3′-Daidzein sulfonate sodium protects against memory impairment and hippocampal damage caused by chronic cerebral hypoperfusion

3′-Daidzein sulfonate sodium(DSS) is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment.To validate this hypothesis,we established rat models of chronic cerebral hypoperfusion(CCH) by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method.Three weeks after modeling,rat models were intragastrically administered 0.1,0.2,and 0.4 mg/kg DSS,once a day,for 5 successive weeks.The Morris water maze test was performed to investigate CCH-induced learning and memory deficits.TUNEL assay was used to analyze apoptosis in the hippocampal CA1,CA3 regions and dentate gyrus.Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1,CA3 regions and dentate gyrus.Western blot analysis was performed to investigate the phosphorylation of PKA,ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway.Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH,reduced apoptosis of neurons in the hippocampal CA1,CA3 regions and dentate gyrus,and increased the phosphorylation of PKA,ERK1/2,and CREB in the hippocampus.These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway.     

戊四氮致痫大鼠学习记忆改变及海马CA_1和CA_3区神经颗粒素的表达变化

目的 探讨戊四氮慢性点燃癫痫对大鼠学习记忆能力的影响及海马CA_1、CA_3区神经颗粒素(neu-rogranin,Ng)的表达变化.方法 采用戊四氮(pentylenetetrazole,PTZ)腹腔注射慢性点燃癫痫(chronic epileptic,CEP)模型,用Morris水迷宫和Y迷宫对大鼠进行学习记忆能力检测,运用免疫组织化学方法测定大鼠海马CA_1、CA_3区Ng的表达变化.结果 与对照组比较,慢性癫痫发作组大鼠在水迷宫中的逃避潜伏期延长(P<0.01),穿越平台次数减少(P<0.01),在Y迷宫中的错误反应次数增多(P<0.05).在海马CA_1区Ng的免疫反应强度减弱(P<0.05),CA_3区两组比较差异无统计学意义.结论 戊四氮慢性点燃癫痫大鼠学习记忆能力受损,海马CA_1区Ng表达减少可能参与了这一过程.

Abstract：

Objective To explore the effect of Pentylenetetrazole (PTZ)-kindled epilepsy on rats' learning and memory and the expression of neurogranin(Ng) in hippocampal CA_1 and CA_3. Methods Use chronic model of epilepsy induced by PTZ intraperitoneal injection. The ability of learning and memory were assessed by the Morris water maze and Y maze. The expression of Ng in hippocampal CA_1 and CA_3 was determined by immunocytochemical method respectively. Resuits The learning and memory ability of the epilepsy rats was impaired. Meanwhile,The immunological reaction of Ng for CEP group at CA_1 was weaker than NC group, but it made no difference at CA_3. Conclusion The impairment of learning and memory ability of the epilepsy rats might be related with the changes of Ng in hippocampal CA_1.     

冬南瓜醇提物干预雄性大鼠齿状回细胞增殖和空间学习功能的变化

Previous studies reported that some plants,including butternut squash,exert positive effects on the brain.However,few studies have examined the effects of butternut squash on learning,memory,and neurogenesis.This study studied the effects of butternut squash extract on spatial learning and cell proliferation in the dentate gyrus of healthy male rats.Thirty-five male Wistar rats were intrap-eritoneally injected with 0,50,100,200 and 400 mg/kg butternut squash extract once daily for 2 months.After the last administration,rat’s spatial memory was studied using the Morris water maze.Finally,rats were sacrificed and hippocampal sections were prepared for light microscopy and bromodeoxyuridine immunohistochemistry studies.The results revealed that escape latency and swim distance decreased in all treatment groups compared with the control rats,and that the number of bromodeoxyuridine-positive cells in the dentate gyrus was significantly increased in the treatment groups compared with the controls.These findings suggest that butternut squash extract improves the learning and memory abilities of male rats,and increases the proliferation of dentate gyrus cells.     

Eleutheroside B or E enhances learning and memory in experimentally aged rats

Eleutheroside B or E, the main component of Acanthopanax, can relieve fatigue, enhance memory, and improve human cognition. Numerous studies have confirmed that high doses of acetylcholine significantly attenuate clinical symptoms and delay the progression of Alzheimer’s disease. The present study replicated a rat model of aging induced by injecting quinolinic acid into the hippocampal CA1 region. These rats were intraperitoneally injected with low, medium and high doses of eleutheroside B or E (50, 100, 200 mg/kg), and rats injected with Huperzine A or PBS were used as controls. At 4 weeks after administration, behavioral tests showed that the escape latencies and errors in searching for the platform in a Morris water maze were dose-dependently reduced in rats treated with medium and high-dose eleutheroside B or E. Hematoxylin-eosin staining showed that the number of surviving hippocampal neurons was greater and pathological injury was milder in three eleutheroside B or E groups compared with model group. Hippocampal homogenates showed enhanced cholinesterase activity, and dose-dependent increases in acetylcholine content and decreases in choline content following eleutheroside B or E treatment, similar to those seen in the Huperzine A group. These findings indicate that eleutheroside B or E improves learning and memory in aged rats. These effects of eleutheroside B or E may be mediated by activation of cholinesterase or enhanced reuse of choline to accelerate the synthesis of acetylcholine in hippocampal neurons.     

丰富环境对脑梗死大鼠学习记忆和海马区微血管密度的影响

目的 研究丰富环境对局灶性脑梗死大鼠学习记忆及海马区微血管密度的影响.方法 采用开颅电凝法制作SD大鼠右侧大脑中动脉缺血(MCAO)模型,术后24h随机分为丰富环境组(EE组)和标准环境组(SE组),另设假手术组(Sham组),不电凝大脑中动脉,其余步骤与手术组相同.分别于术后7d、28d进行Mornis水迷宫测试大鼠学习记忆能力;以免疫组织化学法测定海马区微血管密度.结果 在学习记忆能力上,EE组成绩明显优于SE组(P<0.01),与Sham组相比无显著性差异(P>0.05);缺血侧海马区微血管密度显示EE组在术后14d、28d明显高于SE组大鼠(P<0.05),与Sham组相比无显著性差异(P>0.05).结论 丰富环境可促进脑梗死大鼠学习记忆能力的恢复与海马区微血管新生,改善大鼠的预后.

Abstract：

Objective To evaluate the effect of enriched environment on learning and memory and microvessel density in hippocampus of rats after unilateral local cerebral infarction. Methods The right middle cerebral artery occlusion (MCAO) was performed with electric coagulation in SD rats, then the rats were randomly divided into enriched environment stimulation group (EE group) and standard environment stimulation group (SE group). The sham-operation rats were as control group. On 7d and 28d, Morris water maze was used to evaluate the learning and memory ability;microvessel density in hippocampus of rats was measured in the boundary zone to brain infarction on 1d,3d,7d,14d and 28d. Result The learning and memory ability in EE group was significantly better than that in SE group ( P < 0.01 ) and there was no significant difference between EE group and Sham group (P > 0.05 ) ;Compared with SE group, the microvessel density (MVD) of EE group in hippocampus of rats significantly increased on 14d and 28d after MCAO( P <0.05). There was no significant difference in MVD between EE group and sham group (P > 0.05 ). Conclusion The enriched environment can enhance the ability of learning and memory and promote the blood vessel proliferation of rats with unilateral local cerebral infarction.The study suggests enriched environment is good for recovery from brain damage in rats with MCAO.     

Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1

In this study,we investigated the effects of mobile phone radiation on spatial learning,reference memory,and morphology in related brain regions.After the near-field radiation(0.52-1.08 W/kg) was delivered to 8-week-old Wistar rats 2 hours per day for 1 month,behavioral changes were examined using the Morris water maze.Compared with the sham-irradiated rats,the irradiated rats exhibited impaired performance.Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus.Using the physical dissector technique,the number of pyramidal neurons,the synaptic profiles,and the length of postsynaptic densities in the CA1 region were quantified stereologically.The morphological changes included mitochondrial degenerations,fewer synapses,and shorter postsynaptic densities in the radiated rats.These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region.     

亚低温条件下弥漫性脑损伤海马区凋亡蛋白酶激活因子1蛋白的表达

The influence of mild hypothermia on neural cell apoptosis remains poorly understood. Therefore, the present study established rat models of diffuse axonal injury (DAI) at 33 ℃. Morris water maze results demonstrated significantly better learning and memory functions in DAI rats with hypothermia compared with DAI rats with normothermia. Expression of apoptotic protease activating factor-1 in the hippocampal CA1 region was significantly lower in the DAI hypothermia group compared with the DAI normothermia group. Expression of apoptotic protease activating factor-1 positively correlated with latency, but negatively correlated with platform location times and time of swimming in the quadrant area. Results suggested that post-traumatic mild hypothermia in a rat model of DAI could provide cerebral protection by attenuating expression of apoptotic protease activating factor-1.     

亚低温对大鼠弥漫性脑损伤后海马CA1区Apaf-1蛋白表达和学习记忆功能的影响

目的 探讨亚低温对大鼠弥漫性脑损伤(DBI)后海马CA1区Apaf-1蛋白表达及大鼠学习记忆功能的影响.方法 选择雄性Wistar大鼠48只,按照完全随机数字表法分为正常组、假手术组、脑损伤组和亚低温组,每组12只.正常组不做任何处理;假手术组仅给予麻醉及头皮切开、缝合,但不致伤;脑损伤组和亚低温组根据Marmarou方法制作DBI模型,亚低温组大鼠损伤后用冰毯及冰袋物理降温,使大鼠肛温在15 min内控制至30.0～31.0℃,维持2 h.14 d后比较各组大鼠Morris水迷宫实验成绩,同时比较各组大鼠海马CA1区Apaf-1蛋白的表达.结果 正常组、假手术组、脑损伤组和亚低温组大鼠搜索安全岛的次数分别为(10.1±1.9)次、(10.3±1.8)次、(3.8±2.3)次和(6.9±1.1)次,差异有统计学意义(P<0.05).脑损伤组及亚低温组海马CA1区Apaf-1蛋白含量高于正常组及假手术组,其中脑损伤组Apaf-1蛋白含量明显高于亚低温组,差异均有统计学意义(P<0.05).结论 亚低温可能通过抑制神经细胞凋亡对脑组织产生保护作用,从而改善大鼠脑损伤后学习记忆障碍.

Abstract：

Objective To investigate the influence of mild hypothermia on the apoptotic protease activating factor-1 (Apaf-1) protein expression in the hippocampal CA1 area and learning and memory functions of rats after diffuse brain injury (DBI). Methods Forty-eight male Wistar rats were equally randomized into normal group, sham-operated group, brain injury group and mild hypothermia treatment group (n=12). Rats in the normal group did not receive any treatment; rats in the sham-operated group only received anesthesia, and incision and suture of scalp; rats in the brain injury group and mild hypothermia treatment group were induced the DBI models according to Marmarou method; and rats in the mild hypothermia treatment group were performed hypothermia with ice blanket and ice bag to control the rectal temperature within 30.0-31.0 ℃ for 2 h. After DBI for 2 weeks, the times of searching refuge platform and the protein expression of Apaf-1 were compared among the 4 groups. Results The times of searching refuge platform in the normal group, sham operated group, brain injury group and mild hypothermia treatment group were (10.1 ±1.9), (10.3±1.8), (3.8±2.3) and (6.9±1.1), respectively,with significant differences between each 2 groups (P<0.05). The protein expression of Apaf-1 in the brain injury group and mild hypothermia treatment group was obviously higher than that in the other groups (P<0.05), and significantly lower protein expression of Apaf-1 in the mild hypothermia rats was noted as compared with that in the brain injury rats (P<0.05). Conclusion Mild hypothermia might play a protective role by inhibiting neuronal apoptosis for rats with DBI through the Apaf-1 pathway,which can improve learning and memory abilities.     

Korean red ginseng promotes hippocampal neurogenesis in mice

Neurogenesis in the adult hippocampus plays a major role in cognitive ability of animals including learning and memory.Korean red ginseng (KRG) has long been known as a medicinal herb with the potential to improve learning and memory;however,the mechanisms are still elusive.Therefore,we evaluated whether KRG can promote cognitive function and enhance neurogenesis in the hippocampus.Eight-week-old male C57BL/6 mice received 50 mg/kg of 5-bromo-2′-deoxyuridine (BrdU) intraperitoneally and 100 mg/kg of KRG or vehicle orally once a day for 14 days.Pole,Rotarod and Morris water maze tests were performed and the brains were collected after the last behavioral test.Changes in the numbers of BrdU- and BrdU/ doublecortin (DCX;a marker for neuronal precursor cells and immature neurons)-positive cells in the dentate gyrus and the gene expression of proliferating cell nuclear antigen (a marker for cell differentiation),cerebral dopamine neurotrophic factor and ciliary neurotrophic factor in the hippocampus were then investigated.KRG-treated mice came down the pole significantly faster and stood on the rotarod longer than vehicle-treated mice.The Morris water maze test showed that KRG administration enhanced the learning and memory abilities significantly.KRG also significantly increased BrdU- and BrdU/DCX-positive cells in the dentate gyrus as well as the proliferating cell nuclear antigen,cerebral dopamine neurotrophic factor and ciliary neurotrophic factor mRNA expression levels in the hippocampus compared to vehicle.Administration of KRG promotes learning and memory abilities,possibly by enhancing hippocampal neurogenesis.This study was approved by the Pusan National University Institutional Animal Care and Use Committee (approval No.PNU-2016-1071) on January 19,2016.     

Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia

Alzheimer's disease(AD) is associated with oxidative stress, and ultimately results in cognitive deficit. Despite existing literature on the pathophysiology of AD, there is currently no cure for AD. The present study investigated the effects of kaempferol(Kmp) isolated from the extract of Mespilus germanica L.(medlar) leaves on cognitive impairment, hippocampal antioxidants, apoptosis, lipid peroxidation and neuro-inflammation markers in ovariectomized(OVX) rat models of sporadic AD. Kaempferol, as the main flavonoid of medlar extract has been previously known for anti-oxidative, anti-inflammatory and anti-neurotoxic effects. Thirty-two female Wistar rats were ovariectomized, and randomly divided into four groups: sham, OVX + saline, OVX + streptozotocin(STZ) + saline, OVX + STZ + Kmp. Animals received intracerebroventricular injection of STZ(3 mg/kg, twice with one day interval) to establish models of sporadic AD. Intraperitoneal injection of Kmp(10 mg/kg) for 21 days was performed in the OVX + STZ + Kmp group. Spatial learning and memory of rats were evaluated using a Morris water maze. Finally, brain homogenates were used for biochemical analysis by enzyme-linked immunosorbent assay. The results showed a significant improvement in spatial learning and memory as evidenced by shortened escape latency and searching distance in Morris water maze in the OVX + STZ + Kmp group compared with the OVX + STZ group. Kmp also exhibited significant elevations in brain levels of antioxidant enzymes of superoxide dismutase and glutathione, while reduction in tumor necrosis factor-α and malondialdehyde. Our results demonstrate that Kmp is capable of alleviating STZ-induced memory impairment in OVX rats, probably by elevating endogenous hippocampal antioxidants of superoxide dismutase and glutathione, and reducing neuroinflammation. This study suggests that Kmp may be a potential neuroprotective agent against cognitive deficit in AD.     

Molecular mechanisms and the role of the protein kinase pathway in rat spatial memory impairment following isoflurane anesthesia

BACKGROUND:Animal experiments have demonstrated that isoflurane exposure alone induces learning and memory deficits for weeks or months. However, the molecular mechanisms of learning and memory remain poorly understood. Hippocampal expression of calcium/phospholipid- dependent protein kinase (PKC) and cAMP-dependent protein kinase (PKA) in rats have been shown to be associated with memory processing. OBJECTIVE:To investigate changes in rat spatial memory and hippocampal CA1 neuronal kinase system following isoflurane anesthesia, and to explore the correlation between molecular changes in cerebral neurons and behavioral manifestations following anesthesia.DESIGN, TIME AND SETTING:A randomized, controlled, animal study. All experiments were performed at the Department of Anesthesia, Beijing Chaoyang Hospital, Capital Medical University from November 2007 to December 2008.MATERIALS:A total of 72 male, 3 month-old (young group), Sprague Dawley rats, and 36 male, 20 month-old (aged group), Sprague-Dawley rats were used in the study. Isoflurane was purchased from Baxter, USA. METHODS:Young and aged rats were randomly assigned to control, training (no anesthesia, Morris water maze training), and isoflurane (1.2% isoflurane, Morris water maze training) groups. The isoflurane group was further subdivided into four groups, which were exposed to anesthesia for 2 or 4 hours, and were subjected to Morris water maze training at 2 days or 2 weeks post- anesthesia. Finally, each aged group comprised 6 rats, and the young group comprised 12 rats. MAIN OUTCOME MEASURES:Spatial learning and memory were observed during Morris water maze training. Hippocampal CA1 PKA and PKC expression and activity were detected by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA). RESULTS:A 4-hour isoflurane exposure induced spatial memory deficits in all rats for 2 days to 2 weeks. In particular, aged rats exhibited more severe spatial memory deficits. Immunohistochemistry and ELISA results showed a significant increase in PKC and PKA expression and activity in the hippocampus CA1 subfield following Morris water maze training (P < 0.05). Moreover, isoflurane anesthesia inhibited PKC and PKA expression and activity, and this inhibition increased with increasing exposure duration and increasing age. CONCLUSION:Results suggested that increased isoflurane exposure and age could extensively inhibit the hippocampal CA1 kinase system. Inhibition of protein kinases could play an important role in the cognitive decline following anesthesia.     

Angiotensin converting enzyme inhibition partially prevents deficits in water maze performance,hippocampal synaptic plasticity and cerebral blood flow in streptozotocin-diabetic rats

Vascular dysfunction is important in the pathogenesis of peripheral complications of diabetes. However, the effects of diabetes on cerebral blood flow and the role of vascular deficits in the pathogenesis of diabetic encephalopathy are still unknown. The present study examined whether experimental diabetes is associated with reduced cerebral blood flow and whether treatment with enalapril can improve cerebral perfusion and function (blood flow and functional cerebral deficits). Streptozotocin-diabetic rats were treated with the ACE inhibitor enalapril (24 mg/kg) from onset of diabetes. After 14 weeks of diabetes, 12 enalapril treated and 12 untreated diabetic rats, and 12 nondiabetic age-matched control rats were tested in a spatial version of the Morris water maze. After 16 weeks of diabetes, in the same groups, blood flow in the hippocampus and thalamus was measured by hydrogen clearance microelectrode polarography. In a separate study, hippocampal long-term potentiation was measured after 26 weeks of diabetes. Water maze performance and hippocampal long-term potentiation were impaired in diabetic rats. Furthermore, blood flow in diabetic rats was reduced by 30% (P<0.001) in the hippocampus and by 37% (P<0.005) in the thalamus compared to nondiabetic controls. Enalapril treatment significantly improved water maze performance (P<0.05), hippocampal long term potentiation (P<0.05) and hippocampal blood flow (P<0.05). Cerebral perfusion is reduced in diabetic rats compared to controls. Treatment aimed at the vasculature can improve cerebral blood flow, deficits in Morris maze performance and long term potentiation. These findings suggest that vasculopathy plays a role in the development of cerebral dysfunction in diabetic rats.     

Febrile seizures impair memory and cAMP response-element binding protein activation

The long-term effects of brief but repetitive febrile seizures (FS) on memory have not been as thoroughly investigated as the impact of single and prolonged seizure in the developing brain. Using a heated-air FS paradigm, we subjected male rat pups to one, three, or nine episodes of brief FS on days 10 to 12 postpartum. Neither hippocampal neuronal damage nor apoptosis was noted within 72 hours after FS, nor was there significant hippocampal neuronal loss, aberrant mossy fiber sprouting, or altered seizure threshold to pentylenetetrazol in any FS group at adulthood. The adult rats subjected to nine episodes of early-life FS, however, showed long-term memory deficits as assessed by the Morris water maze. They also exhibited impaired intermediate and long-term memory but spared short-term memory in the inhibitory avoidance task. Three hours after inhibitory avoidance training, phosphorylation of cAMP response-element binding (CREB) protein in the hippocampus was significantly lower in nine-FS-group rats than in controls. Furthermore, rolipram administration, which activated the cAMP-CREB signaling pathway by inhibiting phosphodiesterase type IV, reversed the long-term memory deficits in nine-FS-group rats by enhancing hippocampal CREB phosphorylation. These results raise concerns about the long-term cognitive consequences of even brief frequently repetitive FS during early brain development.     

An enriched environment improves cognitive performance after early-life status epilepticus accompanied by an increase in phosphorylation of extracellular signal-regulated kinase 2

An enriched environment can enhance brain recovery in animals with early-life status epilepticus (SE). The purpose of this study was to determine the effects of early-life SE on spatial memory and hippocampal extracellular signal-regulated kinase (ERK) level, and the possible therapeutic effects of the enriched environment. Rats were assigned randomly to four groups: (1) control rats (nonenriched control); (2) control rats housed in an enriched environment from Postnatal Day (P) 25 to P40 (enriched control); (3) rats in which SE was induced with lithium-pilocarpine (Li-PC) at P21 (nonenriched SE); and (4) rats in which SE was induced with Li-PC at P21 and then housed in an enriched environment from P25 to P40 (enriched SE). As adults, the rats underwent spatial learning and memory tests in the Morris water maze between P50 and P55. At P55, subsets of animals were evaluated for expression of hippocampal ERK1/2 phosphorylation immediately following completion of the Morris water maze. At ~P100, another set of animals was tested for seizure threshold. When studied as adults, only the nonenriched SE group had a spatial memory deficit. The nonenriched SE group also exhibited lower levels of phosphorylated ERK2 as compared with the nonenriched control, enriched control, and enriched SE groups. Both the nonenriched SE and enriched SE groups had reduced seizure thresholds as compared with the nonenriched control and enriched control groups. Results from this study demonstrate that an enriched environment improves spatial memory in rats subjected to early-life SE, possibly through upregulation of phosphorylated ERK2 in the hippocampus. However, an enriched environment has no effect on seizure threshold.     

Effect of neonatal isolation on outcome following neonatal seizures in rats--the role of corticosterone

Emerging evidence indicates that early maternal care permanently modifies the activity of hypothalamic-pituitary-adrenal (HPA) axis and is a critical factor in determining the capacity of the brain to compensate for later encountered insults. The purpose of this study was to determine the role of corticosterone (CORT) in the detrimental effects of neonatal isolation (NI) on seizures. Rats were assigned randomly to the following five groups: (1) control (CONT) rats; (2) NI rats that underwent daily separation from their dams from postnatal day 2 (P2) to P9; (3) status epilepticus (SE) rats, induced by lithium-pilocarpine (Li-Pilo) model at P10; (4) NI plus SE (NIS) rats and (5) NISM rats, a subset of NIS rats receiving metyrapone (100 mg/kg), a CORT synthesis inhibitor, immediately after SE induction. At P10, plasma CORT levels were compared at baseline in CONT and NI rats and in response to Li-Pilo-induced SE among SE, NIS and NISM rats. We evaluated the spatial memory in the Morris water maze at P50 approximately 55, the expression of hippocampal cyclic adenosine monophosphate (cAMP)-responsive element-binding protein phosphorylation at serine-133 (pCREBSer-133) at P55, hippocampal neuronal damage at P80 and seizure threshold at P100. The isolated rats exhibited higher CORT release in response to SE than non-isolated rats, and the NIS rats had greater cognitive deficits and decreased seizure threshold compared to the CONT, NI and SE groups. By contrast, the NISM group, compared to the NIS group, showed a normal CORT response to SE and better spatial memory but no difference in seizure threshold. Compared to the CONT group, the hippocampal pCREBSer-133 level was significantly reduced in all experimental groups (NI, SE, NIS, NISM) with no differences between groups. All rats were free of spontaneous seizures later in life and had no discernible neuronal loss in the hippocampus. Results in this model demonstrate repetitive NI enhances response of plasma CORT to SE, and exacerbates the neurological consequences of neonatal SE. Amelioration of neurological sequelae following reduction of the SE-induced excessive rise in plasma CORT implicates CORT in the pathogenesis of NI increasing the vulnerability to seizures.     

吡格列酮对糖尿病大鼠中枢神经系统PPAR-γ表达的影响

目的 研究吡格列酮对糖尿病大鼠海马、下丘脑处PPAR-γ表达的影响及与大鼠认知功能的关系.方法 雄性SD大鼠随机分为对照组(C组)、糖尿病组(D组)、糖尿病+吡格列酮组(DP组),每组10只.8周后行Morris水迷宫评价大鼠的空间学习记忆能力,Western Blot方法检测大鼠海马、下丘脑处PPAR-γ表达水平.结果 Morris水迷宫中,D组大鼠逃避潜伏期较C组和DP组延长差异均有统计学意义(P<0.05).大鼠海马和下丘脑处,PPAR-γ的表达D组较C组减少,DP组较D组增多,差异均有统计学意义(P<0.05).结论 吡格列酮能够增加糖尿病大鼠海马、下丘脑组织局部PPAR-γ表达水平,并且这种表达的增加可能是吡格列酮改善糖尿病大鼠空间学习记忆能力的机制之一.     

Assessment of chronic trigeminal neuropathic pain by the orofacial operant test in rats

The present study examined the effects of Tremella fuciformis (TF) on the learning and memory function and the neural activity in rats with trimethyltin (TMT)-induced memory deficits. The rats were administered saline or TF (TF 25, 50, 100 mg/kg, p.o.) daily for 21 days. The cognitive improving efficacy of TF on the amnesic rats, which was induced by TMT, was investigated by assessing the Morris water maze test and by performing Choline acetyltransferase (ChAT) and cAMP responsive element binding protein (CREB) immunohistochemistry. In order to confirm the underlying mechanisms of the memory enhancing effects of TF, we assessed the neurite outgrowth of PC12 cells. We also administered 18F-fluorodeoxyglucose and performed a PET scan of the frontal lobe.The rats with TMT injection showed impaired learning and memory of the tasks and treatment with TF produced a significant improvement of the escape latency to find the platform in the Morris water maze compared to that of the control group. In the retention test, the TF50 group showed increased time spent around the platform compared to that of the control group. Consistent with the behavioral data, TF50 mg/kg significantly alleviated the loss of ChAT-ir neurons in the hippocampus compared to that of the control group. Treatment with TF significantly increased the CREB positive neurons in the hippocampal CA1 area as compared to that of the control group. In addition, TF treatment (50 mg/kg) increased the glucose uptake approximately sevenfold in the frontal lobe and it significantly promoted neurite outgrowth of the PC12 cells, as compared to that of the controls.These results suggest that TF may be useful for improving the cognitive function via regulation of the CREB signaling pathway and cholinergic system in the hippocampus.     

Anabolic-androgenic steroid and adrenal steroid effects on hippocampal plasticity

Anabolic-androgenic steroids (AAS) are synthetic androgen-like compounds which are taken in high doses by athletes with the intention of enhancing muscular appearance, strength and/or athletic performance. Recent research indicates that high doses of AAS may influence the functions of the hippocampus. This evidence led us to explore the extent to which chronic AAS treatments influence spatial memory and the integrity of the hippocampus in the rat. Gonadally intact adult male Long-Evans rats were treated with either the AAS methandrostenolone, a steroid ‘cocktail’ (TNB; testosterone cypionate, boldenone undecylenate and nandrolone decanoate), or the oil vehicle daily for 12 weeks. A group of male rats treated with corticosterone (CORT; 10 mg/day) was also examined. Spatial memory was assessed in the Morris water maze after 10 weeks of hormone treatment. At 12 weeks, the animals were sacrificed, blood collected and the brain sectioned to assess hippocampal cell number. There were no impairments in the acquisition or retention of the Morris water maze in any hormone treatment group. Although serum testosterone levels were elevated in rats treated with TNB relative to the oil controls, neither the TNB or methandrostenolone treatments produced changes in hippocampal cell number. Serum CORT levels were significantly elevated in the rats treated with CORT and cell loss (15%) was detectable in the CA3b subfield in this group of animals. These results indicate that the AAS administered in the present study were not detrimental to hippocampal spatial memory or cell survival and that, while chronic CORT may produce mild hippocampal cell loss, this loss is not accompanied by deficits on a spatial memory task.     

Cognitive dysfunction after experimental febrile seizures

While the majority of children with febrile seizures have an excellent prognosis, a small percentage are later discovered to have cognitive impairment. Whether the febrile seizures produce the cognitive deficits or the febrile seizures are a marker or the result of underlying brain pathology is not clear from the clinical literature. We evaluated hippocampal and prefrontal cortex function in adult rats with a prior history of experimental febrile seizures as rat pups. All of the rat pups had MRI brain scans following the seizures. Rats subjected to experimental febrile seizures were found to have moderate deficits in working and reference memory and strategy shifting in the Morris water maze test. A possible basis for these hippocampal deficits involved abnormal firing rate and poor stability of hippocampal CA1 place cells, neurons involved in encoding and retrieval of spatial information. Additional derangements of interneuron firing in the CA1 hippocampal circuit suggested a complex network dysfunction in the rats. MRI T2 values in the hippocampus were significantly elevated in 50% of seizure-experiencing rats. Learning and memory functions of these T2-positive rats were significantly worse than those of T2-negative cohorts and of controls. We conclude that cognitive dysfunction involving the hippocampus and prefrontal cortex networks occur following experimental febrile seizures and that the MRI provides a potential biomarker for hippocampal deficits in a model of prolonged human febrile seizures.     

Effects of cytotoxic hippocampal lesions in mice on a cognitive test battery

Mice received cytotoxic lesions which selectively removed all of the hippocampus and dentate gyrus except the most ventral portions. They were impaired on both spontaneous and rewarded discrete-trial alternation in T-mazes. Acquisition of reference memory for the location of a hidden platform in the Morris water maze was impaired in lesioned mice. On an elevated Y-maze reference memory task, in which only one arm was rewarded, lesioned mice showed no evidence of learning. In a Lashley III maze task, however, where maze rotation demonstrated that control performance was independent of distal spatial cues, acquisition in the lesioned mice was unimpaired. Control levels of continuous spontaneous alternation in a Y-maze were too low to reveal a hippocampal deficit. A small impairment in acquisition of a multiple-trial passive avoidance task was seen in lesioned mice, despite a small but significant increase in reactivity to the footshock. These results are largely consistent with findings in hippocampal lesioned rats on the same or similar tasks, and reflect a major impairment of spatial cognition, with relative sparing of non-spatial task performance.