The authors establish the existence and stability of standing wave solutions of a nonlinear singularly perturbed system of integral differential equations and a non- linear scalar integral differential equation. It wi...The authors establish the existence and stability of standing wave solutions of a nonlinear singularly perturbed system of integral differential equations and a non- linear scalar integral differential equation. It will be shown that there exist six standing wave solutions （（u（x,t）,w（x,t）） = （U（x）,W（x）） to the nonlinear singularly perturbed system of integral differential equations. Similarly, there exist six standing wave so- lutions u（x,t） = U（x） to the nonlinear scalar integral differential equation. The main idea to establish the stability is to construct Evans functions corresponding to several associated eigenvalue problems.展开更多
Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to thei...Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.展开更多
Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly m...Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity.Through the C1 q,C3 and CR3"Eat Me"and CD47 and SIRPα"Don't Eat Me"complement pathways,as well as other pathways such as CX3 CR1 signaling,resting microglia regulate synaptic pruning,a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity.By mediating synaptic pruning,resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation,and also in the regulation of learning and memory,including the modulation of memory strength,forgetfulness,and memory quality.As a response to brain injury,infection or neuroinflammation,microglia become activated and increase in number.Activated microglia change to an amoeboid shape,migrate to sites of inflammation and secrete proteins such as cytokines,chemokines and reactive oxygen species.These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and other neurological or mental disorders such as autism,depression and post-traumatic stress disorder.With a focus mainly on recently published literature,here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory,as well as how activated microglia modulate disease-related plasticity and learning and memory deficits.By summarizing the function of microglia in these processes,we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory,and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive 展开更多
Objective： To observe the effects of electroacupuncture （EA） on the structure parameters of synapse and reactive changes of astrocyte in the marginal zone of focal cerebral ischemia in rats at different time zones ...Objective： To observe the effects of electroacupuncture （EA） on the structure parameters of synapse and reactive changes of astrocyte in the marginal zone of focal cerebral ischemia in rats at different time zones so as to further explore its underlying mechanisms in the treatment of cerebral ischemia. Methods： Ninety male Wistar rats were randomly assigned to sham-operation, model, and EA groups, with 30 animals in each group. Each group was subdivided into 1 h, as well as 1, 3, 7, and 21 days post-operation groups, with 6 animals assigned to each time point subgroup. Heat coagulation-induced occlusion of the middle cerebral artery was performed to establish a model of focal cerebral ischemia. EA was applied immediately following surgery to the EA group [4/20 Hz, 2.0-3.0 V, 1-3 mA, to Baihui （GV20） and Dazhui （GV14）] for 30 min. Treatment was performed once a day, and experimental animals were sacrificed at 1 h, as well as 1, 3, 7 and 21 days postoperation. The ultrastructure changes in synapse and astrocytes were observed by using transmission electron microscopy. Glial fibrillary acidic protein （GFAP） expression and Ca2＋ of astrocytes were measured by using laser confocal scanning microscope. Excitatory amino acid transporters-2 （EAAT2） and connexin 43 （CX43） expressions were assayed with immunohistochemical method. Canonical correlation analysis was conducted between structure parameters of synapse and parameters of astrocyte in the same time and group. Results： Broken synapses were observed following cerebral ischemia, and the numbers of synapses were significantly decreased. Compared with the model group, synaptic ultrastructure was significantly improved in the EA group. Compared with the sham-operation group, synaptic number density was significantly decreased, as were postsynaptic density thickness, synaptic cleft width and synaptic interface curvature in the EA and model groups. However, compared with the model group, postsynaptic density thickness was significantly incre展开更多
Synapses are specialized structures that mediate information flow between neurons and target cells,and thus are the basis for neuronal system to execute various functions,including learning and memory.There are around...Synapses are specialized structures that mediate information flow between neurons and target cells,and thus are the basis for neuronal system to execute various functions,including learning and memory.There are around 1011 neurons in the human brain,with each neuron receiving thousands of synaptic inputs,either excitatory or inhibitory.A synapse is an asymmetric structure that is composed of pre-synaptic axon terminals,synaptic cleft,and postsynaptic compartments.Synapse formation involves a number of cell adhesion molecules,extracellular factors,and intracellular signaling or structural proteins.After the establishment of synaptic connections,synapses undergo structural or functional changes,known as synaptic plasticity which is believed to be regulated by neuronal activity and a variety of secreted factors.This review summarizes recent progress in the field of synapse development,with particular emphasis on the work carried out in China during the past 10 years(1999-2009).展开更多
