Explore the vast range of titles available.

Epigenomic abnormalities caused by genetic mutation in epigenetic regulators can result in neurodevelopmental disorders, deficiency in neural plasticity and mental retardation. As a histone demethylase, plant homeodomain finger protein 8 ( Phf8 ) is a candidate gene for syndromal and non-specific forms of X-chromosome-linked intellectual disability (XLID). Here we report that Phf8 knockout mice displayed impaired learning and memory, and impaired hippocampal long-term potentiation (LTP) without gross morphological defects. We also show that mTOR signaling pathway is hyperactive in hippocampus in Phf8 knockout mouse. Mechanistically, we show that demethylation of H4K20me1 by Phf8 results in transcriptional suppression of RSK1 and homeostasis of mTOR signaling. Pharmacological suppression of mTOR signaling with rapamycin in Phf8 knockout mice recovers the weakened LTP and cognitive deficits. Together, our results indicate that loss of Phf8 in animals causes deficient learning and memory by epigenetic disruption of mTOR signaling, and provides a potential therapeutic drug target to treat XLID. Mutations in PHF8 gene are genetically associated with X-linked mental retardation. Here, Chen et al. show that Phf8 KO mouse have cognitive and synaptic plasticity impairment, and pharmacological inhibition of mTOR signaling can partially alleviate such defects.

Obesity is associated with a high prevalence of mood disorders such as anxiety and depression. Both stress and high fat diet can alter the gut microbiota and contribute to obesity. To examine the interrelationships between obesity, stress, gut microbiota and mood disorders, obesity was induced in mice using a high fat diet, and the mice were subsequently stressed using a chronic unpredictable mild stress protocol. During the experiment, the composition of the gut microbiota was analyzed by 16 S rRNA gene high-throughput sequencing, and anxiety-like behaviors were measured. The results revealed distinct gender differences in the impacts of obesity and stress on anxiety-like behaviors, activity levels, and composition of the gut microbiota. Male mice were more vulnerable to the anxiogenic effects of the high fat diet, and obese male mice showed decreased locomotion activity in response to stress whereas obese female mice did not. In females, stress caused the gut microbiota of lean mice to more closely resemble that of obese mice. Taken together, these results suggest the importance of considering gender as a biological variable in studies on the role of gut microbiota in obesity-related mood disorders.

Previously we showed that elevated cerebrospinal fluid (CSF) levels of kininogen during the acute phase of encephalitis are associated with symptomatic epilepsy. However, the functional role of kininogen in epileptogenesis remains unexplored. This study investigated the brain expression of kininogen and its influence on seizure susceptibility. Additionally, we examined the effects of bradykinin, a nonapeptide derived from kininogen, as a potential downstream mediator of kininogen's effect on seizure susceptibility and the underlying circuitry mechanisms. We analyzed brain mRNA expression of kininogen using publicly available single-cell RNA-sequencing (scRNA-seq) datasets and assessed protein expression through immunofluorescence in various brain regions. Immunoblot was conducted following pilocarpine-induced status epilepticus (Pilo-SE) to understand post-seizure kininogen dynamics. Next, to understand its functional role, kininogen was overexpressed in the hippocampal CA1 area via its AAV-mediated gene delivery, and bradykinin was administered through the fourth ventricle in mice. The effects on seizure susceptibility were evaluated using a pentylenetetrazole-induced seizure susceptibility test. Furthermore, two-photon calcium imaging of cortical layer 2/3 glutamatergic neurons and GABAergic parvalbumin-positive neurons was performed to explore the potential circuitry mechanisms. While scRNA-seq analyses found kininogen gene expressions in various cell types across the brain, immunofluorescence revealed its preferential localization in neurons but not in glia. Pilo-SE decreased intact kininogen levels in the hippocampus and increased cleaved to intact kininogen (cHK / iHK) ratio. Overexpression of kininogen and exogenous bradykinin administration significantly increased pentylenetetrazole-induced seizure susceptibility in mice. Mechanistically, bradykinin was found to enhance calcium activities in cortical glutamatergic excitatory neurons in Thy1-GCaMP mice when they were treated with a subthreshold dose of pentylenetetrazole. In contrast, calcium activities in GABAergic parvalbumin-positive inhibitory neurons were reduced by bradykinin in PV -GCaMP mice, suggesting potential circuitry mechanisms by which kininogen may render increased seizure susceptibility. Our findings reveal a novel pathological role of kininogen in seizure occurrence, explaining why kininogen might be elevated in the CSF of epilepsy-susceptible patients and suggest its potential mechanisms where it might regulate the activities of glutamatergic and GABAergic neurons through the downstream release of bradykinin. Altogether, we propose kininogen as a potential target for developing therapeutics for epilepsy intervention.

