Effects of Jiaohong Pills and Its Prescription on Scopolamine-induced Alzheimer's Disease Mice / 中国实验方剂学杂志

ObjectiveTo investigate the effects of Jiaohong pills （JHP） and its prescription， Pericarpium Zanthoxyli （PZ） and Rehmanniae Radix （RR） cognitive dysfunction in scopolamine-induced Alzheimer's disease （AD） mice and its mechanism through pharmacodynamic and metabolomics study. MethodThe animal model of AD induced by scopolamine was established and treated with PZ， RG and JHP， respectively. The effects of JHP and its formulations were investigated by open field test， water maze test， object recognition test， avoidance test， cholinergic system and oxidative stress related biochemical test. Untargeted metabolomics analysis of cerebral cortex was performed by ultra-performance liquid chromatography-Quadrupole/Orbitrap high resolution mass spectrometry （UPLC Q-Exactive Orbitrap MS）. ResultThe behavioral data showed that， compared with the model group， the discrimination indexes of the high dose of JHP， PZ and RR groups was significantly increased （P<0.05）. The staging rate of Morris water maze test in the PZ， RR， high and low dose groups of JHP was significantly increased （P<0.05， P<0.01）， the crossing numbers in the PZ， JHP high and low dose groups were significantly increased （P<0.05， P<0.01）； the number of errors in the avoidance test were significantly reduced in the PZ and high-dose JHP groups （P<0.01）， and the error latencies were significantly increased in the JHP and its prescription drug groups （P<0.01）. Compared with the model group， the activities of acetylcholinesterase in the cerebral cortex of the two doses of JHP group and the PZ group were significantly increased （P<0.05， P<0.01）， and the activity of acetylcholinesterase in the high-dose JHP group was significantly decreased （P<0.05）， and the level of acetylcholine was significantly increased （P<0.01）. At the same time， the contents of malondialdehyde in the serum of the two dose groups of JHP decreased significantly （P<0.05， P<0.01）. The results of metabolomics study of cerebral cortex showed that 149 differential metabolites were identified between the JHP group and the model group， which were involved in neurotransmitter metabolism， energy metabolism， oxidative stress and amino acid metabolism. ConclusionJHP and its prescription can antagonize scopolamine-induced cognitive dysfunction， regulate cholinergic system， and reduce oxidative stress damage. The mechanism of its therapeutic effect on AD is related to the regulation of neurotransmitter， energy， amino acid metabolism， and improvement of oxidative stress.

A Virtual Reality Platform for Context-Dependent Cognitive Research in Rodents / 神经科学通报·英文版

Animal survival necessitates adaptive behaviors in volatile environmental contexts. Virtual reality (VR) technology is instrumental to study the neural mechanisms underlying behaviors modulated by environmental context by simulating the real world with maximized control of contextual elements. Yet current VR tools for rodents have limited flexibility and performance (e.g., frame rate) for context-dependent cognitive research. Here, we describe a high-performance VR platform with which to study contextual behaviors immersed in editable virtual contexts. This platform was assembled from modular hardware and custom-written software with flexibility and upgradability. Using this platform, we trained mice to perform context-dependent cognitive tasks with rules ranging from discrimination to delayed-sample-to-match while recording from thousands of hippocampal place cells. By precise manipulations of context elements, we found that the context recognition was intact with partial context elements, but impaired by exchanges of context elements. Collectively, our work establishes a configurable VR platform with which to investigate context-dependent cognition with large-scale neural recording.

Disrupted Maturation of Prefrontal Layer 5 Neuronal Circuits in an Alzheimer's Mouse Model of Amyloid Deposition / 神经科学通报·英文版

Mutations in genes encoding amyloid precursor protein (APP) and presenilins (PSs) cause familial forms of Alzheimer's disease (AD), a neurodegenerative disorder strongly associated with aging. It is currently unknown whether and how AD risks affect early brain development, and to what extent subtle synaptic pathology may occur prior to overt hallmark AD pathology. Transgenic mutant APP/PS1 over-expression mouse lines are key tools for studying the molecular mechanisms of AD pathogenesis. Among these lines, the 5XFAD mice rapidly develop key features of AD pathology and have proven utility in studying amyloid plaque formation and amyloid β (Aβ)-induced neurodegeneration. We reasoned that transgenic mutant APP/PS1 over-expression in 5XFAD mice may lead to neurodevelopmental defects in early cortical neurons, and performed detailed synaptic physiological characterization of layer 5 (L5) neurons from the prefrontal cortex (PFC) of 5XFAD and wild-type littermate controls. L5 PFC neurons from 5XFAD mice show early APP/Aβ immunolabeling. Whole-cell patch-clamp recording at an early post-weaning age (P22-30) revealed functional impairments; although 5XFAD PFC-L5 neurons exhibited similar membrane properties, they were intrinsically less excitable. In addition, these neurons received smaller amplitude and frequency of miniature excitatory synaptic inputs. These functional disturbances were further corroborated by decreased dendritic spine density and spine head volumes that indicated impaired synapse maturation. Slice biotinylation followed by Western blot analysis of PFC-L5 tissue revealed that 5XFAD mice showed reduced synaptic AMPA receptor subunit GluA1 and decreased synaptic NMDA receptor subunit GluN2A. Consistent with this, patch-clamp recording of the evoked L23>L5 synaptic responses revealed a reduced AMPA/NMDA receptor current ratio, and an increased level of AMPAR-lacking silent synapses. These results suggest that transgenic mutant forms of APP/PS1 overexpression in 5XFAD mice leads to early developmental defects of cortical circuits, which could contribute to the age-dependent synaptic pathology and neurodegeneration later in life.

