Pontine control of rapid eye movement sleep and fear memory.

AIMS: We often experience dreams of strong irrational and negative emotional contents with postural muscle paralysis during rapid eye movement (REM) sleep, but how REM sleep is generated and its function remain unclear. In this study, we investigate whether the dorsal pontine sub-laterodorsal tegmental nucleus (SLD) is necessary and sufficient for REM sleep and whether REM sleep elimination alters fear memory. METHODS: To investigate whether activation of SLD neurons is sufficient for REM sleep induction, we expressed channelrhodopsin-2 (ChR2) in SLD neurons by bilaterally injecting AAV1-hSyn-ChR2-YFP in rats. We next selectively ablated either glutamatergic or GABAergic neurons from the SLD in mice in order to identify the neuronal subset crucial for REM sleep. We finally  investigated the role of REM sleep in consolidation of fear memory using rat model with complete SLD lesions. RESULTS: We demonstrate the sufficiency of the SLD for REM sleep by showing that photo-activation of ChR2 transfected SLD neurons selectively promotes transitions from non-REM (NREM) sleep to REM sleep in rats. Diphtheria toxin-A (DTA) induced lesions of the SLD in rats or specific deletion of SLD glutamatergic neurons but not GABAergic neurons in mice completely abolish REM sleep, demonstrating the necessity of SLD glutamatergic neurons for REM sleep. We then show that REM sleep elimination by SLD lesions in rats significantly enhances contextual and cued fear memory consolidation by 2.5 and 1.0 folds, respectively, for at least 9 months. Conversely, fear conditioning and fear memory trigger doubled amounts of REM sleep in the following night, and chemo-activation of SLD neurons projecting to the medial septum (MS) selectively enhances hippocampal theta activity in REM sleep; this stimulation immediately after fear acquisition reduces contextual and cued fear memory consolidation by 60% and 30%, respectively. CONCLUSION: SLD glutamatergic neurons generate REM sleep and REM sleep and SLD via the hippocampus particularly down-regulate contextual fear memory.

Continuous blood purification ameliorates RhoA-mediated endothelial permeability in severe acute pancreatitis patients with lung injury.

BACKGROUND: In the early phase of severe acute pancreatitis (SAP), serious pulmonary complications which are directly correlated with mortality are very common. Endothelial injury has been shown to play a key role in the pathogenesis of ALI/ARDS. Continuous blood purification (CBP) has been widely used in treating patients with multiple organ dysfunction syndrome (MODS) including ARDS. However, the impact of CBP on endothelial function has been little studied. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to serum samples or replacement fluid taken from patients at specific time points during CBP, or pretreated with Y-27632 followed by treatment with serum, then, changes in cytoskeletal configuration, endothelial monolayer permeability, and RhoA activation were studied. RESULTS: Endothelial permeability, RhoA activity, and stress fiber reorganization increased in HUVECs treated with serum from patients before CBP initiation, and lessened in HUVECs treated with serum from patients after CBP initiation. Endothelial hyperpermeability and stress fiber reorganization reduced in HUVECs pretreated with Rho-kinase inhibitor, Y-27632, and in a dose-dependent fashion. Endothelial permeability and RhoA activity increased in HUVECs treated with waste replacement fluid collected 2 h after CBP initiation. CONCLUSIONS: After CBP treatment, endothelial hyperpermeability induced by serum from SAP patients with lung injury was reduced. The inhibition of RhoA-mediated F-actin remodeling might be the mechanism.