Synaptic Plasticity-related Proteins Research Articles

Electroacupuncture improves V1 cortex synaptic plasticity via the CREB/BDNF/TrkB pathway in juvenile rats with monocular deprivation

The present study aims to investigate the impact of the CREB/BDNF/TrkB signaling pathway on synaptic plasticity in the visual cortex of juvenile amblyopic rats that have undergone monocular deprivation (MD). This study involved sixty 2-week-old Sprague-Dawley (SD) juvenile rats, which were not specified by gender. In the first part of the study, 24 rats were randomized into control and MD groups; In the second part, 36 rats were randomized into MD, electroacupuncture (EA) and EA + CREB antagonist (666–15) groups. The MD model was established using the monocular suture method. 14 d after monocular suture, EA treatment was started for 30 min daily, at a frequency of 2–10 Hz and an intensity of 1 mA, for 2 weeks. According to the results from part 1, the P100 wave latency in the MD group was prolonged, and its amplitude was lower compared to the control group. Additionally, the neuron number in the V1 cortex of the MD group decreased, along with reduced expression levels of CREB, BDNF, p-TrkB, and the key plasticity proteins PSD95 and SYN. In part 2, EA treatment significantly increased the electrophysiological activity of neurons in V1 cortex, shortened the latency of P100 peaks to varying degrees, increased the amplitude significantly, and restored the morphology and structure of neurons to normal levels; The expression of synaptic proteins PSD95 and SYN, as well as the expression of signaling molecules CREB, BDNF, and p-TrkB proteins were increased. However, the effects of EA were reversed when the specific CREB inhibitor 666–16 was administered. These data indicate that EA enhances the expression of V1 cortical synaptic plasticity-related proteins by regulating the expression of CREB/BDNF/TrkB signaling pathway, thereby enhancing V1 neural synaptic plasticity and reversing the effects of MD on visual acuity.

Neuroprotective effect of vitamin B12 supplementation on cognitive functions and neuronal morphology at different time intervals after traumatic brain injury in male Swiss albino mice

Traumatic brain injury is a highly irreversible process that consists of primary as well as secondary injury which develops and progresses over months to years, leading to cognitive dysfunctions. Vitamin B12 received considerable interest due to its potential therapeutic properties. The pathways of vitamin B12 are closely related to neuronal survival but its effects on the pathophysiology of injury with respect to cognition is a relatively unexplored area of research. In this study, we investigated, the effect of vitamin B12 and its involvement in neuroprotection on TBI-induced pathophysiology in male Swiss albino mice. Our findings suggested that vitamin B12 supplementation improves TBI-mediated neurological impairments, spatial and recognition memory, and anxiety-like behavior. Furthermore, the oxidative stress was reduced by declined homocysteine level with vitamin B12 supplementation validating declined expression of astrocytes and TBI biomarkers. The studies on neuronal morphology revealed that vitamin B12 supplementation increases the dendritic arborization and density of mushroom and filopodia-shaped spines and further increases the expression of synaptic plasticity-related genes and proteins. Taken together, our findings reveal that, supplementation of vitamin B12 restored the TBI-induced downregulation of dendritic arborization, and spine density which ultimately increases synaptic plasticity, cell survival, and recovery of cognitive dysfunctions.

MiR-351-5p regulation of CPEB3 affecting aluminium-induced learning and memory impairment in SD rats

Aluminium exposure has been found to impair learning and memory abilities; however, the underlying molecular mechanisms remain unclear. In this study we conducted a double luciferase reporter assay to determine whether miR-351-5p regulates cytoplasmic polyadenylation element binding protein (CPEB) 3 mRNA. To this end, we overexpressed and inhibited miR-351-5p via stereotaxic microinjections of adeno-associated virus (AAV) into the hippocampus of Sprague Dawley rats in a sub-chronic aluminium exposure model to examine learning and memory ability using Morris water maze. Ultrastructural electron microscopy and Golgi staining were used to examine morphological changes in hippocampal neurons. In addition, we examined the levels of synaptic plasticity-related proteins (PRPs) and CPEB3 to determine the involvement of the miR-351-5P/CPEB3/PRPs pathway in aluminium neurotoxicity. Sub-chronic aluminium exposure reduced the spatial learning and memory ability of rats. Overexpression of AAV-miR-351-5P in the hippocampus aggravated the impairment of spatial learning and memory abilities of aluminium-treated rats, whereas inhibition of AAV-miR-351-5p expression alleviated it. Western blotting suggested that sub-chronic aluminium exposure increased miR-351-5p levels and reduced the expression of CPEB3 and PRPs in the hippocampus. Treatment with an AAV-miR-351-5p inhibitor partially recovered CPEB3 and PRPs. Double luciferase reporter assay results showed that CPEB3 was a direct target of miR-351-5p, while electron microscopy suggested that aluminium could damage mitochondria and synapses in the CA1 of the hippocampus. Golgi staining results indicated that aluminium could reduce the number of dendritic spines in hippocampal neurons. Inhibition of miR-351-5p restored the synaptic structure and growth of dendritic spines in the hippocampus. The involvement of the miR-351-5P/CPEB3/RPPs pathway in aluminium neurotoxicity was confirmed. Our findings suggest that inhibition of miR-351-5p can alleviate learning and memory impairments by increasing CPEB3 and PRPs.

