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Environmental challenges, specifically chronic stress, have long been associated with neuropsychiatric disorders, including anxiety and depression. Sirtuin-1 (SIRT1) is a NAD+-dependent deacetylase that is widely distributed in the cortex and is involved in stress responses and neuropsychiatric disorders. Nevertheless, how chronic stress modulates the SIRT1 pathway and associated signaling remains unclear. In this study, we first explored the impact of chronic unpredictable mild stress (CUMS) on the SIRT1/PGC1α/SIRT3 pathway, on GABAergic mechanisms, and on mitophagy, autophagy and apoptosis in mice. We also asked whether activation of SIRT1 by resveratrol (RSV) can attenuate CUMS-induced molecular and behavioral alterations. Two-month-old C57/BL6J mice were subjected to three weeks of CUMS and one week of RSV treatment (30 mg/kg; i.p.) during the third week of CUMS. CUMS caused downregulation of the SIRT1/PGC1α/SIRT3 pathway leading to impaired mitochondrial morphology and function. CUMS also resulted in a reduction in numbers of parvalbumin-positive interneurons and increased oxidative stress leading to reduced expression of autophagy- and mitophagy-related proteins. Strikingly, activation of SIRT1 by RSV ameliorated expression of SIRT1/PGC1α/SIRT3, and also improved mitochondrial function, GABAergic mechanisms, mitophagy, autophagy and apoptosis. RSV also rescued CUMS-induced anxiety-like and depressive-like behavior in mice. Our results raise the compelling possibility that RSV treatment might be a viable therapeutic method of blocking stress-induced behavioral alterations.

Neuroinflammation with excess microglial activation and synaptic dysfunction are early symptoms of most neurological diseases. However, how microglia-associated neuroinflammation regulates synaptic activity remains obscure. We report here that acute neuroinflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) results in cell-type-specific increases in inhibitory postsynaptic currents in the glutamatergic, but not the GABAergic, neurons of medial prefrontal cortex (mPFC), coinciding with excessive microglial activation. LPS causes upregulation in levels of GABAAR subunits, glutamine synthetase and vesicular GABA transporter, and downregulation in brain-derived neurotrophic factor (BDNF) and its receptor, pTrkB. Blockage of microglial activation by minocycline ameliorates LPS-induced abnormal expression of GABA signaling-related proteins and activity of synaptic and network. Moreover, minocycline prevents the mice from LPS-induced aberrant behavior, such as a reduction in total distance and time spent in the centre in the open field test; decreases in entries into the open arm of elevated-plus maze and in consumption of sucrose; increased immobility in the tail suspension test. Furthermore, upregulation of GABA signaling by tiagabine also prevents LPS-induced microglial activation and aberrant behavior. This study illustrates a mode of bidirectional constitutive signaling between the neural and immune compartments of the brain, and suggests that the mPFC is an important area for brain-immune system communication. Moreover, the present study highlights GABAergic signaling as a key therapeutic target for mitigating neuroinflammation-induced abnormal synaptic activity in the mPFC, together with the associated behavioral abnormalities.

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Background. Acute myocardial infarction (AMI) involves a series of complex cellular and molecular events, including circular RNAs (circRNAs), microRNAs (miRNAs) and other noncoding RNAs. Objective. In this study, the regulation mechanism of circEIF4G2 acting on miR-26a on HUVECs (Human Umbilical Vein Endothelial Cells) proliferation, cell cycle and angiogenesis ability was mainly explored in the vascular endothelial growth factor induced (VEGF-induced) angiogenesis model. Methods. VEGF induced HUVECs angiogenesis model was constructed, and the expression of circEIF4G2 and miR-26a in VEGF model was detected by qRT-PCR. When circEIF4G2 and miR-26a were knocked down or overexpressed in HUVECs, qRT-PCR was used to detect the expression of circEIF4G2 and miR-26a, CCK-8 was used to detect cell proliferation, flow cytometry was used to detect the cell cycle transition of HUVECs, and cell formation experiment was used to detect the ability of angiogenesis. MiRanda database and Targetscan predicted the binding site of circEIF4G2 and miR-26a, lucifase reporting assay and RNA pull down assay verified the interaction between circEIF4G2 and miR-26a. Results. After HUVECs were treated with VEGF, circEIF4G2 was significantly upregulated. After circEIF4G2 was knocked down, the proliferation and angiogenesis of HUVECs cells were decreased, and the process of cell cycle G0/G1 phase was blocked. The overexpression of miR-26a reduced the proliferation and angiogenesis of HUVECs cells and blocked the cell cycle progression of G0/G1 phase. Double lucifase reporter gene assay verified that circEIF4G2 could directly interact with miR-26a through the binding site, and RNA Pull down assay further verified the interaction between circEIF4G2 and miR-26a. When circEIF4G2 and miR-26a were knocked down simultaneously in HUVECs, it was found that knocking down miR-26a could reverse the inhibition of circEIF4G2 on cell proliferation, cycle and angiogenesis. Conclusion. In the VEGF model, circEIF4G2 was highly expressed and miR-26a was low expressed. MiR-26a regulates HUVECs proliferation, cycle and angiogenesis by targeting circEIF4G2.

Background Before the deposition of amyloid-beta plaques and the onset of learning memory deficits, patients with Alzheimer’s disease (AD) experience olfactory dysfunction, typified by a reduced ability to detect, discriminate, and identify odors. Rodent models of AD, such as the Tg2576 and APP/PS1 mice, also display impaired olfaction, accompanied by aberrant in vivo or in vitro gamma rhythms in the olfactory pathway. However, the mechanistic relationships between the electrophysiological, biochemical and behavioral phenomena remain unclear. Methods To address the above issues in AD models, we conducted in vivo measurement of local field potential (LFP) with a combination of in vitro electro-olfactogram (EOG), whole-cell patch and field recordings to evaluate oscillatory and synaptic function and pharmacological regulation in the olfactory pathway, particularly in the olfactory bulb (OB). Levels of protein involved in excitation and inhibition of the OB were investigated by western blotting and fluorescence staining, while behavioral studies assessed olfaction and memory function. Results LFP measurements demonstrated an increase in gamma oscillations in the OB accompanied by altered olfactory behavior in both APP/PS1 and 3xTg mice at 3–5 months old, i.e. an age before the onset of plaque formation. Fewer olfactory sensory neurons (OSNs) and a reduced EOG contributed to a decrease in the excitatory responses of M/T cells, suggesting a decreased ability of M/T cells to trigger interneuron GABA release indicated by altered paired-pulse ratio (PPR), a presynaptic parameter. Postsynaptically, there was a compensatory increase in levels of GABAAR α1 and β3 subunits and subsequent higher amplitude of inhibitory responses. Strikingly, the GABA uptake inhibitor tiagabine (TGB) ameliorated abnormal gamma oscillations and levels of GABAAR subunits, suggesting a potential therapeutic strategy for early AD symptoms. These findings reveal increased gamma oscillations in the OB as a core indicator prior to onset of AD and uncover mechanisms underlying aberrant gamma activity in the OB. Conclusions This study suggests that the concomitant dysfunction of both olfactory behavior and gamma oscillations have important implications for early AD diagnosis: in particular, awareness of aberrant GABAergic signaling mechanisms might both aid diagnosis and suggest therapeutic strategies for olfactory damage in AD.

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

Additional file 1: Original Western blotting results.

Alzheimer’s disease (AD) is an example of age-related dementia, and there are still no known preventive or curative measures for this disease. Obesity and associated metabolic changes are widely accepted as risk factors of age-related cognitive decline. Insulin is the prime mediator of metabolic homeostasis, which is impaired in obesity, and this impairment potentiates amyloid-β (Aβ) accumulation and the formation of neurofibrillary tangles (NFTs). Obesity is also linked with functional and morphological alterations in brain mitochondria leading to brain insulin resistance (IR) and memory deficits associated with AD. Also, increased peripheral inflammation and oxidative stress due to obesity are the main drivers that increase an individual’s susceptibility to cognitive deficits, thus doubling the risk of AD. This enhanced risk of AD is alarming in the context of a rapidly increasing global incidence of obesity and overweight in the general population. In this review, we summarize the risk factors that link obesity with AD and emphasize the point that the treatment and management of obesity may also provide a way to prevent AD.

Neuroinflammation and synaptic dysfunction are two early symptoms of most neurological diseases. However, the mechanisms underlying microglia-associated neuroinflammation in the regulation of synaptic activity remain obscure. We report here that acute neuroinflammation induced by a single-dose proinflammatory cytokine inducer, lipopolysaccharide (LPS), results in enhanced inhibitory postsynaptic currents (IPSCs) of glutamatergic neurons, upregulated levels of GABAAR subunits, glutamine synthetase (GS) and vGAT, and downregulated BDNF and pTrkB levels, due to enhanced activation of microglia in the medial prefrontal cortex (mPFC). Blockage of microglial activation by minocycline ameliorated LPS-induced aberrant mIPSCs and associated aberrant protein expression and behavior. Exogenous application of BDNF prior to LPS challenge also ameliorated LPS-induced abnormal mIPSCs. Thus, this study elucidates a critical role for microglia in the neurobiology of GABAergic synaptic dysfunction induced by neuroinflammation, revealing a novel GABAergic signaling pathway that might be targeted therapeutically to treat neuroinflammation-induced abnormal synaptic activity and associated aberrant behavior.

