Effect of Apelin-13 on behavioral changes and hippocampal autophagy of mice with posttraumatic stress disorder / 中华行为医学与脑科学杂志

Objective:To investigate the effect and the neural mechanisms of Apelin-13 on the behavior changes of posttraumatic stress disorder (PTSD) model mice.Methods:Totally 32 SPF grade male C57BL/6J mice aged 6 weeks were divided into 4 groups randomly ( n=8 in each group): control group, model group, normal saline group and Apelin-13 group.The mice model of PTSD was established by single-prolonged stress (SPS) method. The mice in normal saline group and Apelin-13 group were respectively given lateral ventricular microinjection of 0.9% sodium chloride solution (2 μL) and Apelin-13 (1.5 μg/μL, 2 μL)after PTSD modeling. The behaviors of mice were evaluated by open field test, elevated plus maze test and Morris water maze test.The morphological structure and numerical changes of hippocampal neurons were observed by hematoxylin and eosin (HE) staining.The expression of phosphoinositide 3-kinase(PI3K), phosphorylated-PI3K(p-PI3K), protein kinase B(Akt), phosphorylated-Akt (p-Akt), forkhead box O3a (FoxO3a), phosphorylated-FoxO3a(p-FoxO3a), autophagy-related proteins including microtubule-associated protein 1 light chain 3(LC3) and sequestosome 1(p62) were detected by Western blot. SPSS 26.0 software was used for data analysis.The escape latency data of repeated learning training in Morris water maze was conducted by repetitive measurement ANOVA.The comparison of other data among multiple groups was conducted by one-way ANOVA and further pairwise comparisons were conducted by LSD test and Tamhane test. Result:(1) Open field test results showed statistically significant differences in the central area activity distance and residence time in central area among mice in the four groups ( F=15.37, 9.63, both P<0.05). The central area activity distance ((0.06±0.03) m) and residence time ((2.48±1.02) s) of the mice in model group were lower than those of the control group ((0.19±0.05) m, (15.00±8.91) s)(both P<0.05). And the central area activity distance((0.12±0.04)m)and the residence time((13.56±7.64)s)were higher than those of model group((0.06±0.03)m, (2.48±1.02)s)and normal saline group((0.06±0.02)m, (2.82±1.52)s)(all P<0.05). Elevated plus maze test results showed statistically significant differences in the numbers and time entering open arms among the four groups ( F=10.74, 19.12, both P<0.05). The numbers((4.50±2.51) times) and the time ((26.95±17.48) s) entering the open arm of mice in model group were both lower than those of the control group ((13.75±4.71) times, (103.75±42.43)s) and Apelin-13 group ((10.00±5.18) times, (55.98±19.49) s) (all P<0.05). Morris water maze test results showed that in the 4-day learning and training phase, the time and group interaction of escape latency was not significant among the four groups ( F=1.15, P=0.34), but time main effect and group main effect were significant ( F=131.65, 16.98, both P<0.05). On the 2nd to 4th day, mice in model group showed significantly increased escape latency than mice in control group and Apelin-13 group(both P<0.05). And the numbers crossing original platform and the time in the target quadrant of Apelin-13 group were both higher than those of model group and normal saline group (all P<0.05). (2) HE staining results showed that neurons in the hippocampal CA1 and CA3 area of mice in model group and normal saline group were swollen and arranged loosely.The hippocampal neurons in control group and Apelin-13 group were arranged neatly and densely. (3) Western blot results showed statistically significant differences in the protein expression of p-PI3K, p-Akt, p-FoxO3a, p62 and the ratio of LC3Ⅱ/LC3Ⅰ among the four groups ( F=21.37, 37.35, 20.71, 13.26, 37.65, all P<0.05). The protein expression of p-PI3K, p-Akt, p-FoxO3a and p62 in Apelin-13 group((0.92±0.07), (0.90±0.09), (0.89±0.13), (1.03±0.08)) were higher than those in model group((0.59±0.04), (0.50±0.07), (0.49±0.11), (0.68±0.04)) and normal saline group((0.61±0.06), (0.50±0.08), (0.53±0.11), (0.70±0.05))(all P<0.05), and the ratio of LC3Ⅱ/LC3Ⅰ in Apelin-13 group(0.60±0.06) was lower than those in model group(0.92±0.10) and normal saline group(0.99±0.05) (both P<0.05). Conclusion:Apelin-13 can alleviate the anxiety-like behavior and impaired spatial learning and memory in PTSD model mice. The mechanism may be related to the up-regulation of PI3K/Akt/FoxO3a autophagy pathway.

Expression of synapse-related proteins in hippocampus of rats with epilepsy accompanied by depression / 中华行为医学与脑科学杂志

Objective:To investigate the expression of hippocampal synapse-related proteins including synaptophysin (SYN), postsynaptic density protein 95 (PSD95) and growth-associated protein 43 (GAP43) in rats with epilepsy accompanied by depression.Methods:The 3-month-old female clean grade SD rats were selected for the experiment.Lithium chloride pilocarpine was used to establish an epileptic rat model. Rats with successful epilepsy models were divided into epileptic depressive group (EWD group)and epileptic group with 10 in each group based on whether they were accompanied by depression. Furthermore, ten rats with matched body mass were taken as the depressive group and 10 were taken as control group. As for the depressive group rats, chronic unpredictable mild stress stimulation combined with orphanage was adopted to establish a model of depression.The depressive behaviors of rats were evaluated by body mass, sucrose preference test and open field test. Immunohistochemical staining and Western blot were used to detect the expression of SYN, PSD95 and GAP43 proteins in rat hippocampal tissue. SPSS 17.0 software was used for data statistical analysis, repeated measurement ANOVA was used for behavioral results, one-way ANOVA was used for inter group comparison of protein expression data, and LSD test was used for further pairwise comparison.Results:As for the body mass, there was significant interaction effect between the time and group among the 4 groups ( F=7.33, P<0.01). On the 8th day and the 29th day, the body weight of rats in the EWD group and the depressive group were lower than those in the epilepsy group (all P<0.05). The body weight of rats in the EWD group on the 29th day was lower than that on the first day ( P<0.05). As for the sucrose preference rates, there was significant interaction effect between the time and group among the 4 groups( F=2.67, P<0.05). The sucrose preference rate of EWD group on the15th and 29th day were lower than that on the first day (both P<0.05). The results of the open field test showed that the interaction effects of the number of vertical standing times( F=2.74) and the number of horizontal movement lattices ( F=1.76) both were not significant (both P>0.05), but both the time effect and group effect were significant (vertical standing times: Ftime=4.35, P<0.05, Fgroup=25.64, P<0.01; horizontal movement lattices: Ftime=12.75, P<0.01, Fgroup=21.37, P<0.01). The immunohistochemical results showed that there was a statistically significant difference in the number of positive cells expressing synaptic proteins SYN, PSD95 and GAP43 among the four groups of rats ( F=93.85, 58.66, 98.84, all P<0.05). The numbers of positive cells of SYN (11.73±4.30), PSD95 (24.47±7.58) and GAP43 (9.40±3.50) in the epilepsy group were lower than those in the control group ((51.00±15.39), (55.60±13.17) and (29.53±4.05)) (all P<0.05). The numbers of positive cells of SYN (5.80±3.53), PSD95 (12.87±4.03) and GAP43 (5.33±3.50) in the EWD group were lower than those in the depressive group ((11.33±3.22), (48.13±12.69) and (15.47±5.21) )(all P<0.05). Western blot results showed that there were statistically significant differences in the expression of synaptic proteins SYN, PSD95 and GAP43 among the four groups of rats ( F=13.19, 9.38, 16.80, all P<0.05). The expression levels of SYN, PSD95 and GAP43 in the epilepsy group were lower than those in the control group (all P<0.05). The expression levels of SYN, PSD95 and GAP43 in the EWD group were lower than those in the epilepsy group and the depressive group (all P<0.05). Conclusion:The low expression of SYN, PSD95 and GAP43 proteins in the hippocampus of rats with epilepsy accompanied by depression may be related to their pathogenesis.