One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected b...One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings.展开更多
Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by...Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.展开更多
Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were ...Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42（Aβ_（1–42））into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui（GV20;15°obliquely to a depth of 2mm）and Shenshu（BL23;perpendicularly to 4–6 mm depth）,once a day for 20 minutes（each）,for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β（GSK-3β）,p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_（1–40） in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_（1–40）.pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency（50 Hz）electroacupuncture was more effective than low（2 Hz）or medium-frequency（30 Hz）electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_（1–42）-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.展开更多
MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal a...MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development.Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals.Moreover,a link between dysregulation of microRNAs and human brain disorders has become increasingly evident.In this review,we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain,and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases.展开更多
With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate recept...With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.展开更多
Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity imp...Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm^2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H＆E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm^2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits （NR1, NR2A, and NR2B） and related signaling molecules （CaZ＋/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein） were examined. Conclusion 30 mW/cm^2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.展开更多
Cerebral ischemia activates an endogenous repair program that induces plastic changes in neurons. In this study, we investigated the effects of environmental enrichment on spatial learning and memory as well as on syn...Cerebral ischemia activates an endogenous repair program that induces plastic changes in neurons. In this study, we investigated the effects of environmental enrichment on spatial learning and memory as well as on synaptic remodeling in a mouse model of chronic cerebral ischemia, produced by subjecting adult male C57 BL/6 mice to permanent left middle cerebral artery occlusion. Three days postoperatively, mice were randomly assigned to the environmental enrichment and standard housing groups. Mice in the standard housing group were housed and fed a standard diet. Mice in the environmental enrichment group were housed in a cage with various toys and fed a standard diet. Then, 28 days postoperatively, spatial learning and memory were tested using the Morris water maze. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 in the hippocampus were analyzed by western blot assay. The number of synapses was evaluated by electron microscopy. In the water maze test, mice in the environmental enrichment group had a shorter escape latency, traveled markedly longer distances, spent more time in the correct quadrant(northeast zone), and had a higher frequency of crossings compared with the standard housing group. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 were substantially upregulated in the hippocampus in the environmental enrichment group compared with the standard housing group. Furthermore, electron microscopy revealed that environmental enrichment increased the number of synapses in the hippocampal CA1 region. Collectively, these findings suggest that environmental enrichment ameliorates the spatial learning and memory impairment induced by permanent middle cerebral artery occlusion. Environmental enrichment in mice with cerebral ischemia likely promotes cognitive recovery by inducing plastic changes in synapses.展开更多
Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the me...Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17, 展开更多
Synapses in biology provide a variety of functions for the neural system. Artificial synaptic electronics that mimic the biological neuron functions are basic building blocks and developing novel artificial synapses i...Synapses in biology provide a variety of functions for the neural system. Artificial synaptic electronics that mimic the biological neuron functions are basic building blocks and developing novel artificial synapses is essential for neuromorphic computation. Inspired by the unique features of biological synapses that the basic connection components of the nervous system and the parallelism, low power consumption, fault tolerance, self-learning and robustness of biological neural systems, artificial synaptic electronics and neuromorphic systems have the potential to overcome the traditional von Neumann bottleneck and create a new paradigm for dealing with complex problems such as pattern recognition, image classification, decision making and associative learning. Nowadays, two-dimensional(2 D) materials have drawn great attention in simulating synaptic dynamic plasticity and neuromorphic computing with their unique properties. Here we describe the basic concepts of bio-synaptic plasticity and learning, the 2 D materials library and its preparation. We review recent advances in synaptic electronics and artificial neuromorphic systems based on 2 D materials and provide our perspective in utilizing 2 D materials to implement synaptic electronics and neuromorphic systems in hardware.展开更多
