Reduction of excitatory synapses in the medial prefrontal cortex (mPFC) is closely associated with depression and can be mitigated by running exercise. However, precise quantitative studies focusing on subregion-specific excitatory synaptic changes under depression remain limited, and the potential involvement of microglia and astrocytes in exercise-mediated synaptic protection remains unclear. In this study, Sprague-Dawley (SD) rats were subjected to chronic unpredictable stress (CUS) followed by a 6-week treadmill running program. Behavioral assessments included the sucrose preference test and the elevated plus maze test. Nissl staining, immunogold staining, and stereological methods were employed to evaluate the volume of mPFC subregions and the number of dendritic spines in each subregion. Immunofluorescence combined with three-dimensional confocal imaging was used to evaluate microglial and astrocytic density, morphology, and synaptic contacts. Our results demonstrated that running exercise exerted significant antidepressant effects in CUS rats, as evidenced by improved anhedonia-related behaviors. Concurrently, running exercise increased the volume of the mPFC in CUS model rats, particularly in the anterior cingulate cortex (ACC) subregion, and restored the number of dendritic spines across all mPFC subregions. Additionally, running exercise reversed the CUS-induced alterations in microglial and astrocytic morphology and reduced excitatory synapse contacts on glial cells in a subregion-specific manner in the mPFC. These findings provide novel morphological evidence that running exercise protects excitatory synapses in the mPFC, potentially via modulation of glial-synapse interactions, offering insights into the cellular mechanisms underlying exercise-based antidepressant effects.

The gut microbiota is intricately implicated in the pathogenesis of Major Depressive Disorder (MDD), with the vagus nerve serving as a key regulatory bridge. Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) has emerged as a promising non-invasive therapeutic strategy for MDD by modulating the gut-brain axis, yet the precise brain-gut interaction mechanisms underlying its antidepressant effects remain poorly characterized. This study is a registered clinical trial (ChiCTR2200059591; Registered 4 May 2022; https://www.chictr.org.cn ). This study aimed to verify the clinical efficacy of taVNS for MDD and elucidate the underlying brain-gut crosstalk mechanisms, by integrating comprehensive clinical assessments, resting-state functional magnetic resonance imaging (rs-fMRI) neuroimaging data and gut metagenomic profiling. Ninety-five patients diagnosed with MDD were randomly allocated at a 1:1 ratio to either the active taVNS group (auricular concha stimulation) or the sham taVNS group (superior concha of mid-helix stimulation). Eighty patients (40 per group) completed the entire intervention course and were included in the final statistical analysis. All participants underwent 30-minute stimulation twice daily (4/20 Hz, 3–8 mA) for 8 consecutive weeks (5 days per week). Standardized clinical assessments were administered at baseline and post-intervention, including the 17-item Hamilton Depression Rating Scale (HAMD-17), 14-item Hamilton Anxiety Rating Scale (HAMA-14), and Gastrointestinal Symptom Rating Scale (GSRS). Rs-fMRI was performed to quantify core neural activity metrics, including amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), and degree centrality (DC); fecal samples were collected for high-throughput metagenomic analysis. Spearman correlation analysis and mediation analysis were further conducted to dissect the interactive relationships between brain neural activity and gut microbiota. The active taVNS group achieved significantly superior clinical efficacy relative to the sham group, with a HAMD-17 response rate of 62.50

Hemoglobin alpha (Hbα) is localized to neuronal mitochondria, but its role in neuronal health remains unclear. We investigated the impact of Hbα deficiency in hippocampal neurons, focusing on advanced glycation end products (AGEs). Using adeno-associated virus‌-mediated silencing, we found hippocampal Hbα-deficient mice showed spatial memory deficits and pyramidal neuron loss. Molecular analysis revealed that Hbα depletion downregulated mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1α) and disrupted mitochondrial membrane proteins. This was accompanied by increased accumulation of AGEs, elevated levels of the inflammatory factor interleukin-1β and enhancing pro-apoptotic signaling. Consistently, Hbα depletion in HT22 hippocampal neuronal cells compromised cell viability, and this deficit was rescued by treatment with the AGEs inhibitor alagebrium (ALT711). Furthermore, ALT711 treatment modulated mitochondrial membrane integrity and attenuated pro-apoptotic signaling. Our findings indicate Hbα maintains neuronal health by modulating AGEs and inhibiting apoptosis, suggesting AGEs inhibition as a therapeutic strategy for Hbα deficiency-related damage.