Effects of hesperetin on memory function and apoptosis-related protein expression in senile model rats / 中华行为医学与脑科学杂志

Objective:To investigate the effect and mechanism of different doses of luteolin on memory function and apoptosis-related proteins of aging rats induced by D-galactose.Methods:Forty-eight SPF-grade male Wistar rats aged 6-8 weeks were randomly divided into control group, model group, luteolin low-dose group (25 mg/kg), medium-dose group (50 mg/kg), high-dose group (100 mg/kg), and vitamin C group (100 mg/kg), with 8 rats in each group. D-galactose (1 000 mg/kg) was subcutaneously injected to establish the aging rat model, while luteolin was used for preventive treatment. The Morris water maze test was used to evaluate the learning and memory abilities of the rats.Transmission electron microscopy was used to detect the morphology of hippocampal neurons in rats.Spectrophotometry was used to detect the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), superoxide dismutase (SOD), malondialdehyde (MDA), and the total antioxidant capacity (T-AOC). RT-PCR was used to detect miR-34a mRNA expression.Western blot technique was used to detect the expression levels of silent regulator protein 1 (SIRT1), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3, p53, and p21. Statistical analysis was performed using SPSS 22.0, and one-way ANOVA was used for multi-group comparison, followed by LSD- t test for further pairwise comparisons. Results:(1) The differences in escape latency among the 6 groups of rats were statistically significant ( F=120.93, P<0.001). The latency of first finding the platform location of the model group rats ((54.61±3.60) s) was higher than that of the control group ((10.54±4.27) s) ( P<0.05). The latency of first finding the platform location of rats in the low, medium and high dosage groups of luteolin ((45.50±3.81)s, (37.46±2.94) s, (32.32±3.14) s) was lower than that of the model group ((54.61±3.60) s) (all P<0.05). (2) The differences of SOD, MDA, T-AOC, TNF-α, IL-1β, and IL-6 levels in the cerebral cortex of the 6 groups of rats were all statistically significant ( F=281.636, 75.119, 208.228, 38.999, 28.428, 52.767, all P<0.001). Compared with the control group, the model group showed abnormal levels of inflammatory factors and antioxidant indexes. In the medium and high dosage groups of luteolin, the SOD and T-AOC contents in the cerebral cortex of rats were higher than those in the model group (all P<0.05), while the levels of MDA, TNF-α, IL-1β, and IL-6 were lower than those in the model group (all P<0.05). (3) The differences in relative expression levels of miR-34a mRNA among the 6 groups of rats were statistically significant ( F=81.439, P<0.001). The expression levels of miR-34a mRNA in the hippocampal tissues of rats in the luteolin treatment group were lower than those in the model group ( P<0.05). (4) The differences in protein expression levels of SIRT1, p53, and p21 in the hippocampal tissues of the 6 groups of rats were statistically significant ( F=159.946, 38.342, 123.608, all P<0.001). The expression levels of p53 and p21 in the medium and high dosage groups of luteolin were lower than those in the model group (all P<0.05), while the expression level of SIRT1 protein was higher than that in the model group ( P<0.05). (5) The differences in protein expression levels of Bcl-2 and cleaved caspase-3 in the hippocampal tissues of the 6 groups of rats were statistically significant ( F=112.659, 43.296, both P<0.05). The expression levels of Bcl-2 in the low, medium, and high dosage groups of luteolin ((0.24±0.04), (0.40±0.03), (0.48±0.05) pg/μg) were higher than those in the model group ((0.09±0.06) μg) ( P<0.05), while the expression levels of cleaved caspase-3 in the low, medium, and high dosage groups of luteolin ((0.62±0.04), (0.61±0.09), (0.51±0.10) μg) were lower than those in the model group ((0.75±0.05) μg) ( P<0.05). Conclusions:Luteolin can alleviate cellular oxidative damage through downregulating the miR-34a SIRT1/p53 signaling pathway and reducing cell apoptosis.