Mechanism of Learning and Memory Impairment in Rats Exposed to Arsenic and/or Fluoride Based on Microbiome and Metabolome / 生物医学与环境科学（英文）

OBJECTIVE@#Arsenic (As) and fluoride (F) are two of the most common elements contaminating groundwater resources. A growing number of studies have found that As and F can cause neurotoxicity in infants and children, leading to cognitive, learning, and memory impairments. However, early biomarkers of learning and memory impairment induced by As and/or F remain unclear. In the present study, the mechanisms by which As and/or F cause learning memory impairment are explored at the multi-omics level (microbiome and metabolome).@*METHODS@#We stablished an SD rats model exposed to arsenic and/or fluoride from intrauterine to adult period.@*RESULTS@#Arsenic and/fluoride exposed groups showed reduced neurobehavioral performance and lesions in the hippocampal CA1 region. 16S rRNA gene sequencing revealed that As and/or F exposure significantly altered the composition and diversity of the gut microbiome，featuring the Lachnospiraceae_NK4A136_group, Ruminococcus_1, Prevotellaceae_NK3B31_group, [Eubacterium]_xylanophilum_group. Metabolome analysis showed that As and/or F-induced learning and memory impairment may be related to tryptophan, lipoic acid, glutamate, gamma-aminobutyric acidergic (GABAergic) synapse, and arachidonic acid (AA) metabolism. The gut microbiota, metabolites, and learning memory indicators were significantly correlated.@*CONCLUSION@#Learning memory impairment triggered by As and/or F exposure may be mediated by different gut microbes and their associated metabolites.

Research progress on the modulation mechanism of electroacupuncture for learning and memory impairment after ischemic stroke / 中国针灸

Electroacupuncture may play a role in treatment of learning and memory impairment after ischemic stroke by regulating phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA)/cAMP response element binding protein (CREB) signaling pathway, nerve growth factor (NGF)/tyrosine kinase-A (TrkA) signaling pathway, Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, Notch signaling pathway, erythropoietin-producing hepatocyte (Eph)/ephrin signaling pathway. The interactions among these pathways should be further explored in treatment of learning and memory impairment after ischemic stroke.

Effects of moxa smoke through olfactory pathway on learning and memory ability in rapid aging mice / 中国针灸

OBJECTIVE@#To observe the effects of moxa smoke through olfactory pathway on learning and memory ability in rapid aging (SAMP8) mice, and to explore the action pathway of moxa smoke.@*METHODS@#Forty-eight six-month-old male SAMP8 mice were randomly divided into a model group, an olfactory dysfunction group, a moxa smoke group and an olfactory dysfunction + moxa smoke group, with 12 mice in each group. Twelve age-matched male SAMR1 mice were used as the blank group. The olfactory dysfunction model was induced in the olfactory dysfunction group and the olfactory dysfunction + moxa smoke group by intraperitoneal injection of 3-methylindole (3-MI) with 300 mg/kg, and the moxa smoke group and the olfactory dysfunction + moxa smoke group were intervened with moxa smoke at a concentration of 10-15 mg/m3 for 30 min per day, with a total of 6 interventions per week. After 6 weeks, the emotion and cognitive function of mice was tested by open field test and Morris water maze test, and the neuronal morphology in the CAI area of the hippocampus was observed by HE staining. The contents of neurotransmitters (glutamic acid [Glu], gamma-aminobutyric acid [GABA], dopamine [DA], and 5-hydroxytryptamine [5-HT]) in hippocampal tissue of mice were detected by ELISA.@*RESULTS@#The mice in the blank group, the model group and the moxa smoke group could find the buried food pellets within 300 s, while the mice in the olfactory dysfunction group and the olfactory dysfunction + moxa smoke group took more than 300 s to find them. Compared with the blank group, the model group had increased vertical and horizontal movements (P<0.05) and reduced central area residence time (P<0.05) in the open field test, prolonged mean escape latency on days 1-4 (P<0.05), and decreased search time, swimming distance and swimming distance ratio in the target quadrant of the Morris water maze test, and decreased GABA, DA and 5-HT contents (P<0.05, P<0.01) and increased Glu content (P<0.05) in hippocampal tissue. Compared with the model group, the olfactory dysfunction group had increased vertical movements (P<0.05), reduced central area residence time (P<0.05), and increased DA content in hippocampal tissue (P<0.05); the olfactory dysfunction + moxa smoke group had shortened mean escape latency on days 3 and 4 of the Morris water maze test (P<0.05) and increased DA content in hippocampal tissue (P<0.05); the moxa smoke group had prolonged search time in the target quadrant (P<0.05) and increased swimming distance ratio, and increased DA and 5-HT contents in hippocampal tissue (P<0.05, P<0.01) and decreased Glu content in hippocampal tissue (P<0.05). Compared with the olfactory dysfunction group, the olfactory dysfunction + moxa smoke group showed a shortened mean escape latency on day 4 of the Morris water maze test (P<0.05). Compared with the moxa smoke group, the olfactory dysfunction + moxa smoke group had a decreased 5-HT content in the hippocampus (P<0.05). Compared with the blank group, the model group showed a reduced number of neurons in the CA1 area of the hippocampus with a disordered arrangement; the olfactory dysfunction group had similar neuronal morphology in the CA1 area of the hippocampus to the model group. Compared with the model group, the moxa smoke group had an increased number of neurons in the CA1 area of the hippocampus that were more densely packed. Compared with the moxa smoke group, the olfactory dysfunction + moxa smoke group had a reduced number of neurons in the CA1 area of the hippocampus, with the extent between that of the moxa smoke group and the olfactory dysfunction group.@*CONCLUSION@#The moxa smoke could regulate the contents of neurotransmitters Glu, DA and 5-HT in hippocampal tissue through olfactory pathway to improve the learning and memory ability of SAMP8 mice, and the olfactory is not the only effective pathway.