Depression represents a growing global health challenge, with current pharmacological treatments often exhibiting limited efficacy and significant side effects. Although physical exercise, particularly running exercise, has shown promising antidepressant properties, its underlying neurobiological mechanisms remain poorly understood. In this study, we investigated whether cannabinoid receptor type 1 (CB1R) in the medial prefrontal cortex (mPFC) contributed to the therapeutic benefits of running exercise, which might be associated with astrocyte-related changes. Using a chronic restraint stress (CRS) male rat model of depression, we integrated behavioral assessments (saccharin preference and forced swim tests) with multimodal molecular and cellular analyses, including immunohistochemistry, stereology, immunofluorescence, RT-PCR, and Western blotting. Our findings demonstrate that running exercise alleviated depressive-like behaviors, restored mPFC CB1R expression, and reversed stress-induced reductions in GFAP-positive cells. Conversely, mPFC-specific CB1R knockdown induced depressive-like phenotypes and astrocytic alterations, while CB1R overexpression reproduced some benefits of running exercise. Notably, running exercise failed to improve behavior or astrocytic changes when mPFC CB1R was knocked down, supporting a necessary role for intact mPFC CB1R signaling. These results suggested that mPFC CB1R contributes to running exercise-induced antidepressant effects, and this process is closely associated with the regulation of astrocytic states, providing a potential molecular framework for future therapeutic strategies.

Amygdala dysfunction is implicated in stress-related affective disorders, and astrocytes are key regulators of amygdalar neuroplasticity. Here, we examined whether running exercise modulates astrocyte number, morphology, proliferation, and excitatory synaptic contacts in the basolateral amygdala (BLA) and central amygdala (CeA) in rats exposed to chronic unpredictable stress (CUS). Anhedonia-like behaviors were evaluated using the sucrose preference test, while anxiety-related behaviors were assessed using the elevated plus maze and open field tests. Unbiased stereological three-dimensional quantification was used to assess amygdalar volume and estimate astrocyte numbers in BLA and CeA, and immunofluorescence with morphological reconstruction was performed to quantify astrocytic complexity, proliferation, and astrocyte-associated PSD95+ puncta. Running exercise significantly increased sucrose preference in CUS rats, whereas elevated plus maze and open field measures were not significantly changed. CUS reduced astrocyte number and proliferation, and induced astrocytic morphological atrophy in both subregions. These alterations were reversed by running. Moreover, running increased the number of excitatory synapses contacted by astrocytes in the BLA and CeA of CUS rats. These findings suggest that running promotes astrocyte-mediated structural remodeling in amygdalar subregions, which may contribute to the regulation of anhedonia-like behavioral alterations associated with chronic stress.

Endometriosis (EMs) is a chronic enigmatic gynecological disorder which pathogenesis have not been fully elucidated. Exosomes have been proven to participate in endometriosis. However, the role of exosomes in the pathogenesis of EMs remains poorly defined. Exosomes were isolated from cyst fluid of EMs patients and pelvic fluid of non-EMs patients, and characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot. Exosomal miRNAs were performed by small RNA sequencing. Q-PCR and cell function were performed to identify the relationship between exosomal miRNAs and endometriosis. Dual luciferase reporter assay, cell transfection, Q-PCR, Western blotting and CCK8 assays, Transwell assays and Boyden assays were conducted to explore the regulatory effects of exosomal miRNA on EMs pathogenesis in vitro using primary human endometrial stromal cells (HESCs) derived from endometriotic lesions. Compare with non-EMs group, there are 118 miRNAs were up-regulated and 40 miRNAs were down-regulated in CF group, meanwhile 22 miRNAs were up-regulated and 32 miRNAs were down-regulated in PF group. Q-PCR verified that miR-125b-5p, miR-328-3p, miR-125a-5p, miR-30e-3p were significant down-regulated, whereas miR-3141, miR-223-3p, miR-142-5p, miR-1246 were significant up-regulated in EMs patients. ROC analysis indicated that miR-125b-5p (AUC = 0.925, p < 0.001) was highly correlated with EMs pathogenesis. Dual luciferase reporter assay results demonstrated miR-125b-5p directly targeted VEGF gene. MiR-125b-5p suppressed endometrial stromal cells proliferation, migration and invasion by regulating the Phosphatidylinositol 3-Kinase (PI3K) /Protein Kinase B (AKT) signaling pathway. Exosomal miR-125b-5p was highly correlated with EMs, and it regulates the PI3K/Akt signaling pathways through VEGF to inhibit endometrial stromal cells proliferation, migration and invasion, acting as an important suppressing miRNA in endometriosis pathogenesis.