Sodium cyanide exacerbates hypoxia induced brain nerve damage in mice and its mechanism / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect and mechanism of acute exposure to sodium cyanide(NaCN)on brain nerve damage induced by closed hypoxia in mice.METHODS ① Mice were randomly divided into hypoxia+NaCN 0(hypoxia control group),2.56,3.8,and 5.1 mg·kg-1 groups.After ip adminis-tration of different concentrations of NaCN,the mice were immediately placed into a closed hypoxic tank and the hypoxia survival time was observed.②Mice were divided into normal control,NaCN 3.8 mg·kg-1,hypoxia(30 and 60 min)and NaCN 3.8 mg·kg-1+hypoxia(30 and 60 min)groups.After grouping,the pH,oxygen saturation(sO2),oxygen tension(pO2)and carbon dioxide partial pressure(pCO2)of arterial blood of mice were detected using an arterial blood gas analyzer.The cortical cerebral blood flow of mice was detected using a laser speckle imager.The dry and wet brain tissue were weighed separately,and the brain moisture content was calculated.The kit was used to detect the activity of total superoxide dismutase(T-SOD)and the content of malondialdehyde(MDA)in the hippocampus.TUNEL staining was used to detect the apoptosis rate of cells in the hippocampus.HE staining was used to detect path-ological changes in the hippocampus.RESULTS ①Compared with the hypoxic control group,the sur-vival time of mice in the hypoxic+NaCN groups was significantly prolonged(P<0.01).②Compared with the normal control group,the hypoxia 30 min group showed upregulation of arterial blood p CO2(P<0.05),downregulation of p O2(P<0.05).The hypoxia 60 min group showed upregulation of arterial blood p CO2(P<0.05)and downregulation of cortical cerebral blood flow(P<0.05).In the NaCN 3.8 mg·kg-1 group,arterial blood p O2 and s O2 were significantly downregulated(P<0.05),so was cortical cerebral blood flow(P<0.01),but MDA content and T-SOD activity were significantly upregulated(P<0.01),and the brain moisture content was increased(P<0.01).Compared with the hypoxia 30 min group,s O2 and p O2 of arterial blood in the NaCN+hypoxia 30 min group were significantly upregulated(P<0.05),while p CO2 was significantly downregulated(P<0.05).Compared with the hypoxia group at corresponding time points,the NaCN+hypoxia 30 or 60 min groups showed significant downregulation of cerebral blood flow(P<0.01),significant upregulation of MDA content and T-SOD activity(P<0.01),and signifi-cant upregulation of brain moisture content(P<0.01).HE staining results showed that the NaCN 3.8 mg·kg-1 group and the NaCN+hypoxia group(30 or 60 min)showed significant cell swelling and vacuolization in cells in the hippocampal tissue,a decrease in the number of neurons,nuclear pyknosis and deep staining.TUNEL fluorescence results showed that the NaCN 3.8 mg·kg-1 group significantly increased the apop-tosis rate of the mouse hippocampus compared with the normal control group(P<0.05).The NaCN+ hypoxia 30 and 60 min groups significantly increased the apoptosis rate of the mouse hippocampus compared with the hypoxia group at corresponding time points(P<0.05).CONCLUSION NaCN can exacerbate hypoxia induced decrease in cerebral blood flow,oxidative stress in brain tissue,and neuro-nal apoptosis in mice,thereby reducing oxygen consumption in closed hypoxic tanks and prolonging their survival time.The mechanism is related to reduced utility of cell oxygen,delaying CO2 accumulation and increasing free oxygen in vivo.

Effects of Electroacupuncture on the Hippocampus Glutamate System of Acute Myocardial Ischemia Rats / 中国中医药信息杂志

Objective To observe the effects of electroacupuncture(EA)on glutamate(Glu),metabotropic glutamate receptor 2/3(mGluR2/3)and apoptosis related proteins expression in hippocampus in rats with acute myocardial ischemia(AMI);To explore the mechanism of EA against AMI.Methods Totally 50 SD rats were randomly divided into sham-operation group,model group,EA group and inhibitor group,with 10 rats in each group.Except for the sham-operation group,the rats were treated with ligation at the left anterior descending coronary artery to establish AMI model.The rats in the EA group was treated with EA at"Shenmen"and"Tongli",30 minutes each time,once a day for 3 consecutive days.The rats in the inhibitor group were treated with injection of LY341459 via the lateral ventricle 30 min after modeling.HE staining was used to observe myocardial tissue morphology,and ELISA was used to detect Caspase-3 activity in myocardial tissue and Glu content in hippocampal tissue,immunofluorescence staining was used to detect mGluR2/3 expression in hippocampal tissue,TUNEL staining was used to detect apoptosis in hippocampal tissue cells,Western blot was used to detect the expressions of PI3K,Akt,and Caspase-3 protein in hippocampal tissue.Results Compared with the sham-operation group,the myocardial cells of the model group rats showed sparse and swelling with severe infiltration of inflammatory cells;the activity of Caspase-3 in myocardial tissue significantly increased,and the Glu content,positive expression of mGluR2/3,number of apoptotic cells in hippocampal tissue significantly increased(P<0.01),and the expressions of PI3K and Akt proteins in hippocampal tissue were significantly decreased,while the expression of Caspase-3 protein significantly increased(P<0.01).Compared with the model group,myocardial cell edema and inflammatory cell infiltration were reduced in the EA group and inhibitor group,the activity of Caspase-3 in myocardial tissue was significantly decreased,the Glu content,positive expression of mGluR2/3,and number of apoptotic cells in hippocampal tissue were significantly reduced(P<0.01),the expressions of PI3K and Akt proteins in hippocampal tissue significantly increased,while the expression of Caspase-3 protein significantly decreased(P<0.01).Conclusion EA can improve myocardial injury in AMI rats,and its mechanism may be related to activation of PI3K/Akt signaling pathway,inhibition of hippocampal mGluR2/3 overexpression,reduction of Glu accumulation,inhibition of apoptosis of hippocampal neurons and reduction of neurotoxicity.

Effects of Regulation of SHH/Gli1 Signaling Pathway by Baishile Capsules on Hippocampal Neurogenesis Depression Model Rats / 中国中医药信息杂志

Objective To explore the effects and mechanism of Baishile Capsules regulating SHH/Gli1 signaling pathway on hippocampal neurogenesis of depression model rats.Methods Totally 32 SD rats were randomly divided into control group,model group,fluoxetine(5.4 mg/kg)group and Baishile Capsules(2.88 g/kg)group,with 8 rats in each group.A depression rat model was established using chronic unpredictable mild stress and single cage feeding method.The model was established and administered simultaneously for 21 consecutive days.Depression-like behavior in rats were evaluated by sucrose preference experiment and open field experiment,ELISA was used to detect brain derived neurotrophic factor(BDNF)contents in rat serum and hippocampal tissue,the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus was observed by immunofluorescence,immunofluorescence and Western blot were used to detect the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue.Results Compared with the control group,the degree of sucrose preference significantly decreased in the model group(P<0.01),the number of horizontal and vertical movements significantly decreased(P<0.01),the contents of BDNF in serum and hippocampal tissue significantly decreased(P<0.05),the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly decreased(P<0.01),and the fluorescence intensity and protein expression of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly decreased(P<0.01,P<0.05).Compared with the model group,the degree of sucrose preference and the number of horizontal and vertical movements in fluoxetine group and Baishile Capsule group increased significantly(P<0.05,P<0.01),the contents of BDNF in serum and hippocampal tissue significantly increased(P<0.05,P<0.01),and the number of BrdU,BrdU/DCX,BrdU/NeuN positive cells in dentate gyrus of the hippocampus significantly increased(P<0.01,P<0.05),the fluorescence intensity and protein expressions of SHH,Gli1,Smo,Ptch in hippocampal tissue significantly increased(P<0.01,P<0.05).Conclusion Baishile Capsule can promote the hippocampus neurogenesis in depression model rats by regulating SHH/Gli1 signaling pathway,and play an antidepressant role.