The Downregulation of ITGAX Exacerbates Amyloid-β Plaque Deposition in Alzheimer's Disease by Increasing Polarization of M1 Microglia.

Alzheimer's disease (AD) is the most common sort of neurodegenerative dementia, characterized by its challenging, diverse, and progressive nature. Despite significant progress in neuroscience, the current treatment strategies remain suboptimal. Identifying a more accurate molecular target for the involvement of microglia in the pathogenic process of AD and exploring potential mechanisms via which it could influence disease. We utilized single-cell RNA sequencing (scRNA-seq) analysis in conjunction with APP/PS1 mouse models to find out the molecular mechanism of AD. With the goal of investigating the cellular heterogeneity of AD, we downloaded the scRNA-seq data from the Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs). Additionally, we evaluated learning and memory capacity using the behavioral experiment. We also examined the expression of proteins associated with memory using western blotting. Immunofluorescence was employed to investigate alterations in amyloid plaques and microglia. Our findings revealed an upregulation of ITGAX expression in APP/PS1 transgenic mice, which coincided with a downregulation of synaptic plasticity-related proteins, an increase in amyloid-β (Aβ) plaques, and an elevation in the number of M1 microglia. Interestingly, deletion of ITGAX resulted in increased Aβ plaque deposition, a rise in the M1 microglial phenotype, and decreased production of synaptic plasticity-related proteins, all of which contributed to a decline in learning and memory. This research suggested that ITGAX may have a beneficial impact on the APP/PS1 mice model, as its decreased expression could exacerbate the impairment of synaptic plasticity and worsen cognitive dysfunction.

Effects of different exercise modes and intensities on cognitive performance, adult hippocampal neurogenesis, and synaptic plasticity in mice.

Exercise can induce beneficial improvements in cognition. However, the effects of different modes and intensities of exercise have yet to be explored in detail. This study aimed to identify the effects of different exercise modes (aerobic and resistance) and intensities (low and high) on cognitive performance, adult hippocampal neurogenesis and synaptic plasticity in mice. A total of 40 C57BL/6J mice were randomised into 5 groups (n = 8 mice per group): control, low-intensity aerobic exercise, high-intensity aerobic exercise, low-intensity resistance exercise, and high-intensity resistance exercise. The aerobic exercise groups underwent treadmill training, while the resistance exercise groups underwent ladder climbing training. At the end of the exercise period, cognitive performance was assessed by the Y-maze and Barnes maze. In addition, adult hippocampal neurogenesis was evaluated immunohistochemically by 5-bromo-2'-deoxyuridine (BrdU)/ neuronal nuclei (NeuN) co-labeling. The levels of synaptic plasticity-related proteins in the hippocampus, including synaptophysin (SYP) and postsynaptic density protein 95 (PSD-95), were analyzed by western blotting. Our results showed no significant differences in cognitive performance among the groups. However, high-intensity aerobic exercise significantly increased hippocampal adult neurogenesis relative to the control. A trend towards increased adult neurogenesis was observed in the low-intensity aerobic group compared to the control group. No significant changes in synaptic plasticity were observed among all groups. Our results indicate that high-intensity aerobic exercise may be the most potent stimulator of adult hippocampal neurogenesis.

