Exendin-4 attenuates pain-induced cognitive impairment by alleviating hippocampal neuroinflammation in a rat model of spinal nerve ligation

Glucagon-like peptide-1 receptor has anti-apoptotic,anti-inflammatory,and neuroprotective effects.It is now recognized that the occurrence and development of chronic pain are strongly associated with anti-inflammatory responses;however,it is not clear whether glucagon-like peptide-1 receptor regulates chronic pain via anti-inflammatory mechanisms.We explored the effects of glucagon-like peptide-1 receptor on nociception,cognition,and neuroinflammation in chronic pain.A rat model of chronic pain was established using left L5 spinal nerve ligation.The glucagon-like peptide-1 receptor agonist exendin-4 was intrathecally injected into rats from 10 to 21 days after spinal nerve ligation.Electrophysiological examinations showed that,after treatment with exendin-4,paw withdrawal frequency of the left limb was significantly reduced,and pain was relieved.In addition,in the Morris water maze test,escape latency increased and the time to reach the platform decreased following exendin-4 treatment.Immunohistochemical staining and western blot assays revealed an increase in the numbers of activated microglia and astrocytes in the dentate gyrus of rat hippocampus,as well as an increase in the expression of tumor necrosis factor alpha,interleukin 1 beta,and interleukin 6.All of these effects could be reversed by exendin-4 treatment.These findings suggest that exendin-4 can alleviate pain-induced neuroinflammatory responses and promote the recovery of cognitive function via the glucagon-like peptide-1 receptor pathway.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Renmin Hospital of Wuhan University of China(approval No.WDRM 20171214)on September 22,2017.     

Frequency‐specific changes in the default mode network in patients with cingulate gyrus epilepsy

To identify abnormal functional connectivity of the default mode network in cingulate gyrus epilepsy, which may yield new information about the default mode network and suggest a new cingulate gyrus epilepsy biomarker. Fifteen patients with cingulate gyrus epilepsy (mean age = 21 years) and 15 healthy controls (mean age = 24 years) were studied in the resting state using magnetoencephalography. Twelve brain areas of interest in the default mode network were extracted and investigated with multifrequency signals that included alpha (α, 8–13 Hz), beta (β, 14–30 Hz), and gamma (γ, 31–80 Hz) band oscillations. Patients with cingulate gyrus epilepsy had significantly greater connectivity in all three frequency bands (α, β, γ). A frequency‐specific elevation of functional connectivity was found in patients compared to controls. The greater functional connectivity in the γ band was significantly more prominent than that of the α and β bands. Patients with cingulate gyrus epilepsy and controls differed significantly in functional connectivity between the left angular gyrus and left posterior cingulate cortex in the α, β, and γ bands. The results of the node degree analysis were similar to those of the functional connectivity analysis. Our findings reveal for the first time that brain activity in the γ band may play a key role in the default mode network in cingulate gyrus epilepsy. Altered functional connectivity of the left angular gyrus and left posterior cingulate cortex may be a new biomarker for cingulate gyrus epilepsy.     

Anatomical and behavioral impact of a lentiviral tool tapping onto hippocampal serotonin reuptake in rats

We aimed at the further characterization of rats in which SERT gene silencing was achieved by hippocampal injection of a lentiviral vector, carrying three si-RNA to block SERT mRNA at 66% of normal levels. Improved self-control and reduced restlessness were already demonstrated in these rats. Present further studies consisted of male adult rats, bilaterally inoculated within the hippocampus; control rats received lentivirus particles inactivated with heat. Both groups were maintained in isolation for 5 months, starting from inoculation. Neurochemical changes were studied by proton magnetic resonance spectroscopy (1H-MRS): we found increased hippocampal viability and bioenergetic potential; however, rats showed a behaviorally depressive pattern, also characterized by enhanced affiliation. Based on the extent of such effects, the whole lenti-SERT group was divided into two subgroups, termed intermediate- and extreme- phenotype profiles. While all rats had a widespread modification within dorsal/ventral striatum, amygdala, and hypothalamus, only the former subgroup showed an involvement of Raphé medialis, while, for the latter subgroup, an increase of SERT within hippocampus was unexpectedly caused. Within the less-affected “intermediate” rats, hippocampal 5-HT7 receptors were down-modulated, and also similarly within substantia nigra, septum, and neocortex. This picture demonstrates that additional rather than fewer neurobiological changes accompany a lower phenotypic expression. Overall, tapping hippocampal SERT affected the balance between habits versus strategies of coping by promoting morphogenetic processes indicative of a serotonergic fiber plasticity. Supplementary studies about serotonergic dynamics and neurogenesis within fronto-striatal circuits are needed.     

Adrenergic β receptor activation reduces amyloid β1-42-mediated intracellular Zn2+ toxicity in dentate granule cells followed by rescuing impairment of dentate gyrus LTP

Adrenergic β receptor activation prevents human soluble amyloid β (Aβ)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aβ_1–42-induced impairment of LTP is due to Aβ_1–42-mediated Zn²⁺ toxicity, we postulated that adrenergic β receptor activation reduces Aβ_1–42-mediated intracellular Zn²⁺ toxicity followed by rescuing Aβ_1–42 toxicity. To test the effect of adrenergic β receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aβ_1–42 injection into the dentate granule cell layer. Human Aβ_1–42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic β receptor agonist, but not by co-injection of phenylephrine, an adrenergic α₁ receptor agonist. Isoproterenol did not reduce Aβ_1–42 uptake into dentate granule cells, but reduced increase in intracellular Zn²⁺ in dentate granule cells induced by Aβ_1–42. In contrast, phenylephrine did not reduce both Aβ_1–42 uptake and increase in intracellular Zn²⁺ by Aβ_1–42. In the case of human Aβ₁₋₄₀ and rat Aβ_1–42, which do not increase intracellular Zn²⁺, human Aβ₁₋₄₀- and rat Aβ_1–42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic β receptor activation reduces Aβ_1–42-mediated increase in intracellular Zn²⁺ in dentate granule cells, resulting in rescuing Aβ_1–42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aβ_1–42-induced cognitive decline that is caused by intracellular Zn²⁺ dysregulation in the hippocampus.     

Meta-analysis of brain structural changes after electroconvulsive therapy in depression

BackgroundIncreases in the volume of the amygdala and hippocampus after electroconvulsive therapy (ECT) are among the most robust effects known to the brain-imaging field. Recent advances in the segmentation of substructures of these regions allow for novel insights on the relationship between brain structure and clinical outcomes of ECT.ObjectiveWe aimed to provide a comprehensive synthesis of evidence available on changes in brain structure after ECT, including recently published data on hippocampal subfields.MethodsA meta-analysis of published studies was carried out using random-effects models of standardized mean change of regional brain volumes measured with longitudinal magnetic resonance imaging of depressive patients before and after a series of ECT.ResultsData from 21 studies (543 depressed patients) were analysed, including 6 studies (118 patients) on hippocampal subfields. Meta-analyses could be carried out for seven brain regions for which data from at least three published studies was available. We observed increases in left and right hippocampi, amygdalae, cornua ammonis (CA) 1, CA 2/3, dentate gyri (DG) and subicula with standardized mean change scores ranging between 0.34 and 1.15. The model did not reveal significant volume increases in the caudate. Meta-regression indicated a negative relationship between the reported increases in the DG and relative symptom improvement (−0.27 (SE: 0.09) per 10%).ConclusionsECT is accompanied by significant volume increases in the bilateral hippocampus and amygdala that are not associated with treatment outcome. Among hippocampal subfields, the most robust volume increases after ECT were measured in the dentate gyrus. The indicated negative correlation of this effect with antidepressant efficacy warrants replication in data of individual patients.     

偏侧咀嚼对紧咬牙运动时海马旁回激活影响的探索

目的探索偏侧咀嚼对紧咬牙运动时脑功能活动的影响。方法选取左、右侧偏侧咀嚼患者各7例，在紧咬牙运动时采集全脑血氧水平依赖对比的功能性磁共振成像（functional magnetic resonance imaging，fMRI）扫描数据。结果7例左侧偏侧咀嚼患者中有4例出现海马旁回的激活，而右侧偏侧咀嚼患者均未见海马旁回的激活。结论发现了左侧偏侧咀嚼患者紧咬牙运动可激活与人类学习记忆能力有重要关系的海马旁回的现象。     

成年大鼠弥漫性脑损伤后海马齿状回神经前体细胞增殖的NOS-NO通路机制研究

目的　观察NO前体及选择性NOS干预剂对弥漫性脑损伤后齿状回神经发生的调控作用 ,探讨NOS -NO通路在成年脑神经发生中的角色。方法　选用成年弥漫性脑损伤大鼠模型 ,采用BrdU标记分裂细胞及免疫组织化学方法比较弥漫性脑损伤后 2、4、6、8、12d时各干预剂干预组大鼠与相应对照组大鼠之间海马齿状回神经前体细胞的增殖速度。结果　L -精氨酸 (L -Arg) 2 0 0mg/kgi.p .后 ,成年大鼠弥漫性脑损伤后各个时间点海马齿状回BrdU免疫阳性细胞数目均显著增多 ,以脑损伤后 6d和 8d时增加最为明显 (P <0 0 1)。 7-硝基引唑 (7-NI) 5 0mg/kgi.p .后 ,明显抑制了大鼠弥漫性脑损伤后不同时间点齿状回细胞增殖 ,在弥漫性脑损伤后 4d时抑制作用相对最为明显 (P <0 0 1)。氨基胍 (AG) 10 0mg/kgi.p .后 ,也明显减少了大鼠弥漫性脑损伤后不同时间点齿状回BrdU免疫阳性细胞数目 ,从第 8天后抑制作用相对更为明显 (P <0 0 1)。结论　弥漫性脑损伤后激活的NOS -NO通路是海马齿状回神经发生过程中一个重要的调控通路 ,不同来源的NO分别在弥漫性脑损伤后不同时间齿状回神经发生中发挥作用。     

静息态fMRI观察经颅电刺激对睡眠剥夺后青年志愿者后扣带回皮质连接紊乱的干预作用

目的 采用静息态功能MRI（rs-fMRI）观察经颅电刺激（tDCS）对睡眠剥夺（SD）后青年志愿者双侧后扣带回皮质（PCC）功能连接紊乱的干预作用。方法 对16名健康志愿者间隔施加2次24 h SD，随后随机给予真/假tDCS，于正常睡眠清醒休息状态（RW）、SD后及真/假tDCS后采集fMRI数据并进行蒙特利尔认知评估（MoCA），选取双侧PCC作为种子点，计算种子点与全脑间功能连接，观察RW、SD后及真/假tDCS组间功能连接变化，比较MoCA差异。结果 SD后受试者平均MoCA分值较RW减低（t=8.047，P<0.05）；真tDCS后平均MoCA分值（27.06±1.53）高于假tDCS后（25.13±1.86，t=-3.081，P=0.008）和SD后（24.75±2.41，t=3.306，P=0.005）。SD后双侧PCC与双侧丘脑功能连接较RW上升，而与右侧楔前叶功能连接下降。真tDCS后双侧PCC与双侧丘脑间功能连接较假tDCS后下降，而左侧PCC与右侧楔前叶间功能连接上升。结论 24 h SD能引起PCC网络连接紊乱；tDCS对SD所致网络功能连接紊乱具有一定干预作用。