Effects of Yizhi Tiaoshen acupuncture on learning and memory function and the expression of phosphorylated tau protein in the hippocampus of Alzheimer's disease model rats / 中国针灸

OBJECTIVE@#To observe the effects of Yizhi Tiaoshen (benefiting mental health and regulating the spirit) acupuncture on learning and memory function, and the expression of phosphorylated tubulin-associated unit (tau) protein in the hippocampus of Alzheimer's disease (AD) model rats, and explore the effect mechanism of this therapy on AD.@*METHODS@#A blank group and a sham-operation group were randomly selected from 60 male SD rats, 10 rats in each one. AD models were established in the rest 40 rats by the intraperitoneal injection of D-galactose and okadaic acid in the CA1 region of the bilateral hippocampus. Thirty successfully-replicated model rats were randomly divided into a model group, a western medication group and an acupuncture group, 10 rats in each one. In the acupuncture group, acupuncture was applied to "Baihui" (GV 20), "Sishencong" (EX-HN 1), "Neiguan" (PC 6), "Shenmen" (HT 7), "Xuanzhong" (GB 39) and "Sanyinjiao" (SP 6); and the needles were retained for 10 min. Acupuncture was given once daily. One course of treatment was composed of 6 days, with the interval of 1 day; the completion of treatment included 4 courses. In the western medication group, donepezil hydrochloride solution (0.45 mg/kg) was administrated intragastrically, once daily; it took 7 days to accomplish one course of treatment and a completion of intervention was composed of 4 courses. Morris water maze (MWM) and novel object recognition test (NORT) were used to assess the learning and memory function of the rats. Using HE staining and Nissl staining, the morphological structure of the hippocampus was observed. With Western blot adopted, the protein expression of the tau, phosphorylated tau protein at Ser198 (p-tau Ser198), protein phosphatase 2A (PP2A) and glycogen synthase kinase-3β (GSK-3β) in the hippocampus was detected.@*RESULTS@#There were no statistical differences in all of the indexes between the sham-operation group and the blank group. Compared with the sham-operation group, in the model group, the MWM escape latency was prolonged (P<0.05), the crossing frequency and the quadrant stay time in original platform were shortened (P<0.05), and the NORT discrimination index (DI) was reduced (P<0.05); the hippocampal cell numbers were declined and the cells arranged irregularly, the hippocampal neuronal structure was abnormal and the numbers of Nissl bodies decreased; the protein expression of p-tau Ser198 and GSK-3βwas increased (P<0.05) and that of PP2A decreased (P<0.05). When compared with the model group, in the western medication group and the acupuncture group, the MWM escape latency was shortened (P<0.05), the crossing frequency and the quadrant stay time in original platform were increased (P<0.05), and DI got higher (P<0.05); the hippocampal cell numbers were elevated and the cells arranged regularly, the damage of hippocampal neuronal structure was attenuated and the numbers of Nissl bodies were increased; the protein expression of p-tau Ser198 and GSK-3β was reduced (P<0.05) and that of PP2A was increased (P<0.05). There were no statistically significant differences in the above indexes between the acupuncture group and the western medication group (P>0.05).@*CONCLUSION@#Acupuncture therapy of "benefiting mental health and regulating the spirit" could improve the learning and memory function and alleviate neuronal injure of AD model rats. The effect mechanism of this therapy may be related to the down-regulation of GSK-3β and the up-regulation of PP2A in the hippocampus, and then to inducing the inhibition of tau protein phosphorylation.