Targeting microbiota–immune–synaptic plasticity to explore the effect of tea polyphenols on improving memory in the aged type 2 diabetic rat model

ABSTRACT Objectives The study aimed to explore whether TP could improve memory in the aged type 2 diabetic rat model by regulating microbiota-immune-synaptic plasticity axis. Methods The experiment was divided into two parts. Firstly, to investigate the effects of TP on the physiopathology of the aged T2DM model rats, rats were randomly divided into the Normal control group, the aged group, the Aged T2DM model group, the TP 75, 150, 300 mg/kg groups, the 150 mg/kg Piracetam group and the 3 mg/kg Rosiglitazone group. Then, to further verify whether TP improved memory in aged T2DM rat model by regulating intestinal flora, the fecal microbiota transplantation (FMT) from the rats in the 300 mg/kg TP group into the rats in the aged T2DM model group was carried out. Effects on gut microbiota, colonic integrity (epithelial tight junction proteins), and endotoxemia (serum LPS) were examined, along with synaptic structure, synaptic plasticity-related structural proteins and inflammation signaling of the hippocampus in our study. Results Our results demonstrated that TP alleviated memory impairments in the aged T2DM rat model. The specific outcomes were as follows: TP 300 mg/kg corrected the gut dysbacteriosis, alleviated intestinal permeability reduction and peripheral/central inflammation, inhibited the TLR4/NF-κB signaling pathway. Meanwhile, TP improved the synaptic plasticity in the hippocampus of the aged T2DM model rats, whose expressions of SYN, PSD 95, NMDAR1 and GluR1 in hippocampus were significantly up-regulated. Surprisingly, rats of the FMT group displayed the same changes. Discussion TP improves the memory in aged T2DM rat model. The mechanism may be related to the alteration of gut flora, which can inhibit hippocampal TLR4/NF-κB signaling to attenuate neuroinflammation, then improve synaptic plasticity. The study proposes that TP interventions aimed at manipulating the gut microbiota may hold great potential as an effective approach for preventing and treating this disease.

Edaravone dexborneol attenuates cognitive impairment in a rat model of vascular dementia by inhibiting hippocampal oxidative stress and inflammatory responses and modulating the NMDA receptor signaling pathway

Exploring the intricate pathogenesis of Vascular Dementia (VD), there is a noted absence of potent treatments available in the current medical landscape. A new brain-protective medication developed in China, Edaravone dexboeol (EDB), has shown promise due to its antioxidant and anti-inflammatory properties, albeit with a need for additional research to elucidate its role and mechanisms in VD contexts. In a research setup, a VD model was established utilizing Sprague-Dawley (SD) rats, subjected to permanent bilateral typical carotid artery occlusion (2VO). Behavioral assessment of the rats was conducted using the Bederson test and pole climbing test, while cognitive abilities, particularly learning and memory, were evaluated via the novel object recognition test and the Morris water maze test. Ensuing, the levels of malondialdehyde (MDA), superoxide dismutase (SOD), IL-1β, IL-6, IL-4, and tumor necrosis factor-α (TNF-α) were determined through Enzyme-Linked Immunosorbent Assay (ELISA). Synaptic plasticity-related proteins, synaptophysin (SYP), post-synaptic density protein 95 (PSD-95), and N-methyl-D-aspartate (NMDA) receptor proteins (NR1, NR2A, NR2B) were investigated via Western blotting technique. The findings imply that EDB has the potential to ameliorate cognitive deficiencies, attributed to VD, by mitigating oxidative stress, dampening inflammatory responses, and modulating the NMDA receptor signaling pathway, furnishing new perspectives into EDB’s mechanism and proposing potential avenues for therapeutic strategies in managing VD.

Protective Mechanism of Polysaccharide ORP-1 Isolated from Oudemansiella raphanipes against Age-Related Cognitive Decline through the Microbiota-Gut-Brain Axis.

Age-related cognitive decline is primarily attributed to the progressive weakening of synaptic function and loss of synapses, while age-related gut microbial dysbiosis is known to impair synaptic plasticity and cognitive behavior by metabolic alterations. To improve the health of the elderly, the protective mechanisms of Oudemansiella raphanipes polysaccharide (ORP-1) against age-related cognitive decline are investigated. The results demonstrate that ORP-1 and its gut microbiota-derived metabolites SCFAs restore a healthy gut microbial population to handle age-related gut microbiota dysbiosis mainly by increasing the abundance of beneficial bacteria Dubosiella, Clostridiales, and Prevotellaceae and reducing the abundance of harmful bacteria Desulfovibrio, strengthen intestinal barrier integrity by abolishing age-related alterations of tight junction (TJ) and mucin 2 (MUC2) proteins expression, diminish age-dependent increase in circulating inflammatory factors, ameliorate cognitive decline by reversing memory- and synaptic plasticity-related proteins levels, and restrain hyperactivation of microglia-mediated synapse engulfment and neuroinflammation. These findings expand the understanding of prebiotic-microbiota-host interactions.