East Kluet District was the first to apply for a public service innovation program, one of which was the service program for receiving death compensation disbursement files in East Kluet District. This research was conducted because there was a gap that occurred in the people of East Kluet when they received deathcompensation services in the district capital, namely Tapaktuan District, the gap gave an unfavorable impression on the quality of public services. This study aims to determine the quality of public services in the service of receiving death compensation disbursement files in East Kluet District. Service quality can be measured by the performance of public organizations in providing services to the community. There are 8 indicators of service quality, namely: simplicity, clarity and certainty, security, openness, efficiency, economy, equitable justice, and timeliness. The type of research used in this study is a qualitative descriptive method by taking the focus of research in East Kluet District. Respondents used in this study were service providers, namely Setcam Kluet Timur and people who received death compensation services in East Kluet District. Data collection techniques used are interviews and field observations. After testing, the quality of public services in the service program for receiving death compensation disbursement files in East Kluet District according to the indicators, obtained maximum results. This means that the service program for receiving death compensation disbursement files in East Kluet District has met the quality of public services

Sleep deprivation (SD) is the hallmark of modern society and may increase risk of Alzheimer’s disease (AD). However, it is unclear how SD facilitates early cognitive impairments observed in AD models, as the underlying molecular mechanism is largely unknown. Here, we aim to investigate SD-induced cellular and molecular alterations in hippocampus of young APP/PS1 mice and whether jujuboside A (JuA) treatment could negate these alterations. Our results reveal that although SD causes spatial memory impairments in both genotypes, SD decreases frequency and amplitude of mEPSCs and pCREB levels in WT, but increases frequency and amplitude of mEPSCs, NMDAR, GluR1, pCaMKII (β, α) and decreases CREB levels in APP/PS1 mice, implicating that SD may facilitate abnormalities in young APP/PS1 mice via enhancing neuronal excitability. Moreover, JuA suppresses SD-induced enhancement of mEPSCs and prevents memory impairment in APP/PS1 mice. Further, whole-cell puff experiment suggests that JuA may function to activate GABAergic inhibition to reduce SD-induced enhancement of excitatory synaptic transmission in APP/PS1 mice. The present study reveals that sleep loss induces spatial memory impairment in an AD mouse model by disrupting the excitatory signaling pathway, and JuA prevents this via GABAergic mechanism.

EEG is a useful method to detect electrical activity in the brain. Moreover, it is a widely used diagnostic tool for various neurological conditions, such as epilepsy and neurodegenerative disorders. However, it is technically difficult to obtain EEG recordings in neonates as it requires specialized handling and great care. Here, we present a novel method to record EEG in neonatal rat pups (P8-P15). We designed a simple and reliable electrode using computer pin loci; it can be easily implanted into the skull of a rat pup to record high-quality EEG signals in the normal and epileptic brain. Pups were given an intraperitoneal (i.p.) injection of the neurotoxin kainic acid (KA) to induce epileptic seizures. The surgical implantation performed in this procedure is less expensive than other EEG procedures for neonates. This method allows one to record high-quality and stable EEG signals for more than 1 week. Furthermore, this procedure can also be applied to adult rats and mice to study epilepsy or other neurological disorders.

Das Ziel dieser Untersuchung ist zu beweisen, ob die Film Medien die Sprechkompetenz der Schüler in der SMA Negeri 2 Binjai im Jahrgang 2013/2014 steigern kann. Diese Untersuchung benutzt die Klassenhandlunguntersuchung, die in zwei Zyklen durchgeführt wird. Jeder Zyklus besteht aus drei Treffen. In dieser Untersuchung geht es darum, Die Anwendung von Audiovisual Medien “Film” auf die Steigerung der Sprechfertigkeit von den Schülern in der Klasse XI IPA SMA Negeri 2 Binjai im Jahrgang 2013/2014 zu dokumentieren. Die Probanden dieser Untersuchung sind Klasse XI IPA 1 SMA Negeri 2 Binjai im Jahrgang 2013/2014. Als Probanden galten 36 Personen, 25 Schülerinnen und 11 Schüler. Keine Schüler (0%), die den Erfolgsindikator erreicht hat. Aber im Zyklus I haben vierzehn Schüler (38,89%) den Erfolgsindikator erreicht. Zweiundzwanzig Schüler (61,11%) sind nicht kompetent. Und im Zyklus II haben sechsundzwanzig Schüler (72,22%) den Erfolgsindikator erreicht. Zehn Schüler (27,78%) sind nicht kompetent. Die Ergebnisse vom Vorwissenstest im ersten Zyklus und zweiten Zyklus zeigen eine Steigerung der Sprechfertigkeit der Schüler der Klasse XI IPA SMA Negeri 2 Binjai. Die Ergebnisse werden mit Prozentsätzen bewertet. Das durchschnittliche Ergebniss des Vorwissenstests liegt bei 54,86. Das durchschnittliche Ergebnis vom ersten Zyklus ist 79,17 und das durchsnittliche Ergebnis von zweiten Zyklus ist 92,36. Schlüsselwort: Die Medien Film, Die Sprechfertigkeit der Schüler