Effects of Dianxianqing granules on tau protein in P301S mice by regulating mitophagy / 中国药房

OBJECTIVE To study the effects of Dianxianqing granules on the tau protein in P301S mice by regulating mitophagy. METHODS Totally 36 P301S mice were randomly divided into model group， Dianxianqing granule group （12.48 g/kg）， donepezil hydrochloride group （positive control， 1.3 mg/kg）， with 12 mice in each group； another 10 C57BL6 mice were selected as control group. Administration groups were given relevant drug solutions intragastrically， and control group and model group were given constant volume of water intragastrically. The gavage volume was 20 mL/kg， once a day， for consecutive 5 months. During the experiment， the general condition of mice was observed in each group. After the last medication， the learning and memory ability was determined by Y maze test and Morris water maze test； HE staining was used to observe the morphological changes in brain tissue， and Nissl staining was used to observe the structure of neural cells and the number of Nissl bodies in cerebral tissue. Immunohistochemistry was used to detect the expressions of phospho-tau serine 202/threonine 205 （abbreviated as AT8） in brain tissue. Western blot assay was used to determine the expressions of mitophagy-associated proteins [PTEN-induced putative kinase-1 （PINK1）， Parkin， microtubule-associated protein 1 light chain 3B （LC3B）， p62]， synaptic-associated proteins [postsynaptic density protein-95 （PSD-95）， synaptophysin （SYP）， and growth-associated protein-43 （GAP-43）] and the phosphorylation of tau protein [expressed by the phosphorylation levels of serine 199 （Ser199） and Ser202] in brain tissue. RESULTS The mice in E-mail：lnzyxyqy2003@163.com model group showed symptoms such as white hair， decreased body mass， and lower limb paralysis， with incomplete hippocampal structures in their brain tissue， as well as incomplete cell membrane edges and cell structures； the spontaneous alternating response rate， the times of crossing platform， the number of Nissl bodies， the protein expressions of PINK1， Parkin， LC3B， SYP， GAP-43， and PSD-95 were decreased significantly， compared with control group； swimming latency （fourth and fifth day）， the protein expressions of AT8 and p62，the phosphorylation levels of Ser199 and Ser202 were increased or lengthened significantly， compared with control group （P＜0.05 or P＜0.01）. Compared with model group， the above symptoms and indexes of mice were improved significantly in administration groups （P＜0.05 or P＜0.01）. CONCLUSIONS Dianxianqing granules can effectively improve cognitive impairment in P301S mice，the mechanism of which may be associated with inducing mitochondrial autophagy， reducing the hyperphosphorylation of tau protein， up-regulating the expression of synaptic-associated proteins in brain tissue，and repairing damaged neural cells.

Protective effects of taurine on learning and memory impairment after exposure to formaldehyde and benzene analogues in young rats / 环境与职业医学

Background Formaldehyde and benzene homologues are common environmental pollutants, and their neurotoxicity has aroused widespread concern. Objective To investigate the effect of taurine on cognitive impairment after exposure to formaldehyde and benzene analogues in young rats. Methods Twenty four-week old SD rats were randomly divided into four groups, with six rats in each group: control group (clean air), model group (5 mg·m−3 formaldehyde + 5 mg·m−3 benzene + 10 mg·m−3 toluene + 10 mg·m−3 xylene), low-dose taurine intervention group (5 g·L−1 taurine + mixture of formaldehyde and benzene analogues), and high-dose taurine intervention group (10 g·L−1 taurine + formaldehyde and mixture of benzene analogues), and the exposure was administered by oral and nasal aerosol inhalation for 28 d. At the end of exposure, the learning and memory ability of rats in each group was measured by Morris water maze test. After the behavioral test, the rats were anesthetized and neutralized, and the brain tissue was harvested for histopathological and molecular biological tests. The apoptosis rate of neurons in hippocampal CA1 area was detected by Tunel assay, and the expression levels of apoptosis-related proteins such as caspase 3, bax, and bcl-2 in hippocampal tissue were detected by Western blotting. Results The growth and development of rats in each group were good during inhalation. During the Morris water maze experiment, the escape latencies of rats in the taurine intervention groups were not different from that in the control group (P>0.05) from day 3 to day 5 of training, while the escape latency of rats in the model group was significantly higher than that in the control group (P <0.05). The number of crossing platform and the target quadrant residence time in the high-dose taurine intervention group were not different from those in the control group (P>0.05), while the two variables in the model group and low-dose taurine intervention group were significantly lower than those in the control group (P <0.05). The apoptotic rates of neurons in the hippocampal CA1 area of rats in the control group, model group, and low-dose and high-dose taurine intervention groups were 5.11%, 18.87%, 9.39%, and 4.63%, respectively. The apoptotic rate in the model group was higher than those in the control group and low-dose and high-dose taurine intervention groups (P<0.05). The expression levels of caspase 3, bax, and bcl-2 in the hippocampus of rats in the low-dose and high-dose taurine intervention groups showed no difference compared with the control group (P>0.05). The expression levels of caspase 3 and bax in the model group were higher than those in the control group and low-dose or high-dose taurine intervention groups (P<0.05), and the expression levels of bcl-2 was lower (P<0.05). Conclusion The mixed exposure to formaldehyde and benzene analogues can damage the learning and memory ability of young rats, and increase the apoptosis of neurons in hippocampal CA1 region. Taurine can reverse the damage induced by formaldehyde and benzene analogues.

Effects of microwave radiation on learning and memory and neurotransmitters in the hippocampus / 中国辐射卫生

@#The central nervous system is one of the most sensitive targets of microwave radiation. Microwave radiation can affect spatial learning and memory and neural information transmission. The effects of microwave radiation on neurotransmitters in the hippocampus and the underlying mechanisms are still unclear. This paper reviews the effects of microwave radiation on learning/memory and neurotransmitters as well as the mechanisms of action on neurotransmitters. This paper aims to provide a scientific basis for future research in this area.

