Homeostatic plasticity is hypothesized to bidirectionally regulate neuronal activity around a stable set point to compensate for learning-related plasticity, but to date only upward firing rate homeostasis (FRH) has been demonstrated in vivo. We combined chronic electrophysiology in freely behaving animals with an eyereopening paradigm to enhance firing in primary visual cortex (V1) and found that neurons bidirectionally regulate firing rates around an individual set point. Downward FRH did not require N-methyl-D-aspartate receptor (NMDAR) signaling and was associated with homeostatic scaling down of synaptic strengths. Like upward FRH, downward FRH was gated by arousal state but in the opposite direction: it occurred during sleep, not during wake. In contrast, firing rate depression associated with Hebbian plasticity happened independently of sleep and wake. Thus, sleep and wake states temporally segregate upward and downward FRH, which might prevent interference or provide unopposed homeostatic compensation when it is needed most.

BackgroundInflammation can induce cognitive dysfunction in patients who undergo surgery. Previous studies have demonstrated that both acute peripheral inflammation and anaesthetic insults, especially isoflurane (ISO), are risk factors for memory impairment. Few studies are currently investigating the role of ISO under acute peri-inflammatory conditions, and it is difficult to predict whether ISO can aggravate inflammation-induced cognitive deficits. HDACs, which are essential for learning, participate in the deacetylation of lysine residues and the regulation of gene transcription. However, the cell-specific mechanism of HDACs in inflammation-induced cognitive impairment remains unknown.MethodsThree-month-old C57BL/6 mice were treated with single versus combined exposure to LPS injected intraperitoneally (i.p.) to simulate acute abdominal inflammation and isoflurane to investigate the role of anaesthesia and acute peripheral inflammation in cognitive impairment. Behavioural tests, Western blotting, ELISA, immunofluorescence, qRT-PCR, and ChIP assays were performed to detect memory, the expressions of inflammatory cytokines, HDAC2, BDNF, c-Fos, acetyl-H3, microglial activity, Bdnf mRNA, c-fos mRNA, and Bdnf and c-fos transcription in the hippocampus.ResultsLPS, but not isoflurane, induced neuroinflammation-induced memory impairment and reduced histone acetylation by upregulating histone deacetylase 2 (HDAC2) in dorsal hippocampal CaMKII+ neurons. The hyperexpression of HDAC2 in neurons was mediated by the activation of microglia. The decreased level of histone acetylation suppressed the transcription of Bdnf and c-fos and the expressions of BDNF and c-Fos, which subsequently impaired memory. The adeno-associated virus ShHdac2, which suppresses Hdac2 after injection into the dorsal hippocampus, reversed microglial activation, hippocampal glutamatergic BDNF and c-Fos expressions, and memory deficits.ConclusionsReversing HDAC2 in hippocampal CaMKII+ neurons exert a neuroprotective effect against neuroinflammation-induced memory deficits.

Brain-derived neurotrophic factor (BDNF) is essential for cognitive and memory functions. Abnormal BDNF expression in the central nervous system may impair these functions. Anaesthesia and surgery can induce perioperative neurocognitive disorders (PND). Clinical studies show that BDNF expression is decreased in patients presenting with cognitive impairment after anaesthesia and surgery. However, the molecular mechanism is still unclear. Epigenetic regulation plays an important role in cognition. The hypermethylation of H3K9 is crucial for transcriptional silencing and the onset of cognitive disorders. Here, we hypothesised that H3K9 trimethylation repressed BDNF expression and impaired memory formation or recall during anaesthesia and surgery. Laparotomy under isoflurane inhalation anaesthesia, behavioural tests, Western blotting, quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR), chromatin immunoprecipitation (ChIP), and immunohistochemistry were used in this study. BDNF expression was decreased in the hippocampus after anaesthesia and surgery. Cognitive impairment affected memory formation but not recall. The trimethylation of H3K9 downregulated BDNF expression. The overexpression of BDNF or use of exogenous BDNF improved the impairment of memory formation caused by anaesthesia and surgery. Therefore, inhibiting H3K9 trimethylation and increasing the expression of BDNF may help prevent PND in the clinical setting.

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Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured rat neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to excitatory neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

AIM To investigate the hepatitis C virus (HCV) infection in the tissues of carcinoma of extrahepatic bile duct and study their correlation. METHODS HCV NS5 protein and HCV RNA were detected by labeled streptavidin biotin (LSAB) method and in situ reverse transcription polymerase chain reaction (IS-RT-PCR) in sections of 51 cases of carcinoma of extrahepatic bile duct and 34 cases of control group (without malignant biliary disease). RESULTSIn 51 cases of carcinoma of extrahepatic bile duct, HCV NS5 protein was detected in 14 (27.5%), which was clearly stained in the cytoplasm of cancer cell but not in the nucleus or cell membrane. HCV RNA was detected in 18 (35.4%), which was located in the nucleus of cancer cell in 12 cases and in the cytoplasm in 6 cases. HCV NS5 protein and RNA coexistence was found in 2 cases. In 34 cases of control group, HCV RNA was detected in 2 (5.9%). HCV NS5 protein and RNA positive cells were found either scattered or in clusters. CONCLUSION The prevalence of hepatitis C viral infection in the tissues of carcinoma of extrahepatic bile duct was significantly higher than in control group (χ χ χ χ χ 2 =9.808, P=0.002). The findings suggest a correlation between HCV infection and carcinoma of extrahepatic bile duct, which is different from the traditional viewpoint. HCV infection might be involved in the development of carcinoma of extrahepatic bile duct.

Primary cilia are compartmentalized sensory organelles present on the majority of neurons in the mammalian brain throughout adulthood. Recent evidence suggests that cilia regulate multiple aspects of neuronal development, including the maintenance of neuronal connectivity. However, whether ciliary signals can dynamically modulate postnatal circuit excitability is unknown. Here we show that acute cell-autonomous knockdown of ciliary signaling rapidly strengthens glutamatergic inputs onto cultured neocortical pyramidal neurons, and increases spontaneous firing. This increased excitability occurs without changes to passive neuronal properties or intrinsic excitability. Further, the neuropeptide receptor somatostatin receptor 3 (SSTR3) is localized nearly exclusively to pyramidal neuron cilia both in vivo and in culture, and pharmacological manipulation of SSTR3 signaling bidirectionally modulates excitatory synaptic inputs onto these neurons. Our results indicate that ciliary neuropeptidergic signaling dynamically modulates excitatory synapses, and suggest that defects in this regulation may underlie a subset of behavioral and cognitive disorders associated with ciliopathies.

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