Artemisinin reduces PTSD-like symptoms, improves synaptic plasticity, and inhibits apoptosis in rats subjected to single prolonged stress.

Post-Traumatic Stress Disorder (PTSD) is a chronic mental disorder characterized by symptoms of panic and anxiety, depression, impaired cognitive functioning, and difficulty in social interactions. While the effect of the traditional Chinese medicine artemisinin (AR) on PTSD is unknown, its therapeutic benefits have been demonstrated by studies on models of multiple neurological disorders. This study aimed to extend such findings by investigating the effects of AR administration on a rat model of PTSD induced by a regimen of single prolonged stress (SPS). After rats were subjected to the SPS protocol, AR was administered and its impact on PTSD-like behaviors was evaluated. In the present study, rats were subjected to a multitude of behavioral tests to evaluate behaviors related to anxiety, memory function, and social interactions. The expression of hippocampal synaptic plasticity-related proteins was detected using Western blot and immunofluorescence. The ultrastructure of synapses was observed under transmission electron microscopy. The apoptosis of hippocampal neurons was examined with Western blot, TUNEL staining, and HE staining. The results showed that AR administration alleviated the PTSD-like phenotypes in SPS rats, including behavior indicative of anxiety, cognitive deficits, and diminished sociability. AR administration was further observed to improve synaptic plasticity and inhibit neuronal apoptosis in SPS rats. These findings suggest that administering AR after the onset of severe traumatic events may alleviate anxiety, cognitive deficits, and impaired social interaction, improve synaptic plasticity, and diminish neuronal apoptosis. Hence, the present study provides evidence for AR's potential as a multi-target agent in the treatment of PTSD.

Annexin A6 mitigates neurological deficit in ischemia/reperfusion injury by promoting synaptic plasticity.

Alleviating neurological dysfunction caused by acute ischemic stroke (AIS) remains intractable. Given Annexin A6 (ANXA6)'s potential in promoting axon branching and repairing cell membranes, the study aimed to explore ANXA6's potential in alleviating AIS-induced neurological dysfunction. A mouse middle cerebral artery occlusion model was established. Brain and plasma ANXA6 levels were detected at different timepoints post ischemia/reperfusion (I/R). We overexpressed and down-regulated brain ANXA6 and evaluated infarction volume, neurological function, and synaptic plasticity-related proteins post I/R. Plasma ANXA6 levels were measured in patients with AIS and healthy controls, investigating ANXA6 expression's clinical significance. Brain ANXA6 levels initially decreased, gradually returning to normal post I/R; plasma ANXA6 levels showed an opposite trend. ANXA6 overexpression significantly decreased the modified neurological severity score (p = 0.0109) 1 day post I/R and the infarction area at 1 day (p = 0.0008) and 7 day (p = 0.0013) post I/R, and vice versa. ANXA6 positively influenced synaptic plasticity, upregulating synaptophysin (p = 0.006), myelin basic protein (p = 0.010), neuroligin (p = 0.078), and tropomyosin-related kinase B (p = 0.150). Plasma ANXA6 levels were higher in patients with AIS (1.969 [1.228-3.086]) compared to healthy controls (1.249 [0.757-2.226]) (p < 0.001), that served as an independent risk factor for poor AIS outcomes (2.120 [1.563-3.023], p < 0.001). This study is the first to suggest that ANXA6 enhances synaptic plasticity and protects against transient cerebral ischemia.