As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphoryla...As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3β(GSK-3β) and protein phosphatase 2A(PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3β or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity.展开更多
Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this s...Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups(which received physiological saline), the doses of KXS(0.7, 1.4 and 2.8 g/kg per day) and donepezil(3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following.(1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze.(2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze.(3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies.(4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus.(5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxi展开更多
The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source o...The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN presympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension.This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.展开更多
Epidemiological studies have shown that particulate matter 2.5（PM（2.5）） not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering ...Epidemiological studies have shown that particulate matter 2.5（PM（2.5）） not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM（2.5）is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM（2.5）exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM（2.5）altered the expression of apoptosis-related proteins（mainly bax and bcl-2）, activated caspase-3 and caused neuronal apoptosis. Additionally, PM（2.5）decreased the levels of synaptic structural protein postsynaptic density（PSD-95） and synaptic functional protein N-methyl-D-aspartate（NMDA） receptor subunit（NR2B） expression. These effects occurred in a season-dependent manner, and PM（2.5）collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2（p-ERK1/2） and phosphorylated c AMP-response element binding protein（p-CREB）. Based on the findings, we analyzed the correlations between the chemical composition of PM（2.5）samples and the biological effects, and confirmed that winter PM（2.5）played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.展开更多
Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although th...Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.展开更多
文摘The authors establish the existence and stability of standing wave solutions of a nonlinear singularly perturbed system of integral differential equations and a non- linear scalar integral differential equation. It will be shown that there exist six standing wave solutions （（u（x,t）,w（x,t）） = （U（x）,W（x）） to the nonlinear singularly perturbed system of integral differential equations. Similarly, there exist six standing wave so- lutions u（x,t） = U（x） to the nonlinear scalar integral differential equation. The main idea to establish the stability is to construct Evans functions corresponding to several associated eigenvalue problems.
基金supported by a grant (AG012694-16) from the National Institue of Aging,USA
文摘Death-mediating proteases such as caspases and caspase-3 in particular, have been implicated in neurodegenerative processes, aging and Alzheimer＇s disease. However, emerging evidence suggests that in addition to their classical role in cell death, caspases play a key role in modulating synaptic function. It is remarkable that active caspases-3, which can trigger widespread damage and degeneration, aggregates in structures as delicate as synapses and persists in neurons without causing acute cell death. Here, we evaluate this dichotomy, and discuss the hypothesis that caspase-3 may be a bifurcation point in cellular signaling, able to orient the neuronal response to stress down either pathological/apoptotic pathways or towards physiological cellular remodeling. We propose that temporal, spatial and other regulators of caspase activity are key determinants of the ultimate effect of caspase-3 activation in neurons. This concept has implications for differential roles of caspase-3 activation across the lifespan. Specifically, we propose that limited caspase-3 activation is critical for synaptic function in the healthy adult brain while chronic activation is involved in degenerative processes in the aging brain.
文摘Microglia are the resident macrophages of the central nervous system.Microglia possess varied morphologies and functions.Under normal physiological conditions,microglia mainly exist in a resting state and constantly monitor their microenvironment and survey neuronal and synaptic activity.Through the C1 q,C3 and CR3"Eat Me"and CD47 and SIRPα"Don't Eat Me"complement pathways,as well as other pathways such as CX3 CR1 signaling,resting microglia regulate synaptic pruning,a process crucial for the promotion of synapse formation and the regulation of neuronal activity and synaptic plasticity.By mediating synaptic pruning,resting microglia play an important role in the regulation of experience-dependent plasticity in the barrel cortex and visual cortex after whisker removal or monocular deprivation,and also in the regulation of learning and memory,including the modulation of memory