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Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by the infiltration of inflammatory cells and demyelination of nerves. Mitochondrial dysfunction has been implicated in the pathogenesis of MS, as studies have shown abnormalities in mitochondrial activities, metabolism, mitochondrial DNA (mtDNA) levels, and mitochondrial morphology in immune cells of individuals with MS. The presence of mitochondrial dysfunctions in immune cells contributes to immunological dysregulation and neurodegeneration in MS. This review provided a comprehensive overview of mitochondrial dysfunction in immune cells associated with MS, focusing on the potential consequences of mitochondrial metabolic reprogramming on immune function. Current challenges and future directions in the field of immune-metabolic MS and its potential as a therapeutic target were also discussed. [ABSTRACT FROM AUTHOR]

Sepsis-associated encephalopathy (SAE) is a risk factor for cognitive and memory dysfunction; however, the mechanism remains unclear. Brain-derived neurotrophic factor (BDNF) was reported to have a positive effect on cognition and emotion regulation, but the study of its precursor, proBDNF, has been limited. This study aimed to elucidate the effects and associated mechanisms of hippocampal proBDNF in a lipopolysaccharide (LPS)-induced SAE mouse model. In this study, we found that the mice exhibited cognitive dysfunction on day 7 after LPS injection. The expression of proBDNF and its receptor, p75 NTR , was also increased in the hippocampus, while the levels of BDNF and its receptor, TrkB, were decreased. A co-localization study showed that proBDNF and p75 NTR were mainly co-localized with neurons. Furthermore, LPS treatment reduced the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, and NR2B in the hippocampus of SAE mice. Furthermore, an intrahippocampal or intraperitoneal injection of anti-proBDNF antibody was able to ameliorate LPS-induced cognitive dysfunction and restore the expression of NeuN, Nissl bodies, GluR4, NR1, NR2A, NR2B, and PSD95. These results indicated that treatment with brain delivery by an intrahippocampal and systemic injection of mAb-proBDNF may represent a potential therapeutic strategy for treating patients with SAE. [ABSTRACT FROM AUTHOR]

Major depressive disorders (MDD) are often comorbid with the gastrointestinal (GI) disorders. Brain-derived neurotrophic factor precursor (proBDNF) has been reported to contribute to the development of depression in mouse models. However, the role of proBDNF in depression-associated GI disorders is still unrevealed. Mice experienced unpredictable chronic mild stress (UCMS) procedure and were then intraperitoneally injected with fluoxetine (20 mg/kg). Open field test (OFT), forced swimming test (FST), and sucrose preference test (SPT) were performed to evaluate the severity of depression. Oral administration of food dye gel and histological staining were performed to assess GI transit and morphological alterations. QPCR was performed to assess the mRNA levels of inflammatory cytokines. Additionally, flow cytometry, immunohistochemistry, and immunofluorescence were performed to examine the expression and cellular localization of proBDNF. It was found that (a) in the peripheral blood, the expression of proBDNF and its receptor pan neurotrophin receptor 75 (p75NTR) in CD11b+ cells in depressive mice was higher than in controls; (b) the GI motility was decreased after the UCMS procedure and partly reversed by fluoxetine treatment; (c) proBDNF/p75NTR was highly expressed in macrophages in the intestinal lamina propria; (d) the upregulated proBDNF/p75NTR and the activated cytokines, including IL (interleukin)-1β, IL-6, IL-10, and IFN (interferon)-γ, were positively correlated with the depression and GI disorders, and were inhibited by fluoxetine treatment. UCMS procedure upregulated the expression of proBDNF and p75NTR in monocytes/macrophages of peripheral blood and intestinal lamina propria, which may be involved in the pathogenesis of depression-associated GI disorders. Fluoxetine reversed the GI dysfunction, infiltration of macrophages, and upregulation of proBDNF signaling in the depressive mice. [ABSTRACT FROM AUTHOR]

Major depression disorder is one of the most common psychiatric disorders that greatly threaten the mental health of a large population worldwide. Previous studies have shown that endoplasmic reticulum (ER) stress plays an important role in the pathophysiology of depression, and current research suggests that brain-derived neurotrophic factor precursor (proBDNF) is involved in the development of depression. However, the relationship between ER and proBDNF in the pathophysiology of depression is not well elucidated. Here, we treated primary hippocampal neurons of mice with corticosterone (CORT) and evaluated the relationship between proBDNF and ERS. Our results showed that CORT induced ERS and upregulated the expression of proBDNF and its receptor, Follistatin-like protein 4 (FSTL4), which contributed to significantly decreased neuronal viability and expression of synaptic-related proteins including NR2A, PSD95, and SYN. Anti-proBDNF neutralization and ISRIB (an inhibitor of the ERS) treatment, respectively, protected neuronal viabilities and increased the expression of synaptic-related proteins in corticosterone-exposed neurons. ISRIB treatment reduced the expression of proBDNF and FSTL4, whereas anti-proBDNF treatment did not affect ERS markers (Grp78, p-PERK, ATF4) expression. Our study presented evidence that CORT-induced ERS negatively regulated the neuronal viability and the level of synaptic-related protein of primary neurons via the proBDNF/FSTL4 pathway. [ABSTRACT FROM AUTHOR]