Hypoxia-caused spermatogenesis impairment may contribute to male infertility. FOXA2 has been found to be abundant in spermatogonial stem cells and critical for spermatogenesis. Here we aimed to explore the roles of FOXA2 in regulating spermatogonial cells against hypoxia stimulation. Our results showed that FOXA2 expression was downregulated in hypoxia-stimulated spermatogonial cells. Overexpression of FOXA2 prevented hypoxia-induced endoplasmic reticulum (ER) stress with decreased expression levels of associated markers including GRP78, CHOP, and ATF-4. FOXA2 overexpression caused a decrease in MDA content and an increase in activities of SOD, CAT, and GSH-Px in spermatogonial cells under hypoxic conditions, implying its inhibitory effect on oxidative stress. Besides, cell apoptosis under hypoxic conditions was also prevented by FOXA2 overexpression, as shown by reduced apoptotic rate and caspase-3 activity. Moreover, we found that hypoxia stimulation inactivated the Nrf2 pathway, which could be prevented by FOXA2 overexpression. Nrf2 knockdown attenuated the effects of FOXA2 overexpression on hypoxia-induced ER stress, oxidative stress, and apoptosis in spermatogonial cells. In conclusion, FOXA2 exerted protective effects on spermatogonial cells against hypoxia-induced ER stress, oxidative stress, and apoptosis via regulating Nrf2/HO-1 signaling. These findings suggested that FOXA2 might be a therapeutic target for treating hypoxia-induced spermatogenesis impairment.

Depression disrupts central nervous system function and may further elevate the risk of systemic diseases by triggering inflammatory responses. However, the precise mechanisms underlying its role in driving inflammation remain elusive. Adenosine (Ado), a critical molecule in depression, exhibits abnormal concentration changes that are closely associated with neuroinflammation. Thus, precise imaging of adenosine in the whole brain is essential for unraveling the mechanisms linking depression and inflammatory responses. However, current biosensors face limitations in whole-brain adenosine imaging. To address this limitation, a fluorescent nanoprobe with high spatiotemporal resolution was developed. The nanoprobe incorporates a targeting unit consisting of ferrocene-containing aptamers and phospholipid vesicles, ensuring excellent blood-brain barrier (BBB) penetration and high specificity for adenosine detection. Additionally, the nanoprobe features a near-infrared (NIR)-activated light-switching unit, enabling precise and real-time imaging of adenosine dynamics. The results revealed that adenosine activates the A2A receptor (A2AR) and downstream extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, inducing the secretion of proinflammatory cytokines by microglia and driving neuroinflammation. Elevated levels of inflammatory cytokines in the blood of depressed mice further suggest that depression may exacerbate systemic disease risk via peripheral inflammation. In summary, this nanoprobe not only achieves high spatiotemporal resolution imaging of adenosine in the brain but also serves as a powerful tool for elucidating the inflammatory mechanisms linking depression to systemic diseases.