Application of optimized hippocampus-avoidance prophylactic cranial irradiation in limited-stage small cell lung cancer / 中华放射肿瘤学杂志

Objective:To analyze the treatment efficacy, safety and dose parameters of optimized hippocampus-avoidance prophylactic cranial irradiation (HA-PCI) in limited-stage small cell lung cancer (LS-SCLC) and explore the corresponding dosimetric parameters under the condition of narrowing the hippocampus avoidance region as hippocampus region plus 2 mm in three dimensions.Methods:Clinical data of patients with LS-SCLC receiving HA-PCI (hippocampus avoidance region defined as hippocampus region plus 2 mm in three dimensions) in Cancer Hospital Chinese Academy of Medical Sciences from August 2014 to June 2020 were retrospectively analyzed. Dose parameters of HA-PCI and adverse events were analyzed using descriptive statistics analysis. Changes of neurocognitive function, such as mini-mental state examination (MMSE) and Hopkins verbal learning test-revised (HVLT-R) scores, were evaluated by analysis of variance and Kruskal-Wallis H test. Overall survival (OS), progression-free survival (PFS) and intracranial PFS (iPFS) were calculated using Kaplan-Meier method. The cumulative incidence of local-regional recurrence (LRR), extracranial distant metastases (EDM), and locoregional recurrence (LR) were investigated under competing risk analysis. Results:A total of 112 patients were included, the median follow-up time was 50 months (95% CI: 45.61-54.38). The median volume of hippocampus was 4.85 ml (range: 2.65-8.34 ml), with the average dose ≤9 Gy in 106 patients (94.6%), ≤8 Gy in 92 patients (82.1%). The median volume of hippocampus avoidance area was 15.00 ml (range: 8.61-28.06 ml), with the average dose ≤12 Gy in 109 patients (97.3%), ≤10 Gy in 101 patients (90.2%). The 2-year cumulative LRR, EDM, LR rates were 16.9%, 23.2% and 28.5%, respectively. The 5-year cumulative LRR, EDM, LR rates were 23.2%, 26.9% and 33.3%, respectively. The 2-year iPFS, PFS and OS rates were 66.1% (95% CI: 57.9%-75.4%), 53.6% (95% CI: 45.1%-63.7%) and 80.4% (95% CI: 73.3%-88.1%), respectively. The most common grade I-Ⅱ adverse events were nausea (33.9%) and dizziness (31.3%), and only 1 patient developed grade Ⅲ nausea and dizziness. MMSE ( n=57) and HVLT-R tests ( n=56) showed no significant decline. Conclusions:Optimized HA-PCI can achieve similar dose limitation with favorable efficacy and light toxicity. No significant decline is observed in short-term neurocognitive function in evaluable patients.

Intervention effect of HSP60 on learning and memory impairment induced by combined exposure to lead and hypertension in mice / 中国职业医学

ObjectiveTo investigate the intervention effect of heat shock protein 60 (HSP60) on learning and memory impairment induced by combined exposure to lead and hypertension in mice, and the relative mechanism of triggering receptor expressed on myeloid cells 2 (TREM2). Methods Specific pathogen-free C57BL/6J male mice were randomly divided into control group, hypertension group, lead-exposed group and lead-exposed + hypertension group, or into control group, heat shock protein 60 (HSP60) control group, lead-exposed + hypertension group and HSP60 intervention group, with 10 mice in each group. Mice of hypertension group and lead-exposed + hypertension group were intraperitoneally injected with angiotensin Ⅱ at a dose of 0.5 mg/(kg·d) for seven consecutive days to induce hypertension model. Mice of the lead-exposed group, lead-exposed + hypertension group, and HSP60 intervention group were given lead acetate drinking water with a mass concentration of 250.0 mg/L, while mice in the control group, hypertension group, and HSP60 control group were given purified water for 12 weeks. Mice of the HSP60 control group and HSP60 intervention group were intraperitoneally injected with a solution of HSP60 at a dose of 4 mg/kg body weight, every other day for a total of three times at the 12th week. The learning and memory ability of mice was detected using the Morris water maze test. The enzyme-linked immunosorbent assay was used to detect the levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in the hippocampal tissues of the mice. The relative expression of ionized calcium binding adaptor molecule-1 (IBA1) and TREM2 protein in the hippocampus of mice was detected using Western blot. Results i) The number of platform crossings of the mice in the hypertension group and the lead-exposed group was lower than that in the control group (both P<0.05). The escape latency of the mice on the third day was longer and the number of platform crossings was lower in the lead-exposed + hypertension group compared with the control group, hypertension group and lead-exposed group (all P<0.05). The levels of IL-1β, IL-6, and TNF-α in the hippocampus of the other three groups increased compared with the control group (all P<0.05). The relative expression of IBA1 protein in the hippocampus of lead-exposed group and lead-exposed + hypertension group increased (all P<0.05), while the relative protein expression of TREM2 decreased compared with the control group (all P<0.05). The levels of IL-1β, IL-6, TNF-α, and the relative protein expression of IBA1 protein in the hippocampus of the lead-exposed+hypertension group were higher (all P<0.05), and relative expression of TREM2 protein was lower (P<0.05) than those in the hypertension group. The level of TNF-α and the relative expression of IBA1 protein in the hippocampus of lead-exposed+hypertension group were higher than those in lead-exposed group (all P<0.05). ii) The escape latency of mice in the lead-exposed + hypertension group was longer than that in the control group (P<0.05), and the number of platform crossings was fewer than that in the control group (P<0.05). The escape latency of mice in the HSP60 intervention group was shortened (P<0.05), the number of platform crossings increased (P<0.05), and the levels of IL-1β, IL-6, TNF-α and relative expression of IBA1 protein decreased in the hippocampus (all P<0.05), while the relative expression of TREM2 protein increased (P<0.05) compared with the lead-exposed+hypertension group. Conclusion Combined exposure of lead and hypertension has a synergistic effect on learning and memory impairment in mice. The mechanism may be related to the inhibition of TREM2 expression by lead in the hippocampus of hypertensive mice and aggravating the neuroinflammatory response. Intervention with TREM2 receptor agonist HSP60 can alleviate learning and memory impairment in mice exposed to lead and hypertension by up-regulating TREM2 expression in the hippocampus.

The Mechanism of miR-124 in Depression / 生物化学与生物物理进展

Depression is a prevalent mental illness worldwide, its multifaceted pathogenesis is still in the exploratory stage. MicroRNA (miRNA), as a crucial epigenetic regulator, plays an important role in depression. miR-124 is one of the most abundant miRNAs in the central nervous system including neurons and microglia, and involved in various biological events like neuron development and differentiation, synaptic and axonal growth, neural plasticity, inflammation and autophagy. Recent studies have reported abnormal expression of miR-124 in both depression patients and animal models. Most of the studies showed that miR-124 is upregulated in the hippocampus or prefrontal cortex in stress-induced rodent depression animal models such as CUMS, CSDS, CORT, CRS and LH but some evidence for divergence. Upregulation of miR-124 expression may be involved in depression-like behavior via CREB/BDNF/TrkB pathway, GR pathway, SIRT1 pathway, apoptosis and autophagy pathways by directly targeting these genes including Creb, Bdnf, Sirt1, Nr3c1, Ezh2 and Stat3. The downregulation of miR-124 expression in neurons is mainly involved in the neurogenesis and neuroplasticity impairments in depression by targeting the Notch signaling pathway and DDIT4/TSC1/2/mTORC1 pathway. The downregulation of miR-124 expression also was found in the activated microglia in the stress-induced models, and resulted in neuroinflammation. In summary, the abnormal expression of miR-124 in the brain of depression-related models and its related mechanisms are complex and even contradictory, and still need further research. This review provides a summary of the research progress of miR-124 in depression.

Exercise induction at expression immediate early gene (c-Fos, ARC, EGR-1) in the hippocampus: a systematic review / Indução de exercício físico na expressão do gene precoce imediato (c-Fos, ARC, EGR-1) no hipocampo: uma revisão sistemática

ABSTRACT. The immediate early gene exhibits activation markers in the nervous system consisting of ARC, EGR-1, and c-Fos and is related to synaptic plasticity, especially in the hippocampus. Immediate early gene expression is affected by physical exercise, which induces direct ARC, EGR-1, and c-Fos expression. Objective: To assess the impact of exercise, we conducted a literature study to determine the expression levels of immediate early genes (ARC, c-Fos, and EGR-1). Methods: The databases accessed for online literature included PubMed-Medline, Scopus, and ScienceDirect. The original English articles were selected using the following keywords in the title: (Exercise OR physical activity) AND (c-Fos) AND (Hippocampus), (Exercise OR physical activity) AND (ARC) AND (Hippocampus), (Exercise OR physical activity) AND (EGR-1 OR zif268) AND (Hippocampus). Results: Physical exercise can affect the expression of EGR-1, c-Fos, and ARC in the hippocampus, an important part of the brain involved in learning and memory. High-intensity physical exercise can increase c-Fos expression, indicating neural activation. Furthermore, the expression of the ARC gene also increases due to physical exercise. ARC is a gene that plays a role in synaptic plasticity and regulation of learning and memory, changes in synaptic structure and increased synaptic connections, while EGR-1 also plays a role in synaptic plasticity, a genetic change that affects learning and memory. Overall, exercise or regular physical exercise can increase the expression of ARC, c-Fos, and EGR-1 in the hippocampus. This reflects the changes in neuroplasticity and synaptic plasticity that occur in response to physical activity. These changes can improve cognitive function, learning, and memory. Conclusion: c-Fos, EGR-1, and ARC expression increases in hippocampal neurons after exercise, enhancing synaptic plasticity and neurogenesis associated with learning and memory.

RESUMO. O gene precoce imediato (GPI) exibe marcadores de ativação no sistema nervoso constituídos por ARC, EGR-1 e c-Fos e está relacionado à plasticidade sináptica, especialmente no hipocampo. A expressão do GPI é afetada pelo exercício físico, que induz a expressão direta de ARC, EGR-1 e c-Fos. Objetivo: Para avaliar o impacto do exercício físico, realizamos um estudo de literatura para determinar os níveis de expressão dos GPIs (ARC, c-Fos e EGR-1). Métodos: A base de dados utiliza literatura on-line, PubMed-Medline, Scopus e ScienceDirect. O artigo original em inglês usa as seguintes palavras-chave em seu título: (Exercise) AND (c-Fos) AND (Hippocampus), (Exercise) AND (ARC) AND (Hippocampus), (Exercise) AND (EGR-1) AND (Hippocampus). Resultados: O exercício físico pode afetar a expressão de EGR-1, c-fos e ARC no hipocampo, uma parte importante do cérebro envolvida na aprendizagem e na memória. O exercício físico aumenta a expressão do gene c-Fos; sua alta intensidade pode aumentar a expressão de c-Fos, indicando ativação neural. Além disso, a expressão do gene ARC aumentou devido ao exercício físico, onde ARC é um gene que desempenha um papel na plasticidade sináptica e na regulação da aprendizagem e da memória, nas mudanças na estrutura sináptica e no aumento das conexões sinápticas, enquanto o EGR-1 também desempenha um papel na plasticidade sináptica, uma mudança genética que afeta o aprendizado e a memória. De maneira geral, o exercício físico regular pode aumentar a expressão de ARC, c-fos e EGR-1 no hipocampo. Isso reflete as mudanças na neuroplasticidade e na plasticidade sináptica que ocorrem em resposta à atividade física. Essas mudanças podem melhorar a função cognitiva, o aprendizado e a memória. Conclusão: A expressão de c-Fos, EGR-1 e ARC aumenta após o exercício físico nos neurônios do hipocampo, para aumentar a plasticidade sináptica, a neurogênese associada ao aprendizado e à memória.

Effects of Ziziphi Spinosae Semen-Albiziae Flos on the IRE1α/ASK1/JNK Pathway of Endoplasmic Reticulum Stress in Hippocampus of Depression Model Rats / 中药新药与临床药理

Objective Based on the endoplasmic reticulum stress(ERS)inositol-requiring enzyme-1α(IRE1α)/apoptosis signal-regulated kinase 1(ASK1)/c-Jun N-terminal kinase(JNK)pathway to investigate the intervention effect of Ziziphi Spinosae Semen(ZSS)-Albiziae Flos(AF)on the depression model of rats,which were prepared by solitary rearing combined with chronic unpredictable mild stress(CUMS).Methods A total of 144 rats were randomly divided into normal group,model group,high-,medium-and low-dose groups of ZSS-AF,and Venlafaxine group.In addition to the normal group,the rats in other groups were isolated for 21 days combined with CUMS to prepare the depression model.The behavioral changes of rats were observed by open field test and Morris water maze test.The ultrastructural changes of hippocampal neurons were observed by transmission electron microscope.TUNEL staining was used to observe the apoptosis of nerve cells in hippocampus.The protein expression levels of IRE1α,phosphorylated(P)-IRE1α,ASK1,P-ASK1,JNK,P-JNK,B cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax)and cysteme aspartate specific protease-3(Caspase-3)in hippocampus were detected by Western Blot.The mRNA expression levels of IRE1α,ASK1,JNK,Bax,Bcl-2 and Caspase-3 in hippocampus were detected by Real-Time PCR.Results Compared with the normal group,the scores of horizontal movement and vertical movement in the open field test of rats in the model group were decreased(P＜0.01).In the water maze test,the escape latency was increased and the number of crossing the original platform was decreased(P＜0.01).The number of hippocampal apoptosis was increased(P＜0.01).The protein expression levels of P-IRE1 α/IRE1 α,P-ASK1/ASK1,P-JNK/JNK,Bax,Caspase-3 and mRNA expressions of IRE1α,ASK1,JNK,Bax,Caspase-3 in hippocampus were increased,while the protein and mRNA expression levels of Bcl-2 were decreased(P＜0.01).Compared with model group,the scores of horizontal movement and vertical movement in the open field test of rats in each dose ZSS-AF groups and Venlafaxine group were increased(P＜0.01).In the water maze test,the escape latency was decreased and the times of crossing the original platform was increased(P＜0.01).The number of hippocampal apoptosis was decreased(P＜0.01).The mRNA expression levels of P-IRE1α/IRE1α,P-ASK1/ASK1,P-JNK/JNK,Bax,Caspase-3 protein and IRE1α,ASK1,JNK,Bax,Caspase-3 in hippocampus were decreased,while the protein and mRNA expression levels of Bcl-2 were increased(P＜0.05,P＜0.01).The effect of medium-dose ZSS-AF group was better than that of high-and low-dose groups.Conclusion ZSS-AF may play an antidepressant role by regulating IRE1α/ASK1/JNK pathway of endoplasmic reticulum stress.

Expression profile analysis of long non-coding RNAs in hippocampus of alcohol-dependent mice induced by double-bottle selective drinking / 中国生物制品学杂志

@#Objective To analyze the expression profiles of long non-coding RNAs(lncRNA)in hippocampus of alcoholdependent mice induced by double-bottle selective drinking.Methods The alcohol-dependent mouse model was established by double-bottle selective drinking method,and the control group was set up(drinking water). Three male mice with alcohol preference more than 60% and alcohol consumption more than 10 g/(kg·24 h)in alcohol group and random three male mice in control group were selected,of which bilateral hippocampal brain tissues were isolated and stored in liquid nitrogen. LncRNA and mRNA of mouse hippocampal brain tissue RNA samples were sequenced by using Agilent-084388 microarray,and the differential expression of lncRNA in samples was detected by using ncRNA microarray. The biological processes and signaling pathways involved in differential expression of lncRNA were clustered and enriched by Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis. Pearson correlation analysis was used to predict the coding genes co-expressed by each differentially expressed lncRNA. Hypergeometric distribution test was used to calculate the significance of differential gene enrichment in each corresponding transcription factor item,and Cytoscape software was used to draw a visual network diagram.Results Compared with the control group,totally 855 lncRNAs(FC ≥ 2. 0,P < 0. 05)were differentially expressed in the hippocampus of mice in alcohol group,of which 337 lncRNAs were up-regulated significantly,with NONMMUT025786.2 and NONMMUT072246.2 being the most up-regulated,and 518 significant downward adjustments were observed,with the largest downward adjustments being NONMMUT113098.1 and NONMMUT076455.1. There were 361 mRNAs differentially expressed in the two groups(FC ≥ 2. 0,P < 0. 05)with 271 mRNAs up-regulated significantly and 90 significant downward adjustments,among which,the most obvious up-regulated were Upf3b and Zfp943,and Adamts 13 and Ift 27 showed the largest downward adjustments. The differential expression of lncRNAs was most obvious in the positive regulation of cell surface,GTPase activity and cell vesicle transport;The main signaling pathways involved were propanoate metabolism,taurine metabolism,extracellular matrix receptor interaction and AMPK signaling pathway. The most abundant transcription factors were FOXL1 and LHX3,with 25 and 21 corresponding co-expressed genes,respectively.Conclusion Through high-throughput gene expression profile microarray analysis,the possible key regulatory sites of lncRNAs and mRNAs were obtained,which provided experimental basis for research of the molecular mechanism of alcohol dependence in the hippocampus.

Recent advance in multimodal magnetic resonance imaging of the hippocampus and its circuits in cognitive impairment / 中华神经医学杂志

The hippocampus and its circuits play crucial roles in human learning, memory, and emotional regulation. Whether it is vascular cognitive impairment (VCI) or Alzheimer's disease (AD), damage to the hippocampus is a prominent pathological feature. This review summarizes the recent advance in multimodal magnetic resonance imaging in anatomy, blood supply, structure and function of the hippocampus and the circuits related to VCI and AD in recent years, aiming to provide help in early recognizing and differentially diagnosing VCI and AD.

Effect and Mechanism of Epigallocatechin-3-gallate on Learning and Memory Abilities of Epileptic Rats / 中国实验方剂学杂志

ObjectiveTo investigate the effects of epigallocatechin-3-gallate （EGCG） on learning and memory abilities of amygdala electrical kindling-induced epilepsy in rats and its mechanism. MethodMale SD rats were randomly divided into the normal group， model group， intervention group （model+25 mg·kg-1 EGCG）， and EGCG group （25 mg·kg-1 EGCG）. Rats in the EGCG group were only given EGCG intraperitoneal injection， those in the normal group were only given electrode implantation， and those in the other experimental groups were given amygdala electrical kindling stimulation to establish a chronic kindling epilepsy model. EGCG was injected intraperitoneally daily before electrical stimulation. Twenty-four hours after the last electrical stimulation， the escape latency and percentage of target quadrant were recorded by the Morris water maze. Twenty-four hours after the behavioral test， rats in each group were sacrificed by decapitation. The number of hippocampal neurons was observed by Nissl staining. The thickness of postsynaptic density in the hippocampus， synaptic cleft， length of active zone and the curvature of synaptic interface were observed by transmission electron microscopy （TEM）. The expressions of synapse-related proteins synaptotagmin （Syt）， postsynaptic density-95 （PSD-95） and Kalirin-7 in the hippocampus were examined by Western blot. ResultCompared with those in the normal group， the escape latency was significantly prolonged （P<0.05， P<0.01） and the target quadrant ratio was significantly decreased in the model group （P<0.05）. The number of hippocampus neurons decreased significantly （P<0.01）. The synaptic cleft of the hippocampus was widened significantly， and the length of active zone and the thickness of postsynaptic density were significantly decreased （P<0.05， P<0.01）. The expressions of synapse-related proteins Syt， PSD-95 and Kalirin-7 in the hippocampus were significantly decreased （P<0.05，P<0.01）. Compared with those in the model group， the escape latency was significantly shortened and the percentage of target quadrant was significantly increased in the intervention group （P<0.05， P<0，01）. The number of hippocampal neurons significantly increased （P<0.01）. The synaptic cleft of the hippocampus was significantly shortened， and the length of active zone and postsynaptic density were significantly increased （P<0.05， P<0.01）. The expressions of synaptic related proteins Syt， PSD-95 and Kalirin-7 were significantly increased （P<0.05， P<0.01）. ConclusionEGCG can effectively improve cognitive dysfunction after epilepsy. Its protective effect may be achieved by protecting the ultrastructure of hippocampal synapses and regulating the expressions of synapse-related proteins Syt， PSD-95 and Kalirin-7.

