuclei to regulate vasopressin release, while polysynaptic pathways from MnPO to cortical sites may drive thirst and water intake, (ii) thermoregulatory pathways to the dorsomedial hypothalamic nucleus and medullary raph\ue9 to regulate shivering, brown adipose tissue and skin vasoconstriction, (iii) parvocellular neurones in the hypothalamic paraventricular nucleus that drive autonomic pathways influencing cardiovascular function. As well, (iv) other efferent pathways from the MnPO to sites in the ventrolateral pre-optic nucleus, perifornical region of the lateral hypothalamic area and midbrain influence sleep mechanisms

The endogenous inflammatory reflex inhibits the inflammatory response to different immune challenges in mice

The splanchnic anti-inflammatory pathway, the efferent arm of the endogenous inflammatory reflex, has been shown to suppress the acute inflammatory response of rats to systemic lipopolysaccharide (LPS). Here we show for the first time that this applies also to mice, and that the reflex may be engaged by a range of inflammatory stimuli. Experiments were performed on mice under deep anaesthesia. Half the animals were subjected to bilateral section of the splanchnic sympathetic nerves, to disconnect the splanchnic anti-inflammatory pathway, while the remainder underwent a sham operation. Mice were then challenged intravenously with one of three inflammatory stimuli: the toll-like receptor (TLR)-4 agonist, LPS (60 \ub5g/kg), the TLR-3 agonist Polyinosinic:polycytidylic acid (Poly I:C, 1 mg/kg) or the TLR-2 and -6 agonist dipalmitoyl-S-glyceryl cysteine (Pam2cys, 34 \ub5g/kg). Ninety minutes later, blood was sampled by cardiac puncture for serum cytokine analysis. The splanchnic anti-inflammatory reflex action was assessed by comparing cytokine levels between animals with cut versus those with intact splanchnic nerves. A consistent pattern emerged: Tumor necrosis factor (TNF) levels in response to all three challenges were raised by prior splanchnic nerve section, while levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were reduced. The raised TNF:IL-10 ratio after splanchnic nerve section indicates an enhanced inflammatory state when the reflex is disabled. These findings show for the first time that the inflammatory reflex drives a coordinated anti-inflammatory action also in mice, and demonstrate that its anti-inflammatory action is engaged, in similar fashion, by inflammatory stimuli mimicking a range of bacterial and viral infections

Sympathetic nerves control bacterial clearance

A neural reflex mediated by the splanchnic sympathetic nerves regulates systemic inflammation in negative feedback fashion, but its consequences for host responses to live infection are unknown. To test this, conscious instrumented sheep were infected intravenously with live E. coli bacteria and followed for 48 h. A month previously, animals had undergone either bilateral splanchnic nerve section or a sham operation. As established for rodents, sheep with cut splanchnic nerves mounted a stronger systemic inflammatory response: higher blood levels of tumor necrosis factor alpha and interleukin-6 but lower levels of the anti-inflammatory cytokine interleukin-10, compared with sham-operated animals. Sequential blood cultures revealed that most sham-operated sheep maintained high circulating levels of live E. coli throughout the 48-h study period, while all sheep without splanchnic nerves rapidly cleared their bacteraemia and recovered clinically. The sympathetic inflammatory reflex evidently has a profound influence on the clearance of systemic bacterial infection