strength,forgetfulness,and memory quality.As a response to brain injury,infection or neuroinflammation,microglia become activated and increase in number.Activated microglia change to an amoeboid shape,migrate to sites of inflammation and secrete proteins such as cytokines,chemokines and reactive oxygen species.These molecules released by microglia can lead to synaptic plasticity and learning and memory deficits associated with aging,Alzheimer's disease,traumatic brain injury,HIV-associated neurocognitive disorder,and other neurological or mental disorders such as autism,depression and post-traumatic stress disorder.With a focus mainly on recently published literature,here we reviewed the studies investigating the role of resting microglia in synaptic plasticity and learning and memory,as well as how activated microglia modulate disease-related plasticity and learning and memory deficits.By summarizing the function of microglia in these processes,we aim to provide an overview of microglia regulation of synaptic plasticity and learning and memory,and to discuss the possibility of microglia manipulation as a therapeutic to ameliorate cognitive
基金Supported by the National Basic Research Program of China (973 Program,No.2010CB530500)National Natural Science Foundation of China(No.30572420)Program for New Century Excellent Talents in University,Ministry of Education of China (No.NCET-04-0831)
文摘Objective： To observe the effects of electroacupuncture （EA） on the structure parameters of synapse and reactive changes of astrocyte in the marginal zone of focal cerebral ischemia in rats at different time zones so as to further explore its underlying mechanisms in the treatment of cerebral ischemia. Methods： Ninety male Wistar rats were randomly assigned to sham-operation, model, and EA groups, with 30 animals in each group. Each group was subdivided into 1 h, as well as 1, 3, 7, and 21 days post-operation groups, with 6 animals assigned to each time point subgroup. Heat coagulation-induced occlusion of the middle cerebral artery was performed to establish a model of focal cerebral ischemia. EA was applied immediately following surgery to the EA group [4/20 Hz, 2.0-3.0 V, 1-3 mA, to Baihui （GV20） and Dazhui （GV14）] for 30 min. Treatment was performed once a day, and experimental animals were sacrificed at 1 h, as well as 1, 3, 7 and 21 days postoperation. The ultrastructure changes in synapse and astrocytes were observed by using transmission electron microscopy. Glial fibrillary acidic protein （GFAP） expression and Ca2＋ of astrocytes were measured by using laser confocal scanning microscope. Excitatory amino acid transporters-2 （EAAT2） and connexin 43 （CX43） expressions were assayed with immunohistochemical method. Canonical correlation analysis was conducted between structure parameters of synapse and parameters of astrocyte in the same time and group. Results： Broken synapses were observed following cerebral ischemia, and the numbers of synapses were significantly decreased. Compared with the model group, synaptic ultrastructure was significantly improved in the EA group. Compared with the sham-operation group, synaptic number density was significantly decreased, as were postsynaptic density thickness, synaptic cleft width and synaptic interface curvature in the EA and model groups. However, compared with the model group, postsynaptic density thickness was significantly incre
文摘Synapses are specialized structures that mediate information flow between neurons and target cells,and thus are the basis for neuronal system to execute various functions,including learning and memory.There are around 1011 neurons in the human brain,with each neuron receiving thousands of synaptic inputs,either excitatory or inhibitory.A synapse is an asymmetric structure that is composed of pre-synaptic axon terminals,synaptic cleft,and postsynaptic compartments.Synapse formation involves a number of cell adhesion molecules,extracellular factors,and intracellular signaling or structural proteins.After the establishment of synaptic connections,synapses undergo structural or functional changes,known as synaptic plasticity which is believed to be regulated by neuronal activity and a variety of secreted factors.This review summarizes recent progress in the field of synapse development,with particular emphasis on the work carried out in China during the past 10 years(1999-2009).
基金supported by the National Basic Research Program of China (Grant No 2006CB806600)the Knowledge Innovation Program of the Chinese Academy of Sciences (Grant No KSCX2-YW-R-29)
文摘One of the properties of the nervous system is the use-dependent plasticity of neural circuits.The structure and function of neural circuits are susceptible to changes induced by prior neuronal activity,as reflected by short-and long-term modifications of synaptic efficacy and neuronal excitability.Regarded as the most attractive cellular mechanism underlying higher cognitive functions such as learning and memory,activity-dependent synaptic plasticity has been in the spotlight of modern neuroscience since 1973 when activity-induced long-term potentiation(LTP) of hippocampal synapses was first discovered.Over the last 10 years,Chinese neuroscientists have made notable contributions to the study of the cellular and molecular mechanisms of synaptic plasticity,as well as of the plasticity beyond synapses,including activity-dependent changes in intrinsic neuronal excitability,dendritic integration functions,neuron-glia signaling,and neural network activity.This work highlight some of these significant findings.