Action mechanism of vinpocetine in improving learning and memory disorders in depressive rats after MECT / 西安交通大学学报(医学版)

【Objective】 To explore the action mechanism of vinpocetine in improving learning and memory disorders in depressive rats after modified electroconvulsive therapy (MECT). 【Methods】 The models of depressive rats were constructed by chronic unpredictable mild stress (CUMS) method. A total of 30 rats with depression were randomly divided into depression group, MECT group, and MECT+vinpocetine (10 mg/kg) group, with 10 in each group. A total of 10 untreated healthy rats were enrolled as control group. The learning and memory ability were tested by Morris water maze test and novel object recognition test. The depression state was evaluated by sugar preference test. The brain slices of the hippocampus were prepared for electrophysiological experiments. The density of dendritic spine was detected by Golgi staining. The expressions of endocannabinoids related genes [diacylglycerol lipase (DAGLα), monoacylglycerol lipase (MAGL), and endocannabinoid type-I receptor (CB1R)] were detected by qPCR and Western blotting. The lentivirus was injected to downregulate the expressions of CB1R and DAGLα in the hippocampus. After re-modeling and treatment, behavioral tests were performed. 【Results】 Compared with control group, sugar preference, spatial exploration time, relative discrimination index, long-term potentiation (LTP), density of dendritic spine, expressions of DAGLα and CB1R were decreased, while escape latency and MAGL were increased in depression group (P<0.05). Compared with depression group, sugar preference, escape latency, and MAGL were increased, while spatial exploration time, relative discrimination index, LTP, density of dendritic spine, expressions of DAGLα and CB1R were decreased in MECT group (P<0.05). Compared with depression group, sugar preference, spatial exploration time, relative discrimination index, LTP, density of dendritic spine, expressions of DAGLα and CB1R were increased, while escape latency and MAGL were decreased in MECT+vinpocetine group (P<0.05). Compared with MECT group, sugar preference, spatial exploration time, relative discrimination index, LTP, density of dendritic spine, expressions of DAGLα and CB1R were increased, while escape latency and MAGL were decreased in MECT+vinpocetine group (P<0.05). The down-regulation of DAGLα or CB1R by lentivirus could inhibit the improvement effect of vinpocetine on behavioral performance of depressive rats after MECT. 【Conclusion】 Vinpocetine can significantly improve learning and memory disorders in depressive rats after MECT, which may be related to regulating the expressions of endocannabinoid-related genes and enhancing synaptic plasticity.

PRE-084 ameliorated learning and memory impairment in T1DM via regulating neuronal MAM / 西安交通大学学报(医学版)

【Objective】 Diabetic mice could show learning and memory dysfunction, and we aimed to investigate the effect of Sigma-1 receptor agonist, PRE-084, on neurons and cognitive impairment in mice with type 1 diabetes (T1DM). 【Methods】 Twenty mice with T1DM induced by streptozocin, aged 8-10 weeks, and 20 control mice (CON) were randomly divided into four groups (CON+Vehicle, CON+PRE-084, T1DM+Vehicle and T1DM+PRE-084). Mouse primary neurons were cultured in high glucose medium with PRE-084 and control solvent, respectively. The body weight, food and water intake, and fasting blood glucose level of mice in each group were detected and recorded. The learning and memory abilities of mice were detected by new object recognition experiment. The mitochondria-associated endoplasmic reticulum membrane (MAM) structure of neurons in hippocampal CA1 area of mice was detected by transmission electron microscope. And the expression levels of ATP and reactive oxygen species (ROS) in hippocampus of mice were detected by biochemical kit. Cell viability and ROS level of primary neurons were detected by CCK8 and cellular ROS kit. 【Results】 PRE-084 reduced the increase of body weight, food and water intake, and blood glucose caused by diabetes. PRE-084 significantly ameliorated the learning and memory impairment of the mice with T1DM, improved the changes of MAM structure in neurons of hippocampal CA1 area of diabetic mice, increased the level of ATP in hippocampus of diabetic mice, and decreased the increase of ROS expression in diabetic hippocampus and neurons under high glucose conditions. 【Conclusion】 Sigma-1 receptor agonist, PRE-084, could improve learning and memory impairment in the mice with T1DM, which might be related to the structural changes of MAM, the increase of ATP production, and the decrease of ROS production in hippocampal neurons.

Improvement effect of diterpene ginkgolides on acute tMCAO rats and chronic tMCAO rats / 药学学报

To study the cognitive effects of diterpene ginkgolides (DG), transient middle cerebral artery occlusion (tMCAO)-induced rats were established. tMCAO-rats induced by suture method were divided into sham operation group, solvent control group, NBP group, DG group. The animal experiments in the present study were performed in accordance with the Ethical Guidelines of the Laboratory Animal Welfare Ethical Committee of Peking Union Medical College (00000646, 00000635). The effects of DG on tMCAO rats were evaluated by neurological severity score, cerebral infarction volume measurement, step-down and Morris water maze test. In the acute tMCAO rat model, 100 mg·kg-1 DG improved the neural score and infarction volume. In the chronic tMCAO rat model, DG 100 mg·kg-1 significantly improved the survival rate of tMCAO-induced rats. The Morris water maze results showed 100 mg·kg-1 DG decreased the latency of tMCAO-induced rats to find the platform, while the effect was weaker than the NBP. However, DG 30 mg·kg-1 did not show a significant effect. In conclusion, DG exerted a therapeutic effect on transient middle cerebral artery occlusion.