Background: Sepsis-associated encephalopathy (SAE) increases the mortality of septic patients, but its mechanism remains unclear. The present study aimed to investigate the roles of T lymphocytes, proBDNF, and their interaction in the pathogenesis of SAE.Methods: Fear conditioning tests were conducted for cognitive assessment in the lipopolysaccharide (LPS, 5 mg kg-1)-induced septic mice. Meninges and peripheral blood were harvested for flow cytometry or qPCR. FTY720 and monoclonal anti-proBDNF antibody (McAb-proB) were used to investigate the effect of lymphocyte depletion and blocking proBDNF on the impaired cognitive functions in the septic mice.Results: In the septic mice, cognitive function was impaired, the percentage of CD4+ T cells were decreased in the meninges (P = 0.0021) and circulation (P = 0.0222), and pro-inflammatory cytokines were upregulated, but the anti-inflammatory cytokines interleukin (IL)-4 (P < 0.0001) and IL-13 (P = 0.0350) were downregulated in the meninges. Lymphocyte depletion by intragastrically treated FTY720 (1 mg kg-1) for 1 week ameliorated LPS-induced learning deficit. In addition, proBDNF was increased in the meningeal (P = 0.0042) and peripheral (P = 0.0090) CD4+ T cells. Intraperitoneal injection of McAb-proB (100 μg) before LPS treatment significantly alleviated cognitive dysfunction, inhibited the downregulation of meningeal (P = 0.0264) and peripheral (P = 0.0080) CD4+ T cells, and normalized the gene expression of cytokines in the meninges. However, intra-cerebroventricular McAb-proB injection (1 μg) did not have such effect. Finally, exogenous proBDNF downregulated the percentage of CD4+ T cells in cultured splenocytes from septic mice (P = 0.0021).Conclusion: Upregulated proBDNF in immune system promoted the pathogenesis of SAE through downregulating the circulating CD4+ T cells, limiting its infiltration into the meninges and perturbing the meningeal pro-/anti-inflammatory homeostasis. [ABSTRACT FROM AUTHOR]

The immune status in the lymphatic system, especially mesenteric lymph nodes (MLNs), is critical to regulate the septic shock. Brain-derived neurotrophic factor (BDNF) in the enteric system has been reported to regulate enteric immunity. However, the role of its precursor, proBDNF, in the immune status of MLNs under sepsis condition is still unclear. This study aimed to characterize the expression pattern of proBDNF in MLNs after lipopolysaccharide (LPS) stimulation, and to investigate the association of pathogenesis of sepsis. LPS (20 mg/kg) was intraperitoneally injected to induce sepsis in mice. Survival curve analysis, routine blood tests, and liver and kidney function tests were performed to evaluate the severity of sepsis. QPCR and histological staining were performed to assess the mRNA levels of proinflammatory cytokines and degree of immune-inflammatory response in the MLNs. Furthermore, Western blotting, flow cytometry, and immunofluorescence were performed to examine the key molecules expression of proBDNF signaling. Intraperitoneal LPS injection significantly decreased the number of lymphocytes in blood but increased the number of T lymphocytes in MLNs. Serum alanine transaminase, aspartate transaminase, and blood urea nitrogen levels were increased in LPS-challenged mice compared to control mice. LPS administration upregulated proinflammatory cytokine gene expression and induced histological changes in the MLNs. LPS injection increased BDNF, proBDNF, and its receptor pan neutrophin receptor 75 (p75NTR) expression in MLNs. The increased proBDNF was mainly localized on CD3+ and CD4+ T cells in the medulla of MLNs. LPS-induced sepsis upregulated proBDNF expression in medulla T cells of MLNs. ProBDNF upregulation may be involved in the pathogenesis of septic shock. [ABSTRACT FROM AUTHOR]

Stress plays a crucial role in several psychiatric disorders, including anxiety. However, the underlying mechanisms remain poorly understood. Here, we used acute stress (AS) and chronic restraint stress (CRS) models to develop anxiety-like behavior and investigate the role of miR-150 in the hippocampi of mice. Corticosterone levels as well as glutamate receptors in the hippocampus were evaluated. We found that anxiety-like behavior was induced after either AS or CRS, as determined by the open-field test (OFT) and elevated plus-maze test (EPM). Increased corticosterone levels were observed in the blood of AS and CRS groups, while the expression of miR-150 mRNA in the hippocampus was significantly decreased. The expressions of GluN2A, GluR1, GluR2, and V-Glut2 in the hippocampus were decreased after either AS or CRS. Hippocampal GAD67 expression was increased by AS but not CRS, and GluN2B expression was decreased by CRS but not AS. Adult miR-150 knockout mice showed anxiety-like behavior, as assessed by the OFT and EPM. The expressions of GluN2A, GluN2B, GluR1, and GluR2 were also downregulated, but the expression of V-Glut2 was upregulated in the hippocampi of miR-150 knockout mice compared with wild-type mice. Interestingly, we found that the miR-150 knockout mice showed decreased dendrite lengths, dendrite branchings, and numbers of dendrite spines in the hippocampus compared with wild-type mice. These results suggest that miR-150 may influence the synaptic plasticity of the hippocampus and play a significant role in stress-induced anxiety-like behavior in adult mice. [ABSTRACT FROM AUTHOR]

Rationale: Environmental enrichment (EE) could influence brain plasticity and behavior in rodents. Whether the early EE may predispose individuals to a particular social hierarchy in the social dominance tube test (SDTT) at adulthood is still unknown. Objective: The present study directly investigated the influence of EE on competitive success in the SDTT among adult rats. Methods: Male rats were maintained in EE from postnatal days 21 to 35. Social dominance behavior was determined by SDTT, competitive food foraging test, and mate preference test at adulthood. IBA-1 expression in the hypothalamus was examined using immunohistochemistry and western blot. Results: EE rats were prone to become submissive during a social encounter with standard environment (SE) rats in the SDTT. No difference was found in food foraging in the competitive food foraging test between SE and EE rats. Male EE rats were more attractive than the SE to the female rats in the mate preference test. IBA-1 expression was found to be decreased in the hypothalamus of EE rats compared to SE group. Infusion of a microglia inhibitor reduced percentage of forward in SE rats in the SDTT. Infusion of DNA methyltransferase inhibitor prevented the development of subordinate status in EE rats and restored the expression of IBA-1 in the hypothalamus. Conclusions: The results suggest that early EE did not lead to reduced social hierarchy in the male rat. However, EE caused a reduction in the percentage of forward in the SDTT, which might be associated with reduced number of microglia in the hypothalamus. [ABSTRACT FROM AUTHOR]

Early-life stress is a potent risk factor for development of psychiatric conditions such as depression. The underlying mechanisms remain poorly understood. Here, we used the early-life social isolation (ESI) model of early-life stress in rats to characterize development of depressive-like behavior, the role of microglia, levels of histone methylation, as well as expression of glutamate receptor subunits in the hippocampus. We found that depressive-like behavior was induced after ESI as determined by sucrose preference and forced swimming tests. Increased expression of microglial activation marker, Iba1, was observed in the hippocampus of the ESI group, while expression of the microglial CD200 receptor, which promotes microglial quiescence, significantly decreased. In addition, increased levels of proinflammatory cytokines, interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were observed in the hippocampus of the ESI group. Moreover, ESI increased levels of neuronal H3K9me2 (a repressive marker of transcription) and its associated 'writer' enzymes, G9a and G9a-like protein, in the hippocampus. ESI also decreased expression of hippocampal NMDA receptor subunits, NR1, and AMPA receptor subunits, GluR1 and GluR2, which are involved in synaptic plasticity, but it did not affect expression of PSD95 and NR2B. Interestingly, treatment with minocycline to block microglial activation induced by ESI inhibited increases in hippocampal microglia and prevented ESI-induced depressive-like behavior as well as increases in IL-1β, IL-6, and TNF-α. Notably, minocycline also triggered downregulation of H3K9me2 expression and restored expression of NR1, GluR1, and GluR2. These results suggest that ESI induces depressive-like behavior, which may be mediated by microglial signaling. [ABSTRACT FROM AUTHOR]

Background: In highly complex social settings, an animal's motivational drive to pursue an object depends not only on the intrinsic properties of the object, but also on whether the decision-making animal perceives an object as being the most desirable among others. Mimetic desire refers to a subject's preference for objects already possessed by another subject. To date, there are no appropriate animal models for studying whether mimetic desire is at play in guiding the decision-making process. Furthermore, the neuropharmacological bases of decision-making processes are not well understood. In this study, we used an animal model (rat) to investigate a novel food-foraging paradigm for decision-making, with or without a mimetic desire paradigm.Results: Faced with the choice of foraging in a competitive environment, rats preferred foraging for the desirable object, indicating the rats' ability for decision-making. Notably, treatment with the non-competitive N-methyl-D-aspartate receptor antagonist MK-801, but not with the dopamine D1 or D2 receptor antagonists, SCH23390 and haloperidol, respectively, suppressed the food foraging preference when there was a competing resident rat in the cage. None of these three antagonists affected the food-foraging preference for palatable food. Moreover, MK-801 and SCH23390, but not haloperidol, were able to abolish the desirable environment effect on standard food-foraging activities in complex social settings.Conclusions: These results highlight the concept that mimetic desire exerts a powerful influence on food-foraging decision-making in rats and, further, illustrate the various roles of the glutamatergic and dopaminergic systems in mediating these processes. [ABSTRACT FROM AUTHOR]

Dr. Chang-Qi Li should be added as co-author because Fig. 1 originated from him. [ABSTRACT FROM AUTHOR]