Decreased hemoglobin (Hb) levels in peripheral blood may be a risk factor for Alzheimer's disease (AD). Hb-α is a monomeric form of Hb that exists in the central nervous system. Our previous RNA sequencing results revealed a decrease in the expression of the Hb-α gene in the hippocampus of AD model mice. However, the effects of Hb-α deficiency in the hippocampus on cognitive function and the underlying mechanism are unclear. Running exercise has been shown to improve cognition, but whether it can reverse the damage caused by Hb-α deficiency in the hippocampus needs to be further researched. In the present study, Mendelian randomization (MR) analyses revealed that lower levels of mean corpuscular Hb and Hemoglobin alpha 1 (HBA1) increased the risk of developing AD. When an adeno-associated virus (AAV) was used to knock down hippocampal Hb-α, the learning and memory ability of the resulting model mice decreased, similar to that of AD model mice. Moreover, the expression levels of advanced glycation end products (AGE) and their receptor (RAGE) were upregulated, microglia were activated, and the number of engulfed synapses increased, which damaged the number and structure of hippocampal synapses in the model mice. However, four weeks of voluntary wheel exercise effectively improved these conditions. In addition, we found that voluntary wheel exercise may compensate for Hb-α protein deficiency in the hippocampus by increasing the expression levels of Hb-α protein in plasma, cerebrospinal fluid, and other brain regions without altering Hb-α mRNA in the hippocampus of model mice. These results highlight the key role of Hb-α in hippocampal synaptic damage, elucidate the mechanism by which running exercise improves cognition by connecting the peripheral circulation and central nervous system through Hb-α, and provide new ideas for the diagnosis and treatment of AD.

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic interneurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic interneurons in AD model mice.

Previous studies have indicated that impaired synaptic plasticity is a main pathological alteration in depression. However, the mechanism underlying this pathological change has not been clarified. Adiponectin, an adipokine, crosses the blood‒brain barrier to function in specific brain regions. Previous studies have suggested that the downregulation of adiponectin signaling is involved in the occurrence of depression. The adiponectin receptors (AdipoRs) AdipoR1 and AdipoR2, which serve as the main receptors for adiponectin in the central nervous system, mediate the downstream biological effects of this compound, which has been reported to have positive effects on synaptic plasticity. However, it is not clear whether alterations in adiponectin/AdipoR signaling are associated with impaired synaptic plasticity in depression. Therefore, the aim of this study was to investigate whether changes in the adiponectin/AdipoR pathway in the hippocampus during depression are involved in the regulation of synaptic plasticity damage. We detected reduced plasma concentrations of adiponectin and lower expression levels of AdipoR1 but not AdipoR2 in the hippocampi of mice exposed to chronic unpredictable stress. An adeno-associated virus was subsequently used to knockdown hippocampal AdipoR1 to further verify the effects of decreased expression levels of this receptor on depressive-like behaviors and hippocampal synaptic plasticity. We found that the mice in which hippocampal AdipoR1 was knocked down presented with anhedonia and passive stress-coping behaviors as well as a decreased number of dendritic spines and density of excitatory and inhibitory synapses. Our results suggest that the downregulation of AdipoR1 expression might be an important factor that causes impaired synaptic plasticity in depression. These results may provide new insights into the pathogenesis of depression and new therapeutic targets for treating this disease.

BACKGROUND:Research on animal models of neurological diseases has primarily focused on understanding pathogenic mechanisms, advacing diagnostic strateggies, developing pharmacotherapies, and exploring preventive interventions. To facilitate comprehensive and systematic studies in this filed, we have developed the Neurological Disease Animal Model Database (ND-AMD), accessible at https://www.uc-med.net/NDAMD. This database is signed around the central theme of "Big Data - Neurological Diseases - Animal Models - Mechanism Research," integrating large-scale, multi-dimensional, and multi-scale data to facilitate in-depth analyses. ND-AMD serves as a resource for panoramic studies, enabling comparative and mechanistic research across diverse experimental conditions, species, and disease models. METHOD:Data were systematically retrieved from PubMed, Web of Science, and other relevant databases using Boolean search strategies with standardized MeSH terms and keywords. The collected data were curated and integrated into a structured SQL-based framework, ensuring consistency through automated validation checks and manual verification. Heterogeneity and sensitivity analyses were conducted using Cochran's Q test and the I2 statistic to assess variability across studies. Statistical workflows were implemented in Python (SciPy, Pandas, NumPy) to support multi-scale data integration, trend analysis, and model validation. Additionally, a text co-occurrence network analysis was performed using Natural Language Processing (TF-IDF and word embeddings) to identify key conceptual linkages and semantic structures across studies. RESULTS:ND-AMD integrates data from 483 animal models of neurological diseases, covering eight disease categories, 21 specific diseases, 13 species, and 152 strains. The database provides a comprehensive repository of experimental and phenotypic data, covering behavioral, physiological, biochemical, molecular pathology, immunological, and imaging characteristics. Additionally, it incorporates application-oriented data, such as drug evaluation outcomes. To enhance data accessibility and facilitate in-depth analysis, ND-AMD features three custom-developed online tools: Model Frequency Analysis, Comparative Phenotypic Analysis, and Bibliometric Analysis, enabling systematic comparison and trend identification across models and experimental conditions. CONCLUSIONS:The centralized feature of ND-AMD enables comparative analysis across different animal models, strains, and experimental conditions. It helps capture intricate interactions between biological systems at different levels, ranging from molecular mechanisms to cellular processes, neural networks, and behavioral outcomes. These models play a vital role as tools in replicating pathological conditions of neurological diseases. By offering users convenient, efficient, and intuitive access to data, ND-AMD enables researchers to identify patterns, trends, and potential therapeutic targets that may not be apparent in individual studies.

The concept of ferroptosis inhibition has gained growing recognition as a promising therapeutic strategy for addressing a wide range of diseases. Here, we present the discovery of four series of ortho-aminophenol derivatives as potential ferroptosis inhibitors beginning with the endogenous substance 3-hydroxyanthranilic acid (3-HA) by employing quantum chemistry techniques, in vitro and in vivo assays. Our findings reveal that these ortho-aminophenol derivatives exhibit unique intra-H bond interactions, compelling ortho-amines to achieve enhanced alignment with the aromatic π-system, thereby expanding their activity. Notably, compounds from all four series display remarkable activity against RSL3-induced ferroptosis, showcasing an activity 100 times more than that of 3-HA. Furthermore, these compounds also demonstrate robust in vivo efficacy in protecting mice from kidney ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity. In summary, we provide four distinct series of active scaffolds that significantly expand the chemical space of ferroptosis inhibitors, serving as valuable insights for future structural modifications.

BackgroundThe knowledge of normal‒appearing cortical gray matter (NAGM) in multiple sclerosis (MS) remains unclear. In this study, we aimed to identify diagnostic biomarkers and explore the immune infiltration characteristics of NAGM in MS through bioinformatic analysis and validation in vivo.MethodsDifferentially expressed genes (DEGs) were analyzed. Subsequently, the functional pathways of the DEGs were determined. After screening the overlapping DEGs of MS with two machine learning methods, the biomarkers’ efficacy and the expression levels of overlapping DEGs were calculated. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) identified the robust diagnostic biomarkers. Additionally, infiltrating immune cell populations were estimated and correlated with the biomarkers. Finally, the characteristics of immune infiltration of NAGM from MS were evaluated.ResultsA total of 98 DEGs were identified. They participated in sensory transduction of the olfactory system, synaptic signaling, and immune responses. Nine overlapping genes were screened by machine learning methods. After verified by ROC curve, four genes, namely HLA‒DRB1, RPS4Y1, EIF1AY and USP9Y were screened as candidate biomarkers. The mRNA expression of RPS4Y1 and USP9Y was significantly lower in MS patients than in the controls. They were selected as the robust diagnostic biomarkers for male MS patients. RPS4Y1 and USP9Y were both positively correlated with memory B cells. Moreover, naive CD4+ T cells and monocytes were increased in the NAGM of MS patients compared with those in controls.ConclusionsLow expressed Y‒linked genes RPS4Y1 and USP9Y were identified as diagnostic biomarkers for MS in male patients. The inhomogeneity of immune cells in NAGM might exacerbate intricate interplay between the CNS and the immune system in the MS.

Background Previous studies have reported that running exercise could improves myelinization in hippocampus. However, the effects of running exercise on the differentiation and maturation of oligodendrocytes, and myelination surrounding Aβ plaques in the medial prefrontal cortex (mPFC) of the Alzheimer's disease (AD) brain have not been reported. Methods Forty 10-month-old male APP/PS1 AD mice were randomly divided into the AD group and the AD running (AD+RUN) group, while 20 age-matched wild-type littermate mice were included in the WT group. The running group received three-month voluntary running exercise in a running cage, while the AD and WT groups were untreated. After the exercise intervention, all mice were given behavioral tests. The total number of mature oligodendrocytes (CC1+) in the mPFC of mice was precisely quantified using unbiased stereology. Myelin basic protein (MBP) and Aβ plaque, as well as the fluorescence area of MBP surrounding Aβ plaques, and the density and morphology of PDGFα+ cells in the mPFC were analyzed using immunofluorescence. Results The levels of working memory, cognitive memory, spatial learning and memory ability were decreased significantly in the AD group compared to the WT group, while these functions were significantly improved in the AD+RUN group compared to the AD group. The Aβ plaques in the mPFC were significantly reduced in the AD+RUN group compared to the AD group. The total number of CC1+ cells and the percentage of MBP fluorescence area surrounding Aβ plaques in the mPFC were significantly lower in the AD group compared to the WT group, but they were significantly higher in the AD+RUN group compared to the AD group. The density and branching complexity of PDGFα+ cells surrounding Aβ plaques in the mPFC were significantly higher in the AD group than in the WT group, while the AD+RUN group showed significantly lower density and branching complexity than the AD group. Changes in MBP expression around Aβ plaques, cell density and cell branching complexity of PDGFα+ cells around Aβ plaques were closely related to the number of Aβ plaques in mPFC, and they were also closely related to behavioral changes in mice. Conclusions Voluntary running exercise could reduce Aβ plaque deposition and promote the maturation and myelination capacity of oligodendrocytes surrounding Aβ plaques in the mPFC of AD mice, thereby improving the learning and memory abilities of APP/PS1 transgenic AD mice.

BACKGROUND:The molecular mechanisms by which exercise improves brain function and capillaries in the cerebral cortex are unclear. Exercise can increase the expression of nitric oxide (NO) in the brain, and endogenous NO is thought to exert beneficial effects on proangiogenic factors, antiangiogenic factors and brain function. Therefore, we hypothesized that running exercise might improve brain function and enhance angiogenesis through endogenous NO.METHODS AND RESULTS:The following three groups of rats were administered intracerebroventricular (i.c.v.) injections before running exercise each day for 4 weeks: exercise+L-NAME group (i.c.v. L-NAME, an NO synthase blocker, dose: 1 μmol/μl and 5 μl/day; treadmill exercise, 20 min/day), exercise group (i.c.v. normal saline, 5 μl/day; treadmill exercise, 20 min/day), and sham group (i.c.v. normal saline, 5 μl/day; no treadmill exercise). Subsequently, the spatial learning and memory abilities were tested using a Morris water maze, and the nitric oxide synthase (NOS) activity in the cerebral cortex in each group of rats was measured using a method involving nitric acid reductase and metabolic chemistry. The parameters of the cortical capillaries were quantitatively investigated using an immunohistochemistry technique and stereological methods. The expression levels of proangiogenic factors (VEGF and FGF-2) and an antiangiogenic inhibitor (endostatin) in the cerebral cortex were tested using a Western blot analysis. Running exercise significantly improved the rats' spatial learning and memory abilities and increased NOS activity in the cortex. Running exercise also subsequently improved the expression of proangiogenic factors (VEGF and FGF-2) and the length, volume and surface area of capillaries and reduced the expression of antiangiogenic factors (endostatin) in the cortex. In contrast, the L-NAME treatment attenuated the effects of running exercise.CONCLUSIONS:Running exercise regulates proangiogenic factors, antiangiogenic factors and angiogenesis in the cerebral cortex via a partially NO-dependent mechanism, and influencing endogenous NO might potentially affect the exercise-related beneficial effects on cognitive ability and cortical capillaries.

Abstract Background The role of physical exercise in the prevention of Alzheimer’s disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear. Methods Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia. Results Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2′-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice. Conclusions Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.