Geniposide improves depression-like behavior in prenatal stress male offspring through restoring HPA axis- and glucocorticoid receptor-associated dysfunction

AimsPrenatal stress (PS) has an important impact on the brain development of offspring, which can lead to attention deficits, anxiety and depression in offspring. Geniposide (GE) is a kind of iridoid glycoside extracted from Gardenia jasminoides Ellis. It has various pharmacological effects and has been proved that have antidepressant effects. The aim of this study was to investigate the effect of GE on depression-like behavior in PS-induced male offspring mice and explore the possible molecular mechanisms. MethodsWe used a prenatal restraint stress model, focusing on male PS-induced offspring mice to study the effects of GE. Key findingsThe results showed that GE administration for 4 weeks significantly improved the depression-like behavior in PS offspring mice, which was manifested by markedly increasing the sucrose preference of PS offspring and the activity in the open field test, and reducing the immobility time in the forced swimming test. In addition, GE significantly reduced the levels of hypothalamic-pituitary-adrenal (HPA) axis-related hormones and exceedingly increased the protein expression of MAP2 and GAP43 in PS offspring. Furthermore, GE increased Glucocorticoid receptors (GR) nuclear translocation in the hippocampus of PS offspring, and enhanced the expression of synaptic plasticity-related proteins. ConclusionThe results of this study showed that GE exerts antidepressant effects in male PS offspring mice by regulating the HPA axis, GR function and proteins related to synaptic plasticity.

The integrated stress response effector GADD34 is repurposed by neurons to promote stimulus-induced translation

Neuronal protein synthesis is required for long-lasting plasticity and long-term memory consolidation. Dephosphorylation of eukaryotic initiation factor 2α is one of the key translational control events that is required to increase de novo protein synthesis that underlies long-lasting plasticity and memory consolidation. Here, we interrogate the molecular pathways of translational control that are triggered by neuronal stimulation with brain-derived neurotrophic factor (BDNF), which results in eukaryotic initiation factor 2α (eIF2α) dephosphorylation and increases in de novo protein synthesis. Primary rodent neurons exposed to BDNF display elevated translation of GADD34, which facilitates eIF2α dephosphorylation and subsequent de novo protein synthesis. Furthermore, GADD34 requires G-actin generated by cofilin to dephosphorylate eIF2α and enhance protein synthesis. Finally, GADD34 is required for BDNF-induced translation of synaptic plasticity-related proteins. Overall, we provide evidence that neurons repurpose GADD34, an effector of the integrated stress response, as an orchestrator of rapid increases in eIF2-dependent translation in response to plasticity-inducing stimuli.

Therapeutic effects of a walnut-derived peptide on NLRP3 inflammasome activation, synaptic plasticity, and cognitive dysfunction in T2DM mice.

NLRP3 inflammasome activation plays a key role in the development of diabetes-induced cognitive impairment. However, strategies to inhibit NLRP3 inflammasome activation remain elusive. Herein, we evaluated the impact of a walnut-derived peptide, TWLPLPR (TW-7), on cognitive impairment in high-fat diet/streptozotocin-induced type 2 diabetes mellitus (T2DM) mice and explored its underlying mechanisms in high glucose-induced HT-22 cells. In the Morris water maze test, TW-7 alleviated cognitive deficits in mice; this was confirmed at the level of synaptic structure and dendritic spine density in the mouse hippocampus using transmission electron microscopy and Golgi staining. TW-7 increased the expression of synaptic plasticity-related proteins and suppressed the NEK7/NLRP3 inflammatory pathway, as determined by western blotting and immunofluorescence analysis. The mechanism of action of TW-7 was verified in an HT-22 cell model of high glucose-induced insulin resistance. Collectively, TW-7 could regulate T2DM neuroinflammation and synaptic function-induced cognitive impairment by inhibiting NLRP3 inflammasome activation and improving synaptic plasticity.

Volatile oil of Angelica sinensis Radix improves cognitive function by inhibiting miR-301a-3p targeting Ppp2ca in cerebral ischemia mice

