No abstract

Background The carotid bodies and baroreceptors are sensors capable of detecting various physiological parameters that signal to the brain via the afferent carotid sinus nerve for physiological adjustment by efferent pathways. Because receptors for inflammatory mediators are expressed by these sensors, we and others have hypothesised they could detect changes in pro-inflammatory cytokine blood levels and eventually trigger an anti-inflammatory reflex. Methods To test this hypothesis, we surgically isolated the carotid sinus nerve and implanted an electrode, which could deliver an electrical stimulation package prior and following a lipopolysaccharide injection. Subsequently, 90 min later, blood was extracted, and cytokine levels were analysed. Results Here, we found that carotid sinus nerve electrical stimulation inhibited lipopolysaccharide-induced tumour necrosis factor production in both anaesthetised and non-anaesthetised conscious mice. The anti-inflammatory effect of carotid sinus nerve electrical stimulation was so potent that it protected conscious mice from endotoxaemic shock-induced death. In contrast to the mechanisms underlying the well-described vagal anti-inflammatory reflex, this phenomenon does not depend on signalling through the autonomic nervous system. Rather, the inhibition of lipopolysaccharide-induced tumour necrosis factor production by carotid sinus nerve electrical stimulation is abolished by surgical removal of the adrenal glands, by treatment with the glucocorticoid receptor antagonist mifepristone or by genetic inactivation of the glucocorticoid gene in myeloid cells. Further, carotid sinus nerve electrical stimulation increases the spontaneous discharge activity of the hypothalamic paraventricular nucleus leading to enhanced production of corticosterone. Conclusion Carotid sinus nerve electrostimulation attenuates inflammation and protects against lipopolysaccharide-induced endotoxaemic shock via increased corticosterone acting on the glucocorticoid receptor of myeloid immune cells. These results provide a rationale for the use of carotid sinus nerve electrostimulation as a therapeutic approach for immune-mediated inflammatory diseases.

Significance Memory formation relies on a plethora of functions, including epigenetic modifications. Over recent years, multiple studies have indicated the potential of HDAC inhibitors (HDACis) as cognitive enhancers, but their mode of action is not fully understood. Here, we tested whether HDACi treatment improves memory formation via “cognitive epigenetic priming,” stipulating that HDACis—without inherent target specificity—specifically enhance naturally occurring plasticity processes. We found that combining HDACis with fear learning, but not either treatment alone, enhances synaptic plasticity as well as memory-promoting transcriptional signaling in the hippocampus, a brain area recruited by fear learning, but not in unrelated areas. These results lend experimental support to the theory of cognitive epigenetic priming.

Long-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers.