Comprehensive Assessment of Anxiolytic Properties in 4-HPAA Derivatives: Bridging in Vivo Validation and Molecular Docking Analyses

Anxiety is a significant mental health issue that substantially affects an individual’s quality of life. Feelings of uneasiness, irritability, and sleep disturbances characterize it. 4-Hydroxyphenyl acetic acid (4-HPAA) is identified in brain cells as a physiological byproduct of tyramine. This study hypothesizes that 4-HPAA may regulate anxiety due to its anxiolytic properties, acting as a modulator of the GABAergic system, which plays a crucial role in the pathophysiology of anxiety disorders. Our study aims to enhance the anxiolytic effects of 4-HPAA through chemical modification to improve its pharmacokinetic properties. Three derivatives, namely Isopropyl-4-hydroxy-[phenyl] acetate (IHPA), Isopropyl-4-hydroxy-[phenyl] acetate (MPAA), and 4-methoxyphenyl acetate (MPHA), have been synthesized from 4-HPAA. This assessment will use well-established animal models, specifically the Elevated Plus-Maze (EPM) and Zero Maze (EZM) tests, selected for their validity in replicating anxiety-like symptoms in animals. Chronic caffeine administration via drinking water (0.3 g/l for 14 days) was employed to induce an anxiety state for testing purposes. IHPA and MPAA demonstrated significant anxiolyticactivity when tested in the EPM and EZM experiments. Molecular docking simulations using AutoDock Vina indicated that 4-HPAA derivatives had docking scores ranging from −5.8 to −4.8 kcal/mol, compared to the standard anxiolytic medication Diazepam, which scored −7.1 kcal/mol. These scores suggest a potential for 4-HPAA derivatives to interact effectively with the Gamma-aminobutyric acid (GABA_A) receptor. In conclusion, our in vivo and in silico analyses indicate a promising anxiolytic potential for 4-HPAA derivatives.

Chronic Kidney Disease Induces Cognitive Impairment in the Early Stage

Objective Previous research indicates a link between cognitive impairment and chronic kidney disease(CKD),but the underlying factors are not fully understood.This study aimed to investigate the progression of CKD-induced cognitive impairment and the involvement of cognition-related proteins by developing early-and late-stage CKD models in Sprague-Dawley rats.Methods The Morris water maze test and the step-down passive avoidance task were performed to evaluate the cognitive abilities of the rats at 24 weeks after surgery.Histopathologic examinations were conducted to examine renal and hippocampal damage.Real-time PCR,Western blotting analysis,and immunohistochemical staining were carried out to determine the hippocampal expression of brain-derived neurotrophic factor(BDNF),choline acetyltransferase(ChAT),and synaptophysin(SYP).Results Compared with the control rats,the rats with early-stage CKD exhibited mild renal damage,while those with late-stage CKD showed significantly increased serum creatinine levels as well as apparent renal and brain damage.The rats with early-stage CKD also demonstrated significantly impaired learning abilities and memory compared with the control rats,with further deterioration observed in the rats with late-stage CKD.Additionally,we observed a significant downregulation of cognition-related proteins in the hippocampus of rats with early-stage CKD,which was further exacerbated with declining renal function as well as worsening brain and renal damage in rats with late-stage CKD.Conclusion These results suggest the importance of early screening to identify CKD-induced cognitive dysfunction promptly.In addition,the downregulation of cognition-related proteins may play a role in the progression of cognitive dysfunction.

文冠果油对雄性小鼠记忆能力的影响

为了对文冠果油相关产品的开发提供数据支撑,将健康雄性小鼠分为4个组,即对照组(玉米油)、文冠果油低剂量组〔2.1 g/(kg·d)〕、文冠果油中剂量组〔4.2 g/(kg·d)〕和文冠果油高剂量组〔12.5 g/(kg·d)〕,分别经口给予小鼠灌胃1个月后,测定小鼠体质量,并进行跳台试验、避暗试验、水迷宫试验以评价文冠果油对雄性小鼠记忆能力的影响,试验结束后测定小鼠海马和大脑皮质组织匀浆中多巴胺(DA)、5-羟色胺(5-HT)、去甲肾上腺素(NE)、乙酰胆碱(ACh)含量及乙酰胆碱酯酶(AChE)活性,探讨文冠果油对小鼠记忆能力的影响机制。结果表明:经过1个月的灌胃试验,各组小鼠体质量及其增长率均无显著差异;文冠果油组小鼠跳台试验、避暗试验、水迷宫试验均为阳性;文冠果油高剂量组小鼠海马和大脑皮质组织匀桨中5-HT、ACh、NE、DA含量明显升高,AChE活性明显降低。综上,文冠果油具有改善小鼠记忆的功能,且是通过改善单胺类神经递质和胆碱能神经递质的代谢发挥作用的。

nNOS-CAPON偶联抑制剂的合成及抗焦虑研究

合成nNOS-CAPON偶联抑制剂并评价其抗焦虑作用。根据nNOS-CPAON蛋白结构域配体结合部位的结构特点设计并合成了一系列缬氨酸类化合物,通过评价化合物抑制nNOS-CAPON蛋白相互作用(PPI)的活性来筛选化合物,并通过高架十字迷宫实验验证其抗焦虑作用。设计并合成了两个系列共15个化合物,其中N-8具有较好的PPI抑制作用,且在高架十字迷宫实验中显著增加小鼠在开臂的停留时间,具有较强的抗焦虑作用。研究丰富了nNOS-CAPON偶联抑制剂的结构类型,并验证了该类型化合物的抗焦虑作用。

一种智能化的Y-型迷宫

本文介绍了一种智能化Ｙ－型迷宫的硬件、软件结构。它利用微机控制大鼠（或小鼠）分辨学习实验的全过程，利用红外光电传感器监测动物活动行为，判断准确，计时精确。由于以ＷＩＮＤＯＷＳ为工作平台，人机界面友好，操作简便。

大鼠Y-型迷宫测试法的筛选与优化

目的对4种大鼠Y-型迷宫测试法进行比较,筛选并优化出一种相对简便可靠的训练方法。方法采用目前常用的四种Y型迷宫测试法检测大鼠的学习功能,通过统计学分析和科学推断,从而筛选出一种相对简便可靠的方法,并在此基础上将其进一步优化。结果 固定次数随机法(FS)、固定次数顺序法(FO)、固定次数随机不休息法(FSR)、不固定次数随机法(NFS)、不固定次数顺序法(NFO)达标所需的次数分别为70.34±5.74、56±4.52、68.21±7.65、42.5±7.1、15.6±1.14;达标所需的天数分别为3.73±0.52、2.75±1.31、3.48±1.03、1、1;其中固定次数随机法和固定次数随机不休息法没有统计学差异。结论固定次数随机不休息法是一种相对准确而简便的Y-型迷宫测试法。

大鼠Y-型迷宫测试指标正常值的确定

目的 确定不同年龄段雄性SD大白鼠明暗辨别性条件反射和一次性被动回避反应各项指标的正常值 ,为基础和临床有关动物学习和记忆能力的实验研究提供参考。方法 采用一种相对简便可靠的“随机不休息法”对不同年龄段雄性SD大白鼠进行Y -型迷宫测试。结果 1月龄、2月龄、4月龄、12月龄、2 4月龄大鼠的EN ;TRT ;Lst ;Lsd的正常值分别为 4.7± 1.2次、1.4± 1.14次、1.62± 0 .5 5次、1.2 5± 0 .7次、3 .8± 1.0 5次 ;12 5 .5± 42 .0 1s、117.8± 2 5 .0 4s、93 .2 2± 18.2 7s、10 9.5 8± 5 .2 7s、161.46± 4.46s ;2 2 .3 9± 8.46s、2 3 .2 5± 6.6s、17.83± 12 .3s、18.83± 13 .42s、2 8.83± 13 .42 ;2 3 .94± 9.0 5s、2 0 1.3± 3 9.1s、2 15 .3 3± 45 .4s、198.6±3 2 .9s、13 4.2± 3 7.2。结论 正常幼年大鼠和老年大鼠的学习记忆能力较差 ,正常成年大鼠学习记忆能力较强。

营养干预对高+Gy暴露小鼠脑功能及相关生化指标的影响

目的研究高 +Gy暴露对小鼠迷宫行为和脑功能相关生化指标的影响和营养干预的效果。 方法昆明种雄性小鼠经迷宫训练后分为对照组 (A组 )、+Gy组 (B组 )、+Gy营养干预组 (C组 ) ;A组不予 +Gy暴露 ;B组、C组均给予 + 1 0Gy暴露 8min ,B组暴露前 3h蒸馏水灌胃 ;C组实验前 1d给予强化VitB6 的饮水 ,暴露前 3h混合氨基酸液灌胃 ;3组动物均记录迷宫实验成绩 ,检测血清氨基酸f、脑组织单胺类递质含量和γ 谷氨酰转移酶活性。结果 +Gy暴露后迷宫实验成绩下降 ,并有行为异常 ,脑内NE明显降低 ,其他单胺类递质均显著升高 (P <0 0 5 ) ,表明脑功能受影响 ;营养干预后迷宫行为改善 ,生化指标改变有所缓解。结论高 +Gy暴露会引起中枢递质相关的生化营养物质代谢紊乱并影响脑功能 。

骨窗封闭对中重型颅脑创伤小鼠模型的影响

目的探讨骨窗封闭对中重型颅脑创伤小鼠模型的影响。方法采用控制性皮质撞击法分别构建中型和重型颅脑创伤小鼠模型,随机分为中型颅脑创伤骨窗封闭组(中型骨窗封闭组,50只)、中型颅脑创伤骨窗未封闭组(中型骨窗未封闭组,50只)、重型颅脑创伤骨窗封闭组(重型骨窗封闭组,50只)、重型颅脑创伤骨窗未封闭组(重型骨窗未封闭组,50只),监测颅内压,测定脑组织含水量和脑水肿体积,采用改良神经功能缺损评分(mNSS)评估神经功能缺损程度,Morris水迷宫实验评估空间学习能力和记忆力,Nissl染色评估大脑皮质和海马CA1区神经元损伤程度。结果颅内压监测,无论中型还是重型颅脑创伤模型小鼠骨窗封闭组与骨窗未封闭组颅内压差异均有统计学意义(P=0.007,0.000),模型制备后不同观察时间点颅内压差异亦有统计学意义(P=0.000,0.000),其中,中型骨窗封闭组模型制备后第1天颅内压高于中型骨窗未封闭组(P=0.009),重型骨窗封闭组第1天(P=0.000)和第3天(P=0.038)颅内压高于重型骨窗未封闭组;模型制备后第7天中型骨窗封闭组(P=0.000,0.000)和重型骨窗封闭组(P=0.000,0.008)颅内压均低于第1天和第3天,第3天亦低于第1天(P=0.000,0.000),仅第7天中型骨窗未封闭组颅内压低于第1天(P=0.031)。脑组织含水量测定显示,重型骨窗封闭组模型制备后第1天(P=0.028)、第3天(P=0.023)和第7天(P=0.023)脑组织含水量均低于重型骨窗未封闭组。脑水肿体积测定,无论中型还是重型颅脑创伤模型小鼠骨窗封闭组脑水肿体积均小于骨窗未封闭组(P=0.021,0.037)。神经功能缺损程度评估,无论中型还是重型颅脑创伤模型小鼠骨窗封闭组与骨窗未封闭组模型制备后不同观察时间点mNSS评分差异均具有统计学意义(P=0.000,0.001),其中,模型制备后第7天中型骨窗封闭组(P=0.002)、中型骨窗未封闭组(P=0.013)、重型骨窗封闭组(P=0.009)mNSS评分均低于第1天,重型骨窗封闭组(P=0.006)和重型骨窗未封闭组(P=0.002)mNSS评分低于第3天。Morris水迷宫实验,重型骨窗封闭组小鼠平台潜伏期长于(P=0.045)、目标象限停留时间短于(P=0.025)重型骨窗未封闭组。Nissl染色显示,对于中型颅脑创伤模型小鼠,骨窗封闭组大脑皮质神经元Nissl小体密度减少,染色变浅;海马CA1区神经元Nissl小体密度减少,染色变浅,形态模糊。对于重型颅脑创伤模型小鼠,骨窗封闭组大脑皮质神经元Nissl小体染色变浅,染色模糊,可见较多异染颗粒;海马CA1区神经元胞体水肿,Nissl小体染色模糊。结论中型颅脑创伤模型小鼠,骨窗封闭虽在急性期增高颅内压,但对脑水肿程度、神经功能和认知功能无明显影响;重型颅脑创伤模型小鼠,骨窗封闭可导致颅内压升高、空间学习能力和记忆力减退,但可减轻脑水肿程度,应根据研究目的选择是否进行骨窗封闭。

丰富运动环境下甲基汞对海马神经毒性减轻效果的Morris water maze实验评价

目的 观察在胎儿期被甲基汞损伤的海马神经在成长过程中通过丰富的运动环境条件对其神经毒性减轻效果的影响。方法 C57BL 6Cr鼠妊娠 12～ 14日在 3d内 ,连续经口投入 4mg kg甲基汞进行染毒 ,对照组用同量的生理盐水投入。出生后的雄性子代分别在单匹、多匹、多匹 +运动装置 (丰富运动环境 )条件下饲养 8周 ,然后进行Mor riswater maze实验。结果 因甲基汞暴露到达坐标的时间 (空间记忆水平 )单匹和多匹群都表现出时间延长的倾向 ,而丰富运动环境群却没有观察到这一现象。结论 从Morriswater maze实验的现象上观察 。

不同频率全身振动训练对去卵巢大鼠学习记忆能力的影响及其机制

探讨不同频率全身振动训练(WBV)对去卵巢大鼠学习记忆能力的影响及其机制.将40只雌性SD大鼠分为假手术组(Sham组)、去卵巢安静组(OVX组)、去卵巢+高频全身振动训练组(HWBV组,35Hz)和去卵巢+低频全身振动训练组(LWBV组,15Hz).采用水迷宫试验检测各组大鼠的学习和记忆能力,检测各组大鼠血清、前额叶皮质、大脑皮层和海马中脑源性神经营养因子(BDNF)的水平及谷胱甘肽过氧化物酶(GPx)、总超氧化物歧化酶(SOD)的活性.结果表明,与Sham组相比,OVX组大鼠表现为空间学习能力障碍和短期记忆能力障碍,高频WBV可改善去卵巢大鼠的学习及记忆障碍,低频WBV只有微弱的改善作用;OVX组大鼠血清、前额叶皮质、大脑皮层和海马中BDNF水平、 GPx和SOD活性显著降低;HWBV组大鼠血清、前额叶皮质、大脑皮层和海马中BDNF水平、 GPx和SOD活性显著高于OVX和LWBV组.高频WBV可改善去卵巢大鼠的学习和记忆障碍,其机制可能与其增加大鼠血清及各脑区中BDNF及抗氧化作用有关.

SHR、WKY大鼠与SD大鼠注意缺陷多动障碍模型行为学特征的比较

目的比较SHR、WKY、SD大鼠行为学特征,探寻研究SHR大鼠注意缺陷多动障碍(ADHD)理想的对照模型。方法运用旷场实验统计大鼠运动距离、运动速度、穿格数及理毛次数来评价SHR、WKY、SD大鼠自主运动情况;运用水迷宫实验检测三组大鼠的学习记忆能力。结果旷场实验结果显示,SHR大鼠在总运动量、平均运动速度及穿格次数上较WKY及SD大鼠均显著增加(P<0.01);与WKY大鼠相比,SD大鼠运动距离显著高于WKY组(P<0.01),其运动速度及穿格数略高于WKY组(P<0.05);水迷宫隐匿站台实验中,与SHR大鼠相比,SD大鼠潜伏期较长(P<0.05),在潜伏期运动距离上,SD大鼠在训练第1天、第3天及第4天运动距离较SHR大鼠延长(P<0.05或P<0.01);比较WKY组,SD大鼠潜伏期及潜伏期运动距离较WKY在各个训练时间均有不同程度的下降(P<0.05或P<0.01)。在空间探索阶段,SD大鼠穿台次数及目标象限运动时间、距离比率等均较SHR大鼠有所减少(P<0.05),而较WKY大鼠则有不同程度的升高(P<0.05或P<0.01)。结论 WKY大鼠与SHR大鼠行为学差异过大,两者的比较存在一定的不足,增设SD大鼠作为SHR大鼠的对照组能够提升SHR大鼠行为学特征的可比性,更为客观的反映SHR大鼠的行为学特征。

An enriched environment increases the expression of fibronectin type Ⅲ domain-containing protein 5 and brain-derived neurotrophic factor in the cerebral cortex of the ischemic mouse brain

Many studies have shown that fibronectin type III domain-containing protein 5(FDNC5) and brain-derived neurotrophic factor(BDNF) play vital roles in plasticity after brain injury. An enriched environment refers to an environment that provides animals with multi-sensory stimulation and movement opportunities. An enriched environment has been shown to promote the regeneration of nerve cells, synapses, and blood vessels in the animal brain after cerebral ischemia;however, the exact mechanisms have not been clarified. This study aimed to determine whether an enriched environment could improve neurobehavioral functions after the experimental inducement of cerebral ischemia and whether neurobehavioral outcomes were associated with the expression of FDNC5 and BDNF. This study established ischemic mouse models using permanent middle cerebral artery occlusion(pMCAO) on the left side. On postoperative day 1, the mice were randomly assigned to either enriched environment or standard housing condition groups. Mice in the standard housing condition group were housed and fed under standard conditions. Mice in the enriched environment group were housed in a large cage, containing various toys, and fed with a standard diet. Sham-operated mice received the same procedure, but without artery occlusion, and were housed and fed under standard conditions. On postoperative days 7 and 14, a beam-walking test was used to assess coordination, balance, and spatial learning. On postoperative days 16–20, a Morris water maze test was used to assess spatial learning and memory. On postoperative day 15, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex were analyzed by western blot assay. The results showed that compared with the standard housing condition group, the motor balance and coordination functions(based on beam-walking test scores 7 and 14 days after operation), spatial learning abilities(based on the spatial learning scores from the Morris water maze test 16–19 days after operation), and memory abilities(based on the memory scores of the Morris water maze test 20 days after operation) of the enriched environment group improved significantly. In addition, the expression levels of FDNC5 and BDNF proteins in the ipsilateral cerebral cortex increased in the enriched environment group compared with those in the standard housing condition group. Furthermore, the Pearson correlation coefficient showed that neurobehavioral functions were positively associated with the expression levels of FDNC5 and BDNF(r = 0.587 and r = 0.840, respectively). These findings suggest that an enriched environment upregulates FDNC5 protein expression in the ipsilateral cerebral cortex after cerebral ischemia, which then activates BDNF protein expression, improving neurological function. BDNF protein expression was positively correlated with improved neurological function. The experimental protocols were approved by the Institutional Animal Care and Use Committee of Fudan University, China(approval Nos. 20160858 A232, 20160860 A234) on February 24, 2016.

Anxiolytic property of hydro-alcohol extract of Lactuca sativa and its effect on behavioral activities of mice

Lactuca sativa, belonging to the Asteraceae family, is a leafy vegetable known for its medicinal properties. This study aimed to understand the mechanism of Lactuca sativa extract with respect to pharmacological action. We investigated the anxiolytic effects of hydro-alcoholic extract of leaves of Lactuca sativa on mice. The behav- ioral tests performed on mice models to assess anti-anxiety properties were： open field test （OFT）, elevated plus maze test （EPM）, elevated T maze test, and marble burying test. Increased locomotor activity and time spent in the ＂open-ann＂ were observed in extract fed group. Malondialdehyde （MDA） and nitrite levels were decreased, cata- lase and glutathione levels were increased in Lactuca sativa treated mice. The data obtained in the present study suggests that the extract of Lactuca sativa can afford significant protection against anxiolytic activity.

Xiao-Xu-Ming decoction extract regulates differentially expressed proteins in the hippocampus after chronic cerebral hypoperfusion

Xiao-Xu-Ming decoction has been widely used to treat stroke and sequelae of stroke. We have previously shown that the active fractions of Xiao-Xu-Ming decoction attenuate cerebral ischemic injury. However, the global protein profile and signaling conduction pathways regulated by Xiao-Xu-Ming decoction are still unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Rats were intragastrically administered 50 or 150 mg/kg Xiao-Xu-Ming decoction for 4 consecutive weeks. Learning and memory abilities were measured with Morris water maze. Motor ability was detected with prehensile test. Coordination ability was examined using the inclined screen test. Neuronal plasticity was observed by immunofluorescent staining. Differentially expressed proteins of rat hippocampus were analyzed by label-free quantitative proteomics. Real time-polymerase chain reaction and western blot assay were used to identify the changes in proteins. Results showed that Xiao-Xu-Ming decoction dramatically alleviated learning and memory deficits, and motor and coordination dysfunction, and increased the expression of microtubule-associated protein 2. Xiao-Xu-Ming decoction extract remarkably decreased 13 upregulated proteins and increased 39 downregulated proteins. The regulated proteins were mainly involved in oxidation reduction process, intracellular signaling cascade process, and protein catabolic process. The signaling pathways were mainly involved in ubiquitin mediated proteolysis and the phosphatidylinositol signaling system. Furthermore, there was an interaction among Rab2 a, Ptpn1, Ppm1 e, Cdk18, Gorasp2, Eps15, Capza2, Syngap1 and Mt-nd1. Protein analyses confirmed the changes in expression of MTND1. The current findings provide new insights into the molecular mechanisms of Xiao-Xu-Ming decoction extract's effects on chronic cerebral hypoperfusion.

Association between Alzheimer's disease pathogenesis and early demyelination and oligodendrocyte dysfunction

The APPSwe/PSEN1 dE9（APP/PS1） transgenic mouse model is an Alzheimer＇s disease mouse model exhibiting symptoms of dementia, and is commonly used to explore pathological changes in the development of Alzheimer＇s disease. Previous clinical autopsy and imaging studies suggest that Alzheimer＇s disease patients have white matter and oligodendrocyte damage, but the underlying mechanisms of these have not been revealed. Therefore, the present study used APP/PS1 mice to assess cognitive change, myelin loss, and corresponding changes in oligodendrocytes, and to explore the underlying mechanisms. Morris water maze tests were performed to evaluate cognitive change in APP/PS1 mice and normal C57 BL/6 mice aged 3 and 6 months. Luxol fast blue staining of the corpus callosum and quantitative reverse transcription-polymerase chain reaction（q RT-PCR） for myelin basic protein（MBP） mRNA were carried out to quantify myelin damage. Immunohistochemistry staining for NG2 and qRT-PCR for monocarboxylic acid transporter 1（MCT1） mRNA were conducted to assess corresponding changes in oligodendrocytes. Our results demonstrate that compared with C57 BL/6 mice, there was a downregulation of MBP mRNA in APP/PS1 mice aged 3 months. This became more obvious in APP/PS1 mice aged 6 months accompanied by other abnormalities such as prolonged escape latency in the Morris water maze test, shrinkage of the corpus callosum, upregulation of NG2-immunoreactive cells, and downregulation of MCT1 mRNA. These findings indicate that the involvement of early demyelination at 3 months and the oligodendrocyte dysfunction at 6 months in APP/PS1 mice are in association with Alzheimer＇s disease pathogenesis.

Chrysophanol attenuates lead exposure-induced injury to hippocampal neurons in neonatal mice

Previous studies have shown that chrysophanol protects against learning and memory impairments in lead-exposed adult mice. In the present study, we investigated whether chrysophanol can alleviate learning and memory dysfunction and hippocampal neuronal injury in lead-exposed neonatal mice. At the end of lactation, chrysophanol（0.1, 1.0, 10.0 mg/kg） was administered to the neonatal mice by intraperitoneal injection for 15 days. Chrysophanol significantly alleviated injury to hippocampal neurons and improved learning and memory abilities in the lead-poisoned neonatal mice. Chrysophanol also significantly decreased lead content in blood, brain, heart, spleen, liver and kidney in the lead-exposed neonatal mice. The levels of malondialdehyde in the brain, liver and kidney were significantly reduced, and superoxide dismutase and glutathione peroxidase activities were significantly increased after chrysophanol treatment. Collectively, these findings indicate that chrysophanol can significantly reduce damage to hippocampal neurons in lead-exposed neonatal mice.

Optimization of food deprivation and sucrose preference test in SD rat model undergoing chronic unpredictable mild stress

Background:The chronic unpredictable mild stress(CUMS)model has long been considered the best model for exploring the pathophysiological mechanisms underlying depression.However,there are no widely recognised standards for strategies for modeling and for behavioral testing.The present study aimed to optimize the protocols for food deprivation and the sucrose preference test(SPT)for the CUMS model.Methods:We first evaluated the effects of different long periods of food deprivation on the body weight of Sprague Dawley(SD)rats by testing food deprivation for 24 hours(8:00-8:00^+),food deprivation for 12 hours during the daytime(8:00-20:00)and food deprivation for 12 hours at night(20:00-8:00^+).Next,we established a SD rat CUMS model with 15 different stimulations,and used body weight measurement,SPT,forced swim test(FST),open field test(OFT)and Morris water maze(MWM)test to verify the success of the modeling.In the SPT,consumption of sucrose and pure water within 1 and 12 hours was measured.Results:Twelve hours of food deprivation during the daytime(8:00-20:00)had no effect on body weight,while 12 hours of food deprivation at night(20:00-8:00^+)and 24 hours of food deprivation(8:00-8:00^+)significantly reduced the mean body weight of the SD rats.When SPT was used to verify the successful establishment of the CUMS rat model,sucrose consumption measured within 12 hours was less variable than that measured within 1 hour.Conclusions:Twelve hours of food deprivation in the daytime(8:00-20:00)may be considered a mild stimulus for the establishment of a CUMS rat model.Measuring sucrose consumption over 12 hours is recommended for SPT.

Neuronal protein-tyrosine phosphatase 1B hinders sensory-motor functional recovery and causes affective disorders in two different focal ischemic stroke models

Ischemic brain injury causes neuronal death and inflammation.Inflammation activates protein-tyrosine phosphatase 1B(PTP1B).Here,we tested the significance of PTP1B activation in glutamatergic projection neurons on functional recovery in two models of stroke:by photothrombosis,focal ischemic lesions were induced in the sensorimotor cortex(SM stroke)or in the peri-prefrontal cortex(peri-PFC stroke).Elevated PTP1B expression was detected at 4 days and up to 6 weeks after stroke.While ablation of PTP1B in neurons of neuronal knockout(NKO)mice had no effect on the volume or resorption of ischemic lesions,markedly different effects on functional recovery were observed.SM stroke caused severe sensory and motor deficits(adhesive removal test)in wild type and NKO mice at 4 days,but NKO mice showed drastically improved sensory and motor functional recovery at 8 days.In addition,peri-PFC stroke caused anxiety-like behaviors(elevated plus maze and open field tests),and depression-like behaviors(forced swimming and tail suspension tests)in wild type mice 9 and 28 days after stroke,respectively,with minimal effect on sensory and motor function.Peri-PFC stroke-induced affective disorders were associated with fewer active(FosB+)neurons in the PFC and nucleus accumbens but more FosB+neurons in the basolateral amygdala,compared to sham-operated mice.In contrast,mice with neuronal ablation of PTP1B were protected from anxiety-like and depression-like behaviors and showed no change in FosB+neurons after peri-PFC stroke.Taken together,our study identifies neuronal PTP1B as a key component that hinders sensory and motor functional recovery and also contributes to the development of anxiety-like and depression-like behaviors after stroke.Thus,PTP1B may represent a novel therapeutic target to improve stroke recovery.All procedures for animal use were approved by the Animal Care and Use Committee of the University of Ottawa Animal Care and Veterinary Service(protocol 1806)on July 27,2018.

Atorvastatin increases dynamin 1 expression in hippocampal CA1 region in a rat model of vascular dementia

The current study examined a rat model of vascular dementia. The model rats exhibited obvious morphological and ultrastructural changes in neurons in the brain, and significantly reduced dynamin 1 expression in hippocampal CA1 region along with decreased learning and memory performance. Following atorvastatin treatment, the morphology and ultrastructure of cells in the model rat brain were significantly improved, dynamin 1 expression in hippocampal CA1 region was significantly enhanced, and learning and memory ability was significantly improved. The results demonstrated that impaired learning and memory abilities in vascular dementia model rats were closely correlated with decreased dynamin 1 expression. These findings indicate that atorvastatin can protect model rats against cognitive impairment by increasing dynamin 1 expression.