基金supported by grants PFB (Basal Financing Program) 12/2007 from the Basal Centre for Excellence in Science and Technology and FONDECYT,No.1120156(to NCI)a pre-doctoral fellowship from the National Commission of Science and Technology of Chile(CONICYT)(to CTR)
文摘Alzheimer＇s disease（AD） is the most common form of dementia in the older population, however, the precise cause of the disease is unknown. The neuropathology is characterized by the presence of aggregates formed by amyloid-β（Aβ） peptide and phosphorylated tau; which is accompanied by progressive impairment of memory. Diverse signaling pathways are linked to AD, and among these the Wnt signaling pathway is becoming increasingly relevant, since it plays essential roles in the adult brain. Initially, Wnt signaling activation was proposed as a neuroprotective mechanism against Aβ toxicity. Later, it was reported that it participates in tau phosphorylation and processes of learning and memory. Interestingly, in the last years we demonstrated that Wnt signaling is fundamental in amyloid precursor protein（APP） processing and that Wnt dysfunction results in Aβ production and aggregation in vitro. Recent in vivo studies reported that loss of canonical Wnt signaling exacerbates amyloid deposition in a transgenic（Tg） mouse model of AD. Finally, we showed that inhibition of Wnt signaling in a Tg mouse previously at the appearance of AD signs, resulted in memory loss, tau phosphorylation and Aβ formation and aggregation; indicating that Wnt dysfunction accelerated the onset of AD. More importantly, Wnt signaling loss promoted cognitive impairment, tau phosphorylation and Aβ1–42 production in the hippocampus of wild-type（WT） mice, contributing to the development of an Alzheimer＇s-like neurophatology. Therefore, in this review we highlight the importance of Wnt/β-catenin signaling dysfunction in the onset of AD and propose that the loss of canonical Wnt signaling is a triggering factor of AD.
基金supported by the National Natural Science Foundation of China,No.81373741a grant from the Chinese Medicine and Integrated Medicine Research Projects funded by the Health and Family Planning Commission of Hubei Province of China,No.24a grant from the Hubei Provincial Collaborative Innovation Center of Preventive Treatment by Acupuncture and Moxibustion of China in 2014,No.8
文摘Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42（Aβ_（1–42））into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui（GV20;15°obliquely to a depth of 2mm）and Shenshu（BL23;perpendicularly to 4–6 mm depth）,once a day for 20 minutes（each）,for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β（GSK-3β）,p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_（1–40） in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_（1–40）.pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency（50 Hz）electroacupuncture was more effective than low（2 Hz）or medium-frequency（30 Hz）electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_（1–42）-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.
文摘MicroRNAs play important roles in post-transcriptional regulation of gene expression by inhibiting protein translation and/or promoting mRNA degradation.Importantly,biogenesis of microRNAs displays specific temporal and spatial profiles in distinct cell and tissue types and hence affects a broad spectrum of biological functions in normal cell growth and tumor development.Recent discoveries have revealed sophisticated mechanisms that control microRNA production and homeostasis in response to developmental and extracellular signals.Moreover,a link between dysregulation of microRNAs and human brain disorders has become increasingly evident.In this review,we focus on recent advances in understanding the regulation of microRNA biogenesis and function in neuronal and glial development in the mammalian brain,and dysregulation of the microRNA pathway in neurodevelopmental and neurodegenerative diseases.
基金supported by the National Natural Science Foundation of China(61401497)
文摘With key roles in essential brain functions ranging from the long-term potentiation(LTP) to synaptic plasticity,the N-methyl-D-aspartic acid receptor(NMDAR) can be considered as one of the fundamental glutamate receptors in the central nervous system.The role of NMDA R was first identified in synaptic plasticity and has been extensively studied.Some molecules,such as Ca^(2+),postsynaptic density 95(PSD-95),calcium/calmodulin-dependent protein kinase II(Ca MK II),protein kinase A(PKA),mitogen-activated protein kinase(MAPK) and cyclic adenosine monophosphate(c AMP) responsive element binding protein(CREB),are of special importance in learning and memory.This review mainly focused on the new research of key molecules connected with learning and memory,which played important roles in the NMDAR signaling pathway.