The pathophysiologic mechanisms of epileptogenesis are poorly understood, and no effective therapy exists for suppressing epileptogenesis. Numerous reports have shown that nicotinamide adenine dinucleotide (NAD + ) has neuroprotective effects, suggesting its potential use for treating epileptogenesis. Here we evaluated the effects of NAD + on epileptogenesis and the mechanisms underlying these effects. In pilocarpine-induced status epilepticus (SE) model mice, NAD + was injected three times within 24.5 h after SE. NAD + intervention significantly reduced the incidence of spontaneous recurrent seizure (SRS) and abnormal electroencephalogram (EEG) activity, rescued contextual fear memory formation, reduced neuronal loss in the CA1 region of the hippocampus at SRS stage. Furthermore, exogenous supply of NAD + distinctly reversed the seizure-induced depletion of endogenous NAD + , reduced neuronal apoptosis in the CA1 region of the hippocampus, and reversed the augmented Acp53/p53 ratio at the early stage of epileptogenesis. Our findings demonstrated that early-stage intervention with NAD + prevents epileptogenesis in pilocarpine-induced SE mice by suppressing neuronal apoptosis.

The idea of aromatherapy, using essential oils, has been considered as an alternative antidepressant treatment. In the present study, we investigated the effect of Roman chamomile essential oil inhalation for two weeks on depressive-like behaviors in Wistar-Kyoto（WKY） rats. We found that inhalation of either Roman chamomile or one of its main components α-pinene,attenuated depressive-like behavior in WKY rats in the forced swim test. Using isobaric tags for relative and absolute quantitation analysis（iTRAQ）, we found that inhalation of α-pinene increased expression of proteins that are involved in oxidative phosphorylation, such as cytochrome c oxidase subunit 6C-2, cytochrome c oxidase subunit 7A2, ATPase inhibitor in the hippocampus, and cytochrome c oxidase subunit 6C-2, ATP synthase subunit e, Acyl carrier protein, and Cytochrome b-c1 complex subunit 6 in the PFC（prefrontal cortex）. In addition, using the quantitative real-time polymerase chain reaction technique, we confirmed an increase of parvalbumin mRNA expression in the hippocampus, which was shown to be upregulated by 2.8-fold in iTRAQ analysis, in α-pinene treated WKY rats. These findings collectively suggest the involvement of mitochondrial functions and parvalbumin-related signaling in the antidepressant effect of α-pinene inhalation.

Accumulating evidence suggests that the nucleus accumbens, which is involved in mechanisms of reward and addiction, plays a role in the pathogenesis of depression and in the action of anti-depressants. In the current study, intraperitoneal injection of nomifensine, a dopamine reuptake inhibitor, decreased depression-like behaviors in the Wistar Kyoto rat model of depression in the sucrose-preference and forced swim tests. Nomifensine also reduced membrane excitability in medium spiny neurons in the core of the nucleus accumbens in the childhood Wistar Kyoto rats as evaluated by electrophysiological recording. In addition, the expression of dopamine D2-like receptor mRNA was downregulated in the nucleus accumbens, striatum and hippocampus of nomifensine-treated childhood Wistar Kyoto rats. These experimental ifndings indicate that impaired inhibition of medium spiny neurons, mediated by dopamine D2-like receptors, may be involved in the formation of depression-like behavior in childhood Wistar Kyoto rats, and that nomifensine can alleviate depressive behaviors by reducing medium spiny neuron membrane excitability.