Effects of Lactobacillus Rhamnosus GG on Activated Microglia and Tau Phosphorylation in the Hippocampus of Aged Mice Induced by Anesthesia and Surgery / 中山大学学报(医学科学版)

ObjectiveTo investigate the effects of Lactobacillus rhamnosus GG （LGG）on microglia and Tau phosphorylation in the hippocampus of aged mice induced by anesthesia and surgery. MethodsA total of thirty 18-month-old C57BL/6J mice were randomly divided into three groups： control group， anesthesia surgery group， and anesthesia surgery + LGG group （10 mice/group）. The aged mice were oral administered by NS or LGG 109 CFU 150 μL once a day for 20 days. Then anesthesia surgery group and anesthesia surgery +LGG group received anesthesia with isoflurane and exploratory laparotomy. The activation status of microglia in the hippocampus was detected by immunofluorescence staining 12 hours after surgery. IL-6 concentration changes was detected by ELISA. The expression changes of Tau protein phosphorylation site （Tau-pS202/pT205） and total Tau protein was detected by western blot. ResultsThe microglia in the hippocampus of the control group were in a resting state， and the concentration of inflammatory factor IL-6 was （82.08 ± 12.07） pg/mL in control group. Compared to the control group， the anesthesia surgery group showed microglial cell Microglia were activated， the concentration of inflammatory factors IL-6 increased significantly to （123.7±5.72） pg/mL （P=0.000）， and the expression of phosphorylated Tau-pS202/pT205 increased the hippocampus （P=0.002）. Compared to the anesthesia surgery group， the activated microglia were inhibited， the concentration of IL-6 decreased to （96.68±9.59） pg/mL （P=0.008）， and the expression of phosphorylated Tau-pS202/pT205 reduced significantly in the AS+LGG group （P=0.002）. While there were no significant changes in total Tau protein among 3 groups. ConclusionPreoperative administration of probiotic LGG can alleviate the activation of microglia， increased secretion of inflammatory factors， and increased Tau protein phosphorylation levels in the hippocampus of elderly mice caused by anesthesia surgery.

Modified Xiaoyaosan Alleviates Depression-like Behaviors by Regulating Activation of Hippocampal Microglia Cells in Rat Model of Juvenile Depression / 中国实验方剂学杂志

ObjectiveTo investigate the mechanism of Baihuan Xiaoyao Decoction （Xiaoyaosan added with Lilii Bulbus and Albiziae Cortex） in alleviating depression-like behaviors of juvenile rats by regulating the polarization of microglia. MethodSixty juvenile SD rats were randomized into normal control， model， fluoxetine， and low-， medium-， and high-dose （5.36， 10.71， 21.42 g·kg-1， respectively） Baihuan Xiaoyao decoction groups. The rat model of juvenile depression was established by chronic unpredictable mild stress （CUMS）. The sucrose preference test （SPT） was carried out to examine the sucrose preference of rats. Forced swimming test （FST） was carried out to measure the immobility time of rats. The open field test （OFT） was conducted to measure the total distance， the central distance， the number of horizontal crossings， and the frequency of rearing. Morris water maze （MWM） was used to measure the escape latency and the number of crossing the platform. The immunofluorescence assay was employed to detect the expression of inducible nitric oxide synthase （iNOS， the polarization marker of M1 microglia） and CD206 （the polarization marker of M2 microglia）. Real-time polymerase chain reaction was employed to determine the mRNA levels of iNOS， CD206， pro-inflammatory cytokines ［tumor necrosis factor （TNF）-α， interleukin （IL）-1β， and IL-6］ and anti-inflammatory cytokines （IL-4 and IL-10） in the hippocampus. Western blotting was employed to determine the protein levels of iNOS and CD206 in the hippocampus. The levels of IL-4 and IL-6 in the hippocampus were detected by enzyme-linked immunosorbent assay. ResultCompared with the normal control group， the model rats showed a reduction in sucrose preference （P<0.05）， an increase in immobility time （P<0.05）， decreased motor and exploratory behaviors （P<0.05）， and weakened learning and spatial memory （P<0.05）. In addition， the model rats showed up-regulated mRNA and protein levels of iNOS and mRNA levels of IL-1β， IL-6， and TNF-α （P<0.05）. Compared with the model group， Baihuan Xiaoyao decoction increased the sucrose preference value （P<0.05）， shortened the immobility time （P<0.01）， increased the motor and exploratory behaviors （P<0.05）， and improved the learning and spatial memory （P<0.01）. Furthermore， the decoction down-regulated the positive expression and protein level of iNOS， lowered the levels of TNF-α， IL-1β， and IL-6 （P<0.01）， promoted the positive expression of CD206， and elevated the levels of IL-4 and IL-10 （P<0.01） in the hippocampus of the high dose group. Moreover， the high-dose Baihuan Xiaoyao decoction group had higher sucrose preference value （P<0.01）， shorter immobility time （P<0.01）， longer central distance （P<0.01）， stronger learning and spatial memory （P<0.01）， higher positive expression and protein level of iNOS （P<0.01）， lower levels of TNF-α， IL-1β， and IL-6 （P<0.05， P<0.01）， lower positive expression and mRNA level of iNOS （P<0.05）， and higher levels of IL-4 and IL-10 （P<0.05， P<0.01） than the fluoxetine group. ConclusionBaihuan Xiaoyao decoction can improve the depression-like behavior of juvenile rats by inhibiting the M1 polarization and promoting the M2 polarization of microglia in the hippocampus.

Wenyang Jieyu Prescription Regulates Hippocampal Neuron Apoptosis and Improves Synaptic Plasticity in Depressed Mice via BDNF/Akt/mTOR Pathway / 中国实验方剂学杂志

ObjectiveTo explore the mechanism of Wenyang Jieyu prescription in regulating hippocampal neuron apoptosis and improving synaptic plasticity in the mouse model of depression induced by maternal separation combined with restraint stress. MethodThe mice on postnatal day 0 （PD0） were randomly assigned into a control group （n=10） and a modeling group （n=50）. Maternal separation combined with restraint stress was adopted to establish the mouse model of depression， and the modeled mice were randomized into model， Wenyang prescription， Jieyu prescription， Wenyang Jieyu prescription， and fluoxetine groups （n=10） on the weaning day （PD21）. From PD21 to PD111， the mice were fed with the diets mixed with corresponding medicines. The sucrose preference test， open field test， O-maze test， and novel object recognition test were then conducted to evaluate the depression， memory， and learning abilities of mice. Immunohistochemistry （IHC） was employed to measure the atomic absorbance （AA） of postsynaptic density protein 95 （PSD95） in the hippocampus. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling （TUNEL） was employed to detect the apoptosis of hippocampal neurons. Western blot was employed to determine the protein levels of brain-derived neurotrophic factor （BDNF）， phosphorylated tyrosine kinase receptor B/tyrosine kinase receptor B （p-TrkB/TrkB）， phosphorylated protein kinase B/protein kinase B （p-Akt/Akt）， phosphorylated mammalian target of rapamycin/mammalian target of rapamycin （p-mTOR/mTOR）， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X （Bax）， cysteinyl aspartate-specific proteinase-3 （Caspase-3）， synaptophysin （Syn）， and PSD95. ResultCompared with the control group， the modeling decreased the sucrose preference rate， time spent in central zone within 5 min， total movement distance， time spent in the open arm， and cognition index （P<0.01）. Furthermore， it decreased the expression of PSD95， increased the neuron apoptosis in the hippocampus （P<0.01）， down-regulated the protein levels of BDNF， p-TrkB/TrkB， p-Akt/Akt， p-mTOR/mTOR， Bcl-2， PSD95， and Syn （P<0.01）， and up-regulated the protein levels of Bax and Caspase-3 （P<0.05） in the hippocampus. Compared with the model group， Wenyang Jieyu prescription and fluoxetine increased the sucrose preference rate， time spent in central zone within 5 min， total movement distance， time spent in the open arm， and cognition index （P<0.05， P<0.01）. Moreover， the drugs increased the expression of PSD95， reduced the neuron apoptosis （P<0.01）， up-regulated the protein levels of BDNF， p-TrkB/TrkB， p-Akt/Akt， p-mTOR/mTOR， Bcl-2， PSD95， and Syn （P<0.01）， and down-regulated the protein levels of Bax and Caspase-3 （P<0.01）. ConclusionWenyang Jieyu prescription outperformed Wenyang prescription and Jieyu prescription in the treatment of the depressive behavior induced by maternal separation combined with restraint stress in mice. It exerted the therapeutic effect by reducing the hippocampal neuron apoptosis and improving the synaptic plasticity via the BDNF/Akt/mTOR pathway.

Role of 5-hydroxytryptamine type 3 receptors in the regulation of anxiety reactions / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT3R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na+, K+, and Ca2+ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT3R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT3Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT3Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT3R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT2R-mediated regulation of anxiety reactions are also activated by 5-HT3R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT3Rs. However, given the circuit specific modulation of 5-HT3Rs on emotion, systemic use of 5-HT3R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT3R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.

Theta Oscillations Support Prefrontal-hippocampal Interactions in Sequential Working Memory / 神经科学通报·英文版

The prefrontal cortex and hippocampus may support sequential working memory beyond episodic memory and spatial navigation. This stereoelectroencephalography (SEEG) study investigated how the dorsolateral prefrontal cortex (DLPFC) interacts with the hippocampus in the online processing of sequential information. Twenty patients with epilepsy (eight women, age 27.6 ± 8.2 years) completed a line ordering task with SEEG recordings over the DLPFC and the hippocampus. Participants showed longer thinking times and more recall errors when asked to arrange random lines clockwise (random trials) than to maintain ordered lines (ordered trials) before recalling the orientation of a particular line. First, the ordering-related increase in thinking time and recall error was associated with a transient theta power increase in the hippocampus and a sustained theta power increase in the DLPFC (3-10 Hz). In particular, the hippocampal theta power increase correlated with the memory precision of line orientation. Second, theta phase coherences between the DLPFC and hippocampus were enhanced for ordering, especially for more precisely memorized lines. Third, the theta band DLPFC → hippocampus influence was selectively enhanced for ordering, especially for more precisely memorized lines. This study suggests that theta oscillations may support DLPFC-hippocampal interactions in the online processing of sequential information.

Overexpression of NRF1 alleviates mitochondrial and cognitive dysfunction in mice models of Alzheimer's disease / 安徽医科大学学报

Objective To investigate the effects of nuclear respiratory factor 1(NRF1)on mitochondrial and cog-nitive dysfunction in Alzheimer's disease(AD)model mice.Methods The 5 × FAD mice were utilized as a mod-el for Alzheimer's disease,and the sparsely labeled AAV virus overexpressing NRF1(AAV-NRF1)was adminis-tered via stereotaxic injection into the brain.The expression of NRF1 in hippocampus was determined by Western blot,the morphology of mitochondria in hippocampus was observed by transmission electron microscope,the den-dritic spines of sparsely labeled neurons in the CA1 region were visualized and quantified using confocal laser mi-croscopy,cognitive and memory functions of mice were evaluated using the Morris water maze test,while electro-physiological methods were employed to detect long-term potentiation(LTP)of synaptic efficacy.Results The ex-pression of NRF1 in the hippocampus was significantly upregulated following stereotactic injection of AAV-NRF1(P＜0.001).This intervention led to notable improvements in mitochondrial morphology within hippocampal neurons,as well as enhanced cognitive and memory functions in mice(P＜0.01).Moreover,there was a significant in-crease in dendritic spine density among neurons located in the CA1 region of the hippocampus(P＜0.001),ac-companied by long-lasting and stable long-term potentiation(LTP)and a substantial elevation in fEPSP slope(P＜0.01).Conclusion The overexpression of NRF1 in a 5 × FAD mouse model of Alzheimer's disease(AD)initia-ted the restoration of mitochondrial dysfunction and enhanced synaptic plasticity,indicating that these alterations may contribute to the therapeutic efficacy of NRF1 overexpression in ameliorating cognitive dysfunction associated with AD.