基金supported by the National Natural Science Foundation of China(No.81172620)
文摘Objective The aim of this study is to investigate whether microwave exposure would affect the N-methyI-D-aspartate receptor （NMDAR） signaling pathway to establish whether this plays a role in synaptic plasticity impairment. Methods 48 male Wistar rats were exposed to 30 mW/cm^2 microwave for 10 min every other day for three times. Hippocampal structure was observed through H＆E staining and transmission electron microscope. PC12 cells were exposed to 30 mW/cm^2 microwave for 5 min and the synapse morphology was visualized with scanning electron microscope and atomic force microscope. The release of amino acid neurotransmitters and calcium influx were detected. The expressions of several key NMDAR signaling molecules were evaluated. Results Microwave exposure caused injury in rat hippocampal structure and PC12 cells, especially the structure and quantity of synapses. The ratio of glutamic acid and gamma-aminobutyric acid neurotransmitters was increased and the intracellular calcium level was elevated in PC12 cells. A significant change in NMDAR subunits （NR1, NR2A, and NR2B） and related signaling molecules （CaZ＋/calmodulin-dependent kinase II gamma and phosphorylated cAMP-response element binding protein） were examined. Conclusion 30 mW/cm^2 microwave exposure resulted in alterations of synaptic structure, amino acid neurotransmitter release and calcium influx. NMDAR signaling molecules were closely associated with impaired synaptic plasticity.
基金supported by the National Natural Science Foundation of China,No.81672242(to YW)the Key Construction Projects of Shanghai Health and Family Planning on Weak Discipline,China,No.2015ZB0401(to YW)
文摘Cerebral ischemia activates an endogenous repair program that induces plastic changes in neurons. In this study, we investigated the effects of environmental enrichment on spatial learning and memory as well as on synaptic remodeling in a mouse model of chronic cerebral ischemia, produced by subjecting adult male C57 BL/6 mice to permanent left middle cerebral artery occlusion. Three days postoperatively, mice were randomly assigned to the environmental enrichment and standard housing groups. Mice in the standard housing group were housed and fed a standard diet. Mice in the environmental enrichment group were housed in a cage with various toys and fed a standard diet. Then, 28 days postoperatively, spatial learning and memory were tested using the Morris water maze. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 in the hippocampus were analyzed by western blot assay. The number of synapses was evaluated by electron microscopy. In the water maze test, mice in the environmental enrichment group had a shorter escape latency, traveled markedly longer distances, spent more time in the correct quadrant(northeast zone), and had a higher frequency of crossings compared with the standard housing group. The expression levels of growth-associated protein 43, synaptophysin and postsynaptic density protein 95 were substantially upregulated in the hippocampus in the environmental enrichment group compared with the standard housing group. Furthermore, electron microscopy revealed that environmental enrichment increased the number of synapses in the hippocampal CA1 region. Collectively, these findings suggest that environmental enrichment ameliorates the spatial learning and memory impairment induced by permanent middle cerebral artery occlusion. Environmental enrichment in mice with cerebral ischemia likely promotes cognitive recovery by inducing plastic changes in synapses.
基金supported by the National Natural Science Foundation of China,No.81571038,81771145(both to YZ)
文摘Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17,
基金supported by the National Natural Science Foundation of China(61622401,61851402 and 61734003)the National Key Research and Development Program of China(2017YFB0405600)+2 种基金Shanghai Education Development FoundationShanghai Municipal Education Commission Shuguang Program(18SG01)support from Shanghai Municipal Science and Technology Commission(18JC1410300)
文摘Synapses in biology provide a variety of functions for the neural system. Artificial synaptic electronics that mimic the biological neuron functions are basic building blocks and developing novel artificial synapses is essential for neuromorphic computation. Inspired by the unique features of biological synapses that the basic connection components of the nervous system and the parallelism, low power consumption, fault tolerance, self-learning and robustness of biological neural systems, artificial synaptic electronics and neuromorphic systems have the potential to overcome the traditional von Neumann bottleneck and create a new paradigm for dealing with complex problems such as pattern recognition, image classification, decision making and associative learning. Nowadays, two-dimensional(2 D) materials have drawn great attention in simulating synaptic dynamic plasticity and neuromorphic computing with their unique properties. Here we describe the basic concepts of bio-synaptic plasticity and learning, the 2 D materials library and its preparation. We review recent advances in synaptic electronics and artificial neuromorphic systems based on 2 D materials and provide our perspective in utilizing 2 D materials to implement synaptic electronics and neuromorphic systems in hardware.
文摘As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3β(GSK-3β) and protein phosphatase 2A(PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3β or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity.
基金supported by the National Natural Science Foundation of China,No.81473740,81673627,81673717(to QW)Guangzhou Science Technology and Innovation Commission Technology Research Projects,China,No.2018050100(to QW)+3 种基金the Foundation for Characteristic Innovation of Educational Commission of Guangdong Province,China,Grant No.2016KTSCX011(to SHF)the Open Tending Project for Construction of High-Level University,Guangzhou University of Chinese Medicine,China,No.34 and 118,2017(to SHF)the Technology Platform of Clinical Trials on New Traditional Medicine,China,No.2012ZX09303009-003(to WXL)the Technology Platform of Clinical Evaluation on New Traditional Medicine,China,No.2008ZX09312-021(to WXL)
文摘Kai Xin San(KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups(which received physiological saline), the doses of KXS(0.7, 1.4 and 2.8 g/kg per day) and donepezil(3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following.(1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze.(2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze.(3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies.(4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus.(5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxi
基金supported by National Institutes of Health Grants HL131161,HL139523,and HL142133
文摘The hypothalamic paraventricular nucleus(PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN presympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension.This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
基金supported by the National Science Foundation of China(Nos.91543203,21377076)the Specialized Research Fund for the Doctoral Program of Higher Education(Nos.20121401110003,20131401110005)the Research Project Supported by Shanxi Scholarship Council of China(No.2015-006)
文摘Epidemiological studies have shown that particulate matter 2.5（PM（2.5）） not only increases the incidence of cardiopulmonary illnesses but also relates to the development of neurodegenerative diseases. Considering that PM（2.5）is highly heterogeneous with regional disparity and seasonal variation, we investigated whether PM（2.5）exposure induced neuronal apoptosis and synaptic injuries in a season-dependent manner. The results indicated that PM（2.5）altered the expression of apoptosis-related proteins（mainly bax and bcl-2）, activated caspase-3 and caused neuronal apoptosis. Additionally, PM（2.5）decreased the levels of synaptic structural protein postsynaptic density（PSD-95） and synaptic functional protein N-methyl-D-aspartate（NMDA） receptor subunit（NR2B） expression. These effects occurred in a season-dependent manner, and PM（2.5）collected from the winter showed the strongest changes. Furthermore, the effect was coupled with the inhibition of phosphorylated extracellular signal-regulated kinase 1/2（p-ERK1/2） and phosphorylated c AMP-response element binding protein（p-CREB）. Based on the findings, we analyzed the correlations between the chemical composition of PM（2.5）samples and the biological effects, and confirmed that winter PM（2.5）played a major role in causing neuronal apoptosis and synaptic injuries among different season samples.
基金supported by the Natural Science Foundation of Inner Mongolia Autonomous Region of China,No.2017LH0301(to JXJ),2016MS08108(to ZJY)Science and Technology Planning Project of Inner Mongolia Autonomous Region of China,No.201602069(to ZJY)+1 种基金PhD Scientific Research Fund of Baotou Medical College of China,No.BSJJ201606(to JXJ)"Dengfeng Project" Scientific Research Fund of Baotou Medical College of China,No.BYJJ-DF 201703(to JXJ)
文摘Cognitive dysfunction in Alzheimer's disease is strongly associated with a reduction in synaptic plasticity, which may be induced by oxidative stress. Testosterone is beneficial in learning and memory, although the underlying protective mechanism of testosterone on cognitive performance remains unclear. This study explored the protective mechanism of a subcutaneous injection of 0.75 mg testosterone on cognitive dysfunction induced by bilateral injections of amyloid beta 1–42 oligomers into the lateral ventricles of male rats. Morris water maze test results demonstrated that testosterone treatment remarkably reduced escape latency and path length in Alzheimer's disease rat models. During probe trials, testosterone administration significantly elevated the percentage of time spent in the target quadrant and the number of platform crossings. However, flutamide, an androgen receptor antagonist, inhibited the protective effect of testosterone on cognitive performance in Alzheimer's disease rat models. Nissl staining, immunohistochemistry, western blot assay, and enzyme-linked immunosorbent assay results showed that the number of intact hippocampal pyramidal cells, the dendritic spine density in the hippocampal CA1 region, the immune response and expression level of postsynaptic density protein 95 in the hippocampus, and the activities of superoxide dismutase and glutathione peroxidase were increased with testosterone treatment. In contrast, testosterone treatment reduced malondialdehyde levels. Flutamide inhibited the effects of testosterone on all of these indicators. Our data showed that the protective effect of testosterone on cognitive dysfunction in Alzheimer's disease is mediated via androgen receptors to scavenge free radicals, thereby enhancing synaptic plasticity.