Elastic migration has been widely paid attention by employing the vector processing of mul- ticomponent seismic data. Ray based elastic Kirchhoff migration has such properties as high flexibility and high efficiency. However, it has failed to solve many problems caused by multipath. On the other hand, elastic reverse-time migration （RTM） based on the two-way wave equation is known to be capable of dealing with these problems, but it is extremely expensive when applied in 3D cases and velocity model building. Based on the elastic Kirchhoff-Helmholtz integral, we calculate deeoupled backward-continued wavefields by introducing elastic Green functions for P- and S-waves, which is expressed by a summation of elastodynamic Gaussian beams. The PP and polarity-corrected PS images are obtained by calculating the correlation between downward and deeoupled backward-continued vector wavefields, where polarity correction is performed by analyzing the relation between the polarization direction of converted PS waves and incident angle on the interface. To a large extent, our method combines the high efficiency of ray-based migration with the high accuracy of wave-equation based reverse-time migration. Application of this method to multicomponent synthetic datasets from the fault model and Marmousi 2 model demonstrates the validity, flexibility and accuracy of the new method.

Aims To explore the role of voltage‐gated calcium channels (VGCC) in 5‐HT2A/2C receptor agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride's improvement of spinal cord injury (SCI) induced detrusor sphincter dyssynergia and the expressions of the 5‐hydroxy tryptamine (5‐HT) 2A receptors and VGCCs in lumbosacral cord after SCI. Methods Female Sprague–Dawley rats were randomized into normal control group and SCI group (N = 15 each). Cystometrogram (CMG), simultaneous CMG, and external urethral sphincter electromyography (EUS‐EMG) were conducted in all groups under urethane anesthesia. Drugs were administered intrathecally during CMG and EUS‐EMG. Rats were euthanized and L6‐S1 spinal cord were acquired for immunofluorescence. Results In SCI rats, intrathecal administration of 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride or L‐type VGCC blocker, nifedipine, could significantly increase voiding volume, voiding efficiency, and the number of high‐frequency oscillations. They could also prolong EUS bursting activity duration on EUS‐EMG. Moreover, the effect of 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride can be eliminated with the combined administration of L‐type VGCC agonist, (±)‐Bay K 8644. No significant differences were observed in CMG after intrathecal administration of T‐type VGCC blocker TTA‐P2. Additionally, immunofluorescence of the lumbosacral cord in control and SCI rats showed that the 5‐HT2A receptor and Cav1.2 immunolabeling‐positive neurons in the anterior horn of the lumbosacral cord were increased in SCI rats. Conclusions Our study demonstrated that 5‐HT2A/2C agonist 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride may improve SCI‐induced DSD by inhibiting the L‐type voltage‐gated calcium channel in lumbosacral cord motoneurons. L‐type voltage‐gated calcium channel blocker, nifedipine, could improve spinal cord injury‐induced detrusor sphincter dyssynergia. 2,5‐dimethoxy‐4‐iodophenyl‐2‐aminopropane hydrochloride may improve SCI‐induced DSD by inhibiting the L‐type voltage‐gated calcium channel in lumbosacral cord motoneurons.

Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.

Background Studies have indicated that depressive disorders are observed frequently in dentists. It’s suggested that dentists encounter numerous sources of stress in their professional career. We noticed that the noises in dental environments are very unpleasant. The animal modeling studies suggested that stressful noise could produce depressive-like phenotypes in rodent animals. We hypothesize that the dental noise may be one of the primary stressors causing depressive disorders in dentists. Results We treated C57BL/6 mice with programmatically played wide-spectrum dental noise for 8 h/day at 75 ± 10 dB SPL level for 30 days, and then tested the behaviors. After exposure to dental noise, animals displayed the depressive-like phenotypes, accompanied by inhibition of neurogenesis in hippocampus. These deficits were ameliorated by orally administered with antidepressant fluoxetine. Conclusions Our results suggested that dental noise could be one of the primary stressors for the pathogenesis of depressive disorders and the dental noise mouse model could be used in further depression studies.