Ethnopharmacological relevanceAngelica Sinensis Radix (ASR) is a commonly used Chinese medicine known for its effects on tonifying blood, promoting blood circulation, and alleviating pain associated with menstrual regulation. Additionally, it has been used in the treatment of vascular cognitive impairment (VCI). The primary pharmacodynamic agent within ASR is volatile oil of Angelica Sinensis Radix (VOASR), which has demonstrated efficacy in combating cognitive impairment, although its mechanism remains unclear. ObjectiveThis study aimed to elucidate the potential molecular mechanisms underlying VOASR's improvement of cognitive function in cerebral ischemic mice. MethodsA model of cerebral ischemic mice was established through unilateral common carotid artery occlusion (UCCAO) surgery, followed by intervention with VOASR. Cognitive function was assessed using the Morris water maze (MWM) test, while RT-qPCR was utilized to measure the differential expression of miR-301a-3p in the hippocampus. To evaluate cognitive function and hippocampal protein differences, wild-type mice and miR-301a-3p knockout mice were subjected to the MWM test and iTRAQ protein profiling. The relationship between miR-301a-3p and potential target genes was validated through a Dual-Luciferase Reporter experiment. RT-qPCR and Western blot were employed to determine the differential expression of Ppp2ca and synaptic plasticity-related proteins in the mouse hippocampus. ResultsIntervention with VOASR significantly improved cognitive impairment in cerebral ischemic mice and reduced the expression of miR-301a-3p in the hippocampus. Our findings suggest that miR-301a-3p may regulate cognitive function by targeting Ppp2ca. Furthermore, VOASR intervention led to an increase in the expression of Ppp2ca and synaptic plasticity-related proteins. ConclusionOur study indicates that VOASR may be involved in regulating cognitive function by inhibiting miR-301a-3p, consequently increasing the expression of Ppp2ca and synaptic plasticity proteins. These results provide a new target and direction for the treatment of cognitive dysfunction.

Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.

Phosphodiesterase 4D negative allosteric modulators (PDE4D NAMs) enhance memory and cognitive function in animal models without emetic-like side effects. However, the relationship between increased cyclic adenosine monophosphate (cAMP) signaling and the effects of PDE4D NAM remains elusive. To investigate the roles of hippocampal cAMP metabolism and synaptic activation in the effects of D159687, a PDE4D NAM, under baseline and learning-stimulated conditions. At 3mg/kg, D159687 enhanced memory formation and consolidation in contextual fear conditioning; however, neither lower (0.3mg/kg) nor higher (30mg/kg) doses induced memory-enhancing effects. A biphasic (bell-shaped) dose-response effect was also observed in a scopolamine-induced model of amnesia in the Y-maze, whereas D159687 dose-dependently caused an emetic-like effect in the xylazine/ketamine anesthesia test. At 3mg/kg, D159687 increased cAMP levels in the hippocampal CA1 region after conditioning in the fear conditioning test, but not in the home-cage or conditioning cage (i.e., context only). By contrast, 30mg/kg of D159687 increased hippocampal cAMP levels under all conditions. Although both 3 and 30mg/kg of D159687 upregulated learning-induced Fos expression in the hippocampal CA1 30min after conditioning, 3mg/kg, but not 30mg/kg, of D159687 induced phosphorylation of synaptic plasticity-related proteins such as cAMP-responsive element-binding protein, synaptosomal-associated protein 25kDa, and the N-methyl-D-aspartate receptor subunit NR2A. Our findings suggest that learning-stimulated conditions can alter the effects of a PDE4D NAM on hippocampal cAMP levels and imply that a PDE4D NAM exerts biphasic memory-enhancing effects associated with synaptic plasticity-related signaling activation.

Electroacupuncture stimulation ameliorates cognitive impairment induced by long-term high-fat diet by regulating microglial BDNF

Long-term high-fat diet (HFD) in adolescents leads to impaired hippocampal function and increases the risk of cognitive impairment. Studies have shown that HFD activates hippocampal microglia and induces hippocampal inflammation, which is an important factor for cognitive impairment. Electroacupuncture stimulation (ES), a nerve stimulation therapy, is anti-inflammatory. This study explored its therapeutic potential and mechanism of action in obesity-related cognitive impairment. 4-week-old C57 mice were given either normal or HFD for 22 weeks. At 19 weeks, some of the HFD mice were treated with ES and nigericin sodium salt. The cognitive behavior was assessed through Morris water maze test at 23 weeks. Western blotting was used to detect the expression levels of pro-inflammatory molecules IL-1β and IL-1R, synaptic plasticity related proteins synaptophysin and Postsynaptic Density-95 (PSD-95), and apoptotic molecules (Caspase-3 and Bcl-2), in the hippocampus. The number, morphology, and status of microglia, along with the brain-derived neurotrophic factor（BDNF） content, were analyzed using immunofluorescence. ES treatment improved cognitive deficits in HFD model mice, and decreased the expressions of microglial activation marker, CD68, and microglial BDNF. Inhibition of proinflammatory cytokine, IL-1β, and IL-1R promoted PSD-95 and synaptophysin expressions. Peripheral NLRP3 inflammasome agonist injections exacerbated the cognitive deficits in HFD mice and promoted the expressions of IL-1β and IL-1R in the hippocampus. The microglia showed obvious morphological damage and apoptosis. Collectively, our findings suggest that ES inhibits inflammation, regulates microglial BDNF, and causes remodeling of hippocampal function in mice to counteract obesity-like induced cognitive impairment. Overexcitation of peripheral inflammasome complexes induces hippocampal microglia apoptosis, which hinders the effects of ES.