Background: According to previous studies, myelin damage may be involved in the occurrence of depression. However, to date, no study has quantitatively investigated the changes in myelinated fibers and myelin sheaths in the hippocampal formation (HF) and hippocampal subfields in the context of depression. Methods: Male Sprague-Dawley (SD) rats (aged 4-5 weeks) were evenly divided into the control group and chronic unpredictable stress (CUS) group. Behavioral tests were performed, and then changes in myelinated fibers and myelin ultrastructure in hippocampal subfields in depression model rats were investigated using modern stereological methods and transmission electron microscopy techniques. Results: After a four-week CUS protocol, CUS rats showed depressive-like and anxiety-like behaviors. The total length and total volume of myelinated fibers were reduced in the CA1 region and DG in the CUS group compared with the control group. The total volumes of myelin sheaths and axons in the CA1 region but not in the DG were significantly lower in the CUS group than in the control group. The decrease in the total length of myelinated nerve fibers in the CA1 region in CUS rats was mainly due to a decrease in the length of myelinated fibers with a myelin sheath thickness of 0.15 mu m-0.20 mu m. Limitations: The exact relationship between the degeneration of myelin sheaths and depression-like, anxiety-like behaviors needs to be further investigated. Conclusions: CUS induces depression- and anxiety-like behaviors, and the demyelination in the CA1 region induced by 4 weeks of CUS might be an important structural basis for these behaviors.

BackgroundStroke-induced immunodepression syndrome is considered the major etiology of stroke-associated pneumonia (SAP). Repulsive guidance molecule A (RGM-A) is an immunomodulatory protein that is closely related to inflammation and immune responses. To explore the relationship between RGM-A and SAP and facilitate the early identification of patients at high risk of developing SAP, we investigated the predictive value of RGM-A in SAP.MethodsWe enrolled 178 patients with acute ischemic stroke (AIS) and finally analyzed 150 patients, among whom 69 had SAP and 81 had non-SAP. During the same period, 40 patients with community-acquired pneumonia and 40 healthy participants were included as controls. SAP was defined according to the modified US Centers for Disease Control and Prevention criteria. Blood samples were collected at 24 h, 48 h, 3 days, 4 to 7 days, and 8 to 14 days after stroke onset. An enzyme-linked immunosorbent assay was used to detect the plasma levels of RGM-A and interleukin-6.ResultsThe plasma RGM-A levels were significantly decreased in both patients with community-acquired pneumonia and those with AIS, and the decline was most pronounced in patients with SAP (P < 0.001). RGM-A started to decline within 24 h after stroke in the SAP group, and the lowest levels were detected on day 3 and days 4 to 7 (P < 0.001). The RGM-A levels in the SAP group were lower than those in the non-SAP group at all blood collection time points (P < 0.05). In the logistic regression analyses, RGM-A was a protective factor for SAP after adjusting for confounders (adjusted odds ratio = 0.22, 95% confidence interval = 0.091–0.538, P = 0.001). Receiver operating characteristic curve analysis showed that the area under the curve for RGM-A was 0.766 (0.091–0.538; P = 0.001), the cutoff value was 4.881 ng/mL, and the sensitivity and specificity were 80.00 and 76.36%, respectively.ConclusionsWe demonstrated that reduced plasma levels of RGM-A might help in the early identification of high-risk patients with SAP and predict the occurrence of SAP in patients with AIS. RGM-A might provide new clues to a potential alternative therapy for SAP.

The medial prefrontal cortex (mPFC) is thought to be closely associated with emotional processes, decision making, and memory. Previous studies have identified the prefrontal cortex as one of the most vulnerable brain regions in Alzheimer's disease (AD). Running exercise has widely been recognized as a simple and effective method of physical activity that enhances brain function and slows the progression of AD. However, the effect of exercise on the mPFC of AD is unclear. To address these issues, we investigated the effects of 4 months of exercise on the numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of 12-month-old APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice using stereological methods. The spatial learning and memory abilities of mice were tested using the Morris water maze. Four months of running exercise delayed declines in spatial learning and memory abilities. The stereological results showed significantly lower numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of APP/PS1 mice than in the wild-type control group. The numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of running APP/PS1 mice were significantly greater than those in the APP/PS1 control mice. In addition, running-induced improvements in spatial learning and memory were significantly associated with running-induced increases in spinophilin-immunoreactive puncta and neurons numbers in the mPFC. Running exercise could delay the loss of spinophilin-immunoreactive puncta and neurons in the mPFC of APP/PS1 mice. This finding might provide an important structural basis for exercise-induced improvements in the spatial learning and memory abilities of individuals with AD.