The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum ...disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.
•Chronic stress changes neural activity of cortico-limbic regions and monoamine systems.•Monoamine and non-monoamine systems are reciprocally interactive at multiple levels.•Reshaping altered neural ...activity dynamics reverses depressive-like behaviors.
The monoamine hypothesis of depression, namely that the reduction in synaptic serotonin and dopamine levels causes depression, has prevailed in past decades. However, clinical and preclinical studies have identified various cortical and subcortical regions whose altered neural activities also regulate depressive-like behaviors, independently from the monoamine system. Our systematic review indicates that neural activities of specific brain regions and associated neural circuitries are adaptively altered after chronic stress in a specific direction, such that the neural activity in the infralimbic cortex, lateral habenula and amygdala is upregulated, whereas the neural activity in the prelimbic cortex, hippocampus and monoamine systems is downregulated. The altered neural activity dynamics between monoamine systems and cortico-limbic systems are reciprocally interwoven at multiple levels. Furthermore, depressive-like behaviors can be experimentally reversed by counteracting the altered neural activity of a specific neural circuitry at multiple brain regions, suggesting the importance of the reciprocally interwoven neural networks in regulating depressive-like behaviors. These results promise for reshaping altered neural activity dynamics as a therapeutic strategy for treating depression.
Harmful, stressful conditions or events in the cardiovascular system result in cellular damage, inflammation, and fibrosis. Currently, there is no targeted therapy for myocardial fibrosis, which is ...highly associated with a large number of cardiovascular diseases and can lead to fatal heart failure. Hydrogen sulfide (H2S) is an endogenous gasotransmitter similar to nitric oxide and carbon monoxide. H2S is involved in the suppression of oxidative stress, inflammation, and cellular death in the cardiovascular system. The level of H2S in the body can be boosted by stimulating its synthesis or supplying it exogenously with a simple H2S donor with a rapid- or slow-releasing mode, an organosulfur compound, or a hybrid with known drugs (e.g., aspirin). Hypertension, myocardial infarction, and inflammation are exaggerated when H2S is reduced. In addition, the exogenous delivery of H2S mitigates myocardial fibrosis caused by various pathological conditions, such as a myocardial infarct, hypertension, diabetes, or excessive β-adrenergic stimulation, via its involvement in a variety of signaling pathways. Numerous experimental findings suggest that H2S may work as a potential alternative for the management of myocardial fibrosis. In this review, the antifibrosis role of H2S is briefly addressed in order to gain insight into the development of novel strategies for the treatment of myocardial fibrosis.
Chronic stress induces adaptive changes in the brain via the cumulative action of glucocorticoids, which is associated with mood disorders. Here we show that repeated daily five-minute restraint ...resolves pre-existing stress-induced depressive-like behavior in mice. Repeated injection of glucocorticoids in low doses mimics the anti-depressive effects of short-term stress. Repeated exposure to short-term stress and injection of glucocorticoids activate neurons in largely overlapping regions of the brain, as shown by c-Fos staining, and reverse distinct stress-induced gene expression profiles. Chemogenetic inhibition of neurons in the prelimbic cortex projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis results in anti-depressive effects similarly to short-term stress exposure, while only inhibition of neurons in the prelimbic cortex projecting to the bed nucleus of the stria terminalis rescues defective glucocorticoid release. In summary, we show that short-term stress can reverse adaptively altered stress gains and resolve stress-induced depressive-like behavior.
Radiologic evaluation of children with Mycoplasma pneumoniae is important for diagnosis and management.
To investigate the correlation between chest radiographic findings and the clinical features in ...children with Mycoplasma pneumoniae pneumonia.
This study included 393 hospitalized children diagnosed with M. pneumoniae pneumonia between January 2000 and August 2016. Their clinical features and chest radiographs were reviewed. Radiographic findings were categorized and grouped as consolidation group (lobar or segmental consolidation) and non-consolidation group (patchy infiltration, localized reticulonodular infiltration, or parahilar peribronchial infiltration).
Lobar or segmental consolidation (37%) was the most common finding, followed by parahilar or peribronchial infiltration (27%), localized reticulonodular infiltration (21%) and patchy infiltration (15%). The consolidation group was more frequently accompanied by pleural effusions (63%), compared to the non-consolidation group (16%). Compared with patients in the non-consolidation group, those in the consolidation group were associated with a significantly higher rate of hypoxia, tachypnea, tachycardia, extrapulmonary manifestations, prolonged fever, and longer periods of anti-mycoplasma therapy and hospitalization. Lobar or segmental consolidation was significantly more frequent in children ≥5 years old (44%) compared with children 2-5 years old (34%) and <2 years old (13%). Parahilar peribronchial infiltration was significantly more frequent in children <2 years old (56%) compared with children 2-5 years old (32%) and ≥5 years old (18%).
The chest radiographic findings of children with M. pneumoniae pneumonia correlate well with the clinical features. Consolidative lesions were frequently observed in older children and were associated with more severe clinical features.
We discuss a role of the electron inertial effect on linearly polarized electromagnetic ion cyclotron (EMIC) waves at Earth. The linearly polarized EMIC waves have been previously suggested to be ...generated via mode conversion from the fast compressional wave at the ion‐ion hybrid (IIH) resonance. When the electron inertial effects are neglected, the wave normal angle of the mode‐converted IIH waves is 90° because the wave vector perpendicular to the magnetic field becomes infinite at the IIH resonance. When the electron inertial effect is considered, the mode‐converted IIH waves can propagate across the magnetic field lines, and the wavelength perpendicular to the magnetic field approaches the electron inertial length scale near the Buchsbaum resonance. These waves are referred to as electron inertial waves. Due to the electron inertial effect, the perpendicular wave number to the ambient magnetic field near the IIH resonance remains finite, and the wave normal angle is less than 90°. The wave normal angle where the maximum absorption occurs in a dipole magnetic field is 30–80°, which is consistent with the observed values near the magnetic equator. Therefore, the numerical results suggest that the linearly polarized EMIC wave generated via mode conversion near the IIH resonance can be detected in between the Buchsbaum and the IIH resonance frequencies, and these waves can have normal angle less than 90°.
Key Points
Mode‐converted ion‐ion hybrid waves can propagate toward the Buchsbaum resonance due to the electron inertial effects
Electron inertial effects allow the mode‐converted ion‐ion hybrid waves have medium normal angle less than 90°
Linearly polarized EMIC waves generated via mode conversion can have relatively small normal angle between 30 and 80°
Translationally controlled tumor protein (TCTP) exhibits numerous biological functions. It has been shown to be involved in the regulation of glucose. However, its specific role in metabolism has not ...yet been clearly elucidated. Here, we aimed to assess the effect of TCTP overexpression on metabolic tissues and systemic energy metabolism.
We investigated whether TCTP can ameliorate the metabolic imbalance that causes obesity using TCTP-overexpressing transgenic (TCTP TG) mice. The mice were subjected to biochemical, morphological, physiological and protein expression studies to define the role of TCTP in metabolic regulation in response to normal chow diet (NCD) compared to high-fat diet (HFD) conditions, and cold environment.
We found that TCTP TG mice show improved metabolic homeostasis under both of NCD and HFD conditions with simultaneous enhancements in glucose tolerance and insulin sensitivity. In particular, we found coincident increases in energy expenditure with significant upregulation of uncoupling protein 1 (UCP1) in the brown adipose tissue (BAT). Moreover, TCTP overexpressing mice exhibit significantly enhanced adaptive thermogenesis of BAT in response to cold exposure.
Overexpression of TCTP ameliorated systemic metabolic homeostasis by stimulating UCP1-mediated thermogenesis in the BAT. This suggests that TCTP may function as a modulator of energy expenditure. This study suggests TCTP may serve as a therapeutic target for obesity and obesity-associated metabolic disorders including type 2 diabetes.
This experimental study was designed to evaluate the effect of ulinastatin, a urinary trypsin inhibitor, on postoperative cognitive dysfunction (POCD) in rats under general anesthesia with ...isoflurane, on the aspect of behavior, as evaluated using a Y-maze test and focusing on microglial activity. Ulinastatin (50,000 U/mL) and normal saline (1 mL) were randomly (1:1) administered intraperitoneally to the ulinastatin and control groups, respectively, before general anesthesia. Anesthesia with isoflurane 1.5 volume% was maintained for 2 h. The Y-maze test was used to evaluate cognitive function. Neuronal damage using caspase-1 expression, the degree of inflammation through cytokine detection, and microglial activation with differentiation of the phenotypic expression were evaluated. Twelve rats were enrolled in the study and evenly allocated into the two groups, with no dropouts from the study. The Y-maze test showed similar results in the two groups before general anesthesia (63 ± 12% in the control group vs. 64 ± 12% in the ulinastatin group,
= 0.81). However, a significant difference was observed between the two groups after general anesthesia (17 ± 24% in the control group vs. 60 ± 12% in the ulinastatin group,
= 0.006). The ulinastatin group showed significantly lower expression of caspase-1. Pro-inflammatory cytokine levels were significantly lower in the ulinastatin group than in the control group. The ulinastatin group had a significantly lower microglial activation (41.74 ± 10.56% in the control group vs. 4.77 ± 0.56% in the ulinastatin,
< 0.001), with a significantly lower activation of M1 phenotypes (52.19 ± 7.83% in the control group vs. 5.58 ± 0.76% in the ulinastatin group,
< 0.001). Administering ulinastatin before general anesthesia prevented neuronal damage and cognitive decline after general anesthesia, in terms of the aspect of behavior, as evaluated by the Y-maze test. The protective effect of ulinastatin was associated with the inhibition of microglial activation, especially the M1 phenotype.
Abstract Physical exercise is considered beneficial in the treatment of depression, but the underlying mechanism is not clearly understood. In the present study, we investigated the mechanism ...regulating antidepressant effects of exercise by focusing on the role of the amygdala using a well-defined animal model of depression. C57BL/6 mice treated with repeated restraint showed depression-like behaviors, which was counteracted by post-stress treatment with physical exercise. The two neuropeptides hypocretin/orexin (Hcrt/Orx) and melanin-concentrating hormone (MCH) were transcriptionally upregulated in the BLA after repeated stress, and their enhanced expression was downregulated by treatment with exercise, mirroring stress-induced depression-like behaviors and their reversal by exercise. Stereotaxic injection of either Hcrt/Orx peptide or MCH peptide within the BLA commonly increased phospho-CaMKIIα level and produced depression-like behaviors, mimicking the neural states in the BLA of mice subjected to repeated stress. In contrast, siRNA-mediated suppression of Hcrt/Orx or MCH in the BLA blocked stress-induced depression-like behaviors. Furthermore, siRNA-mediated inhibition of CaMKIIα in the BLA also counteracted stress-induced depression-like behaviors. Local injection of Hcrt/Orx peptide or MCH peptide within the BLA in exercise-treated animals blocked antidepressant-like effects of exercise. Together these results suggest that exercise produces antidepressant effects via suppression of Hcrt/Orx and MCH neural systems in the BLA.
Abstract
Mounting evidence suggests that probiotics are beneficial for treating Alzheimer’s disease (AD). However, the mechanisms by which specific probiotics modify AD pathophysiology are not ...clearly understood. In this study, we investigated whether
Lactobacillus paracasei
-derived extracellular vesicles (
Lpc
-EV) can directly act on neuronal cells to modify amyloid-beta (Aβ)-induced transcriptional changes and Aβ pathology in the brains of Tg-APP/PS1 mice.
Lpc
-EV treatment in HT22 neuronal cells counteracts Aβ-induced downregulation of
Brain-derived neurotrophic factor (Bdnf)
,
Neurotrophin 3 (Nt3)
,
Nt4/5
, and
TrkB
receptor, and reverses Aβ-induced altered expression of diverse nuclear factors, including the downregulation of
Methyl-CpG binding protein 2 (Mecp2)
and
Sirtuin 1 (Sirt1)
. Systematic siRNA-mediated knockdown experiments indicate that the upregulation of
Bdnf, Nt3, Nt4/5
, and
TrkB
by
Lpc
-EV is mediated via multiple epigenetic factors whose activation converges on
Mecp2
and
Sirt1
. In addition,
Lpc
-EV reverses Aβ-induced downregulation of the Aβ-degrading proteases
Matrix metalloproteinase 2 (Mmp-2)
,
Mmp-9
, and
Neprilysin (Nep)
, whose upregulation is also controlled by MeCP2 and Sirt1.
Lpc
-EV treatment restores the downregulated expression of
Bdnf, Nt4/5, TrkB
,
Mmp-2, Mmp-9
, and
Nep
; induces the upregulation of MeCP2 and Sirt1 in the hippocampus; alleviates Aβ accumulation and neuroinflammatory responses in the brain; and mitigates cognitive decline in Tg-APP/PS1 mice. These results suggest that
Lpc
-EV cargo contains a neuroactive component that upregulates the expression of neurotrophic factors and Aβ-degrading proteases (
Mmp-2, Mmp-9
, and
Nep
) through the upregulation of MeCP2 and Sirt1, and ameliorates Aβ pathology and cognitive deficits in Tg-APP/PS1 mice.
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