FUS-mediated HypEVs: Neuroprotective effects against ischemic stroke.

Few studies have investigated the properties and protein composition of small extracellular vesicles (sEVs) derived from neurons under hypoxic conditions. Presently, the extent of the involvement of these plentiful sEVs in the onset and progression of ischemic stroke remains an unresolved question. Our study systematically identified the characteristics of sEVs derived from neurons under hypoxic conditions (HypEVs) by physical characterization, sEV absorption, proteomics and transcriptomics analysis. The effects of HypEVs on neurites, cell survival, and neuron structure were assessed in vitro and in vivo by neural complexity tests, magnetic resonance imaging (MRI), Golgi staining, and Western blotting of synaptic plasticity-related proteins and apoptotic proteins. Knockdown of Fused in Sarcoma (FUS) small interfering RNA (siRNA) was used to validate FUS-mediated HypEV neuroprotection and mitochondrial mRNA release. Hypoxia promoted the secretion of sEVs, and HypEVs were more easily taken up and utilized by recipient cells. The MRI results illustrated that the cerebral infarction volume was reduced by 45% with the application of HypEVs, in comparison to the non- HypEV treatment group. Mechanistically, the FUS protein is necessary for the uptake and neuroprotection of HypEVs against ischemic stroke as well as carrying a large amount of mitochondrial mRNA in HypEVs. However, FUS knockdown attenuated the neuroprotective rescue capabilities of HypEVs. Our comprehensive dataset clearly illustrates that FUS-mediated HypEVs deliver exceptional neuroprotective effects against ischemic stroke, primarily through the maintenance of neurite integrity and the reduction of mitochondria-associated apoptosis.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Luteolin in the Qi Bi Anshen decoction improves propionic acid-induced autism-like behavior in rats by inhibiting LRP1/MMP9

BackgroundA neurodevelopmental illness with a high frequency and unidentified pathophysiology is known as autism spectrum disorder (ASD). A research hotspot in this field is the identification of disease-specific biomarkers and drug intervention targets. Traditional Chinese medicine (TCM) can eliminate the symptoms of autism by precisely regulating human physiology. The Qi Bi Anshen decoction (QAT) is a commonly used TCM clinical drug commonly-used to treat for treating ASD. However, the primary active ingredients and underlying mechanisms of action of this decoction remain unknown. PurposeThis study aimed to investigate the active ingredients and pharmacodynamics of QAT in the treatment of ASD using a Sprague–Dawley rat model that resembled autism. MethodsAutism-like rat models were established through intracerebroventricular injections of propionic acid (PPA). Subsequently, the rats were treated with QAT, and their efficacy was evaluated using the three-chamber method to analyze social interactions and grooming behavior. Additionally, open-field tests, elevated cross-maze tests, hematoxylin and eosin staining, Nissl staining, and enzyme-linked immunosorbent assays were performed; Western blot analysis was employed to determine the expression of synaptic plasticity-related proteins. Utilizing ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS), the effectiveness of active QAT components was assessed, and potential QAT targets were screened through molecular docking, surface plasmon resonance, and thermal migration experiments. To better understand the precise processes involved in treating ASD with active QAT components, in vivo and in vitro knockdown tests were also performed. ResultsQATexhibited a significant improvement in autism-like behavior and a notable increase in the production of proteins associated with synaptic plasticity. Furthermore, luteolin (LUT), identified as a potentially important active ingredient in QAT for treating ASD, reduced matrix metallopeptidase-9 (MMP9) expression. However, this effect was attenuated by the knockdown of low-density lipoprotein receptor-associated protein 1 (LRP1), which is the target binding site for LUT. ConclusionsLUT emerges as a potentially crucial active component of QAT in the treatment of ASD, with the ability to antagonize LRP1 and subsequently reduce MMP9 expression.

Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.