Caffeic acid effects on oxidative stress in rat hippocampus after pilocarpine-induced seizures

The objective of the study was to evaluate the caffeic acid (CA) effects against the oxidative stress (OS) observed during seizures. Wistar rats were intraperitoneally treated with either 0.9% saline (control), CA (4 mg/kg), pilocarpine (400 mg/kg, pilocarpine group), or the association of CA (4 mg/kg) plus pilocarpine (400 mg/kg). The thiobarbituric-acid-reacting substances and the hippocampal nitrite content were significantly increased (89 and 94%, respectively) in pilocarpine group when compared with control. There were marked decreases in lipid peroxidation level (43%) and nitrite content (45%) in CA group when compared with pilocarpine group. There were no marked alterations in superoxide dismutase (SOD) and catalase (CAT) activities in pilocarpine group; however, the SOD and CAT activities were significantly increased (35 and 51%, respectively) after CA pretreatment. Our findings strongly support the hypothesis that OS was indeed generated in hippocampus. CA