Effect of Tongdu Xingshen Needling Method （通督醒神针刺法） on Expression of AMPA Receptors and Their Accessory Proteins in the Hippocampus of Rats with Learning Memory Impairment After Cerebral Ischaemia-Reperfusion / 中医杂志

ObjectiveTo explore the possible mechanism of Tongdu Xingshen needling method （通督醒神针刺法） on post-stroke cognitive impairment. MethodsSD rats were randomly divided into a normal group （n=12）， a sham surgery group （n=12）， a model group （n=12）， and a electroacupuncture group （n=13）. The rats in the model group and electroacupuncture group were subjected to the wire bolus method to establish the rats model with learning memory impairment after cerebral ischaemia-reperfusion. After successful modelling， the rats in the electroacupuncture group were given electroacupuncture interventions at “Shenting （GV 24）” and “Baihui （GV 20）” once a day for 30 minutes for 14 days. The other three groups did not receive other interventions but grasp. A 5-day localisation navigation experiment was conducted on the 9th day of intervention， and a spatial exploration experiment was conducted on the 14th day of intervention to evaluate the learning and memory abilities of the rats. After the spatial exploration experiment， hippocampal tissues were taken from each group of rats， and the changes in the volume of cerebral infarction were observed by TTC staining； the changes in the morphology of pyramidal neurons and the density of dendritic spines in the CA1 area of the hippocampus were observed by Golgi staining； protein immunoblotting was used to detect the relative protein expression of the subunits of the α-amino-3-carboxy-5-methylisoxazole-4-propionic acid （AMPA） receptor including glutamate receptor 1 （GluR1）， glutamate receptor 2 （GluR2）， glutamate receptor 3 （GluR3） and auxiliary proteins TARPγ2， TARPγ8 in hippocampal tissues of rats in each group； the real-time fluorescence quantitative PCR was used to detect GluR1， GluR2， GluR3 mRNA levels in the hippocampal tissues of rats. ResultsIn the localisation navigation experiment， compared with the normal group and sham surgery group， the escape latency and total distance of rats in the model group were significantly extended （P＜0.05） at day 1， 2， 3， 4， and 5； and the escape latency and total distance of rats in the electroacupuncture group tended to be significantly shorter than those in the model group （P＜0.05）. In the spatial exploration experiment， compared with the normal group and the sham surgery group， the number of rats crossing the platform in the model group was significantly reduced （P＜0.05）， and the number of crossings of the platform in the electroacupuncture group increased significantly （P＜0.05）. The results of TTC staining showed that the volume of cerebral infarction increased clearly in the model group compared with the sham surgery group （P＜0.05）， and apparently decreased in the electroacupuncture group compared with the model group （P＜0.05）. Golgi staining showed that the number of dendritic branches of pyramidal neurons and dendritic spines in hippocampal CA1 region significantly decreased in the model group compared with the normal group and the sham surgery group （P＜0.05）. The number of dendritic branches of pyramidal neurons and the density of dendritic spines in hippocampal CA1 region significantly increased in the electroacupuncture group compared with the model group （P＜0.05）. The protein relative expression levels of GluR1， GluR2， GluR3， TARPγ2 and TARPγ8， and the mRNA levels of GluR1， GluR2 and GluR3 in hippocampus decreased in the model group compared with the normal group and the sham surgery group （P＜0.05）. The protein relative expression levels of GluR1， GluR2， GluR3， TARPγ2 and TARPγ8， and the mRNA levels of GluR1， GluR2 and GluR3 in hippocampus increased in the electroacupuncture group compared with model group （P＜0.05）. ConclusionThe Tongdu Xingshen needling method can improve learning memory impairment after cerebral ischaemia-reperfusion， which may be related to up-regulation of the expression of AMPA receptor and their auxiliary protein TARP， and promoting the synaptic plasticity of hippocampal tissues.

Mechanism of Bugansan Decoction in ameliorating learning and memory impairment in D-galactose-induced aging rats based on AGEs/RAGE/NF-κB pathway / 数字中医药（英文）

@#Objective To investigate the underlying mechanism of the compound Bugansan Decoction (补肝散, BGSD) in intervening learning and memory in D-galactose (D-gal)-induced aging rats. @*Methods@#A total of 40 rats were randomly assigned to four groups: control, model, BGSD [14.06 g/(kg·d)], and piracetam [0.4 g/(kg·d)] groups, with 10 rats in each group. D-gal [400 mg/(kg·d)] was injected intraperitoneally to establish the aging rat model. The rats' body weight, water intake, food intake, and gripping strength were recorded each week. The eightarm maze and step-down test were used to measure the rats' capacity for learning and memory. Liver, thymus, spleen, and brain tissues were weighed to calculate the corresponding organ indices; serum malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured. Hematoxylin and eosin (HE) staining was adopted to observe the pathological changes of the hippocampus; enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the hippocampus. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of receptors for advanced glycation end products (RAGE), nuclear factor-κB (NF-κB), TNF-α, IL-6, and IL-1β mRNA in the hippocampus. Western blot (WB) was employed to detect the expression levels of advanced glycation end products (AGEs), RAGE, and NF-κB protein in the hippocampus. @*Results@#In D-gal-induced aging rats, BGSD significantly increased food intake, water intake, body weight, gripping strength, and organ indices (P < 0.05), and significantly decreased working memory error (WME), reference memory error (RME), and total memory errors (TE) in an eight-arm maze (P < 0.05). In the step-down test, step-down latency was prolonged and the frequency of errors dropped (P < 0.05). Additionally, BGSD could lessen the harm done to hippocampus neurons, increase serum SOD activity, lower MDA levels, and down-regulate the expression levels of the pro-inflammatory molecules TNF-α, IL-6, and IL-1β (P < 0.05). Further findings showed that BGSD significantly decreased hippocampal AGEs, RAGE, and NF-κB expression (P < 0.05). @*Conclusion@#By blocking the AGEs/RAGE/NF-κB signaling pathway, BGSD may regulate the neuroinflammatory damage in D-gal-induced aging rats, and thus improve learning and memory.

The Memory Orchestra: Contribution of Astrocytes / 神经科学通报·英文版

For decades, memory research has centered on the role of neurons, which do not function in isolation. However, astrocytes play important roles in regulating neuronal recruitment and function at the local and network levels, forming the basis for information processing as well as memory formation and storage. In this review, we discuss the role of astrocytes in memory functions and their cellular underpinnings at multiple time points. We summarize important breakthroughs and controversies in the field as well as potential avenues to further illuminate the role of astrocytes in memory processes.

Contextual Fear Learning and Extinction in the Primary Visual Cortex of Mice / 神经科学通报·英文版

Fear memory contextualization is critical for selecting adaptive behavior to survive. Contextual fear conditioning (CFC) is a classical model for elucidating related underlying neuronal circuits. The primary visual cortex (V1) is the primary cortical region for contextual visual inputs, but its role in CFC is poorly understood. Here, our experiments demonstrated that bilateral inactivation of V1 in mice impaired CFC retrieval, and both CFC learning and extinction increased the turnover rate of axonal boutons in V1. The frequency of neuronal Ca2+ activity decreased after CFC learning, while CFC extinction reversed the decrease and raised it to the naïve level. Contrary to control mice, the frequency of neuronal Ca2+ activity increased after CFC learning in microglia-depleted mice and was maintained after CFC extinction, indicating that microglial depletion alters CFC learning and the frequency response pattern of extinction-induced Ca2+ activity. These findings reveal a critical role of microglia in neocortical information processing in V1, and suggest potential approaches for cellular-based manipulation of acquired fear memory.

Influence of microwave radiation on associative learning and memory function and hippocampal structure in mice / 中华放射医学与防护杂志

Objective:To investigate the effects of microwave radiation on associative learning and memory function and hippocampal structure of mice.Methods:C57BL/6N mice were ramdomly divided into sham-radiated group ( n=27) and radiation group ( n=2). The radiation group was exposed to microwave at 2.856 GHz, 8 mW/cm 2 for 15 min, then their spatial and associative learning and memory function were examined with the morris water maze and shuttle box behavior experiment. The pathological changes of hippocampal tissue were observed by HE staining and light microscope, the ultrastructural changes of hippocampal tissue were observed by transmission electron microscope. Results:After microwave radiation, the times of mice crossing the platform for the reverse space exploration decreased from(3.60±0.79) times to (2.55±0.47) times( t=2.21, P=0.046), the average active escape rate decreased significantly ( t = 2.70, P<0.05), and the average active latency and the total shock time was significantly prolonged ( t = -3.09, -3.02, P < 0.05). At 8 d after microwave radiation, the nuclei of some neurons in the CA3 and DG regions of the hippocampus were pyknosis. The neurons were apoptotic, the synaptic spaces blurred, the glial cells swollen, and the perivascular spaces widened in the CA3 region of the hippocampus. Conclusions:Microwave radiation can decline the spatial reference memory ability and associative learning and memory ability of mice. The morphological and pathological changes of hippocampus are the structural basis of this dysfunction.

Protective effect of overexpression of thioredoxin reductase 1 on hippocampal cells of ovariectomized rats / 中华行为医学与脑科学杂志

Objective:To investigate the effects of thioredoxin reductase 1(TR1) overexpression on hippocampus in ovariectomized SD rats.Methods:Totally 54 female SD rats were divided into normal group, ovariectomized group and ovariectomized over-expressioned TR1 group (ovariectomy-TR1 group) according to the random number table method with 18 in each group. The overexpressed TR1 vector was constructed by lentivirus, and the recombinant lentivirus was injected into the hippocampus by a brain stereotactic instrument.The mRNA levels and protein levels of TR1, Bcl-2, p53 and p21 in the hippocampus of SD rats were detected by qRT-PCR and Western blot.The expression of Caspase-3 in the hippocampus of SD rats was detected by Western blot. The activity of SOD was measured by the WST-1 cell proliferation and cytotoxicity method, the content of GSH was measured by the microplate method, and the content of MDA in the hippocampus of SD rats was measured by the TBA method. The behavioral changes of SD rats were detected by the open field test and water maze test. GraphPad Prism 9.0 was used for statistical analysis.One-way analysis of variance was used for comparisons among the three groups, and the LSD test was used for further pairwise comparisons, the t-test was used to compare the mean number of samples between the two groups. Results:(1) The mRNA and protein levels of TR1 in hippocampus of ovariectomized rats were lower than those of normal rats ( t=3.125, 4.402, both P<0.05). The mRNA and protein levels of TR1 in hippocampus of ovariectomized-TR1 rats were higher than those of ovariectomized rats ( t=4.945, 4.845, both P<0.05). (2) There were significant differences among the three groups in the escape latency in water maze test, the movement distance and the stay time in central area in the open field test ( F=44.73, 33.67, 6.51, all P<0.05), the movement distance in the open field test of ovariectomized rats was more than that of the normal group ((4 700±141) mm, (3 967±163) mm, P<0.05), the stay time in the central area was longer than that of the normal group ((87.33±3.93) s, (80.83±2.48) s, P<0.05), the movement distance ((4 267±150) mm) and the stay time in the central area ((82.17±3.43) s) of ovariectomized-TR1 group were lower than that of ovariectomized group ( P<0.05). In the water maze test, the escape latency of ovariectomized rats was longer than that of the normal group ((28.67±2.50) s, (19.50±2.59) s, P<0.05), and the escape latency in the ovariectomy-TR1 group((25.00±1.67) s) was shorter than that of ovariectomized TR1 group ( P<0.05). (3)There were significant differences in the levels of MDA, SOD and GSH in the hippocampus oxidative stress injury indexes among the three groups ( F=87.41, 91.38, 28.69, all P<0.01). The level of MDA in hippocampus of ovariectomized group was higher than that of normal group, and that in the ovariectomized-TR1 group was lower than that of ovariectomized rats group ( P<0.05). And what's more the levels of SOD and GSH in ovariectomized group were lower than those of normal group ( P<0.05), and the ovariectomized-TR1 group was higher than that of ovariectomized group ( P<0.05). (4) The results of Western blot and RT-PCR showed that the levels of p21 and p53 in hippocampal tissue of ovariectomized group were higher than those of normal group ( P<0.05), while the level of aging-related protein p21 and p53 in ovariectomized-TR1 group were significantly lower than those in ovariectomized group ( P<0.05). The level of apoptotic protein Caspase-3 in the hippocampus of ovariectomized rats was higher than that in the normal group ( P<0.05), while the level of Caspase-3 in ovariectomized-TR1 group was significantly lower than that in ovariectomized rats ( P<0.05). The level of anti-apoptotic protein Bcl-2 in hippocampus of ovariectomized group was lower than that of normal rats ( P<0.05), while the level of Bcl-2 in ovariectomized-TR1 group was significantly higher than that in ovariectomized rats ( P<0.05). Conclusion:Overexpression of TR1 can reduce apoptosis of hippocampal cells by regulating oxidative damage and reducing cell senescence.

Effects of high copper diet on cognitive function and hippocampal synaptic protein in rats / 中华行为医学与脑科学杂志

Objective:To observe the effects of high copper diet on neurobehavioral functions and synaptic associated protein expression in hippocampus of rats.Methods:Thirty male SD rats were randomly divided into control group and high copper diet group with 15 rats in each group according to the random number table method. The rats in control group were fed with ordinary diet and ordinary water, while the rats in high-copper diet group were fed with high-copper diet containing 1 g/kg copper sulfate and 0.185% copper sulfate deionized water for 12 weeks. The content of copper in serum and hippocampus of rats were detected by inductively coupled plasma-atomic emission spectrometry(ICP-AES) and ICP-mass spectrometry(ICP-MS). The neurobehavioral indicators were detected by stereotypic behavior test, open field test and Morris water maze test. The expression levels of microtubule associated protein 2(MAP2) and growth associated protein 43 (GAP43) in hippocampus were detected by Western blot.SPSS 22.0 software was used for statistical analysis, and two independent sample t-test was used for comparison between the two groups. Results:Compared with the control group, the content of serum copper((1.67±0.69)mg/L, (1.98±0.24)mg/L, t=17.53, P<0.05) and hippocampal free copper((3.52±1.24)mg/g, (4.78±0.57)mg/g, t=10.34, P<0.05) in the high copper diet group increased significantly, and the stereotypic behavior score increased significantly ((0.29±0.08), (2.97±0.72), t=14.33, P<0.01), the number of space crossing in the open field experiment ((153.40±24.73)points, (92.46±19.46)points, t=7.50, P<0.01) and the times of standing((19.34±1.98)times, (10.57±2.71)times, t=10.12, P<0.01) were significantly decreased. The average latency in Morris water maze navigation test was significantly prolonged ((3.14±1.67)s, (8.29±2.26)s, t=7.10, P<0.01), the number of crossing the original platform position in the space exploration test decreased significantly ((7.89±2.48)times, (2.98±1.73) times, t=3.23, P<0.01). Compared with control group, protein levels of GAP43((1.03±0.05), (0.48±0.02), t=39.56, P<0.05)and MAP2((0.93±0.05), (0.30±0.08), t=25.86, P<0.05) of high copper diet group were significantly decreased. Conclusion:High copper diet causes abnormality in a variety of neurobehavioral function indexes in rats, and a decrease in expression of MAP2 and GAP43 at the synaptic interface of hippocampal neurons may be involved in the process of learning and memory impairment in the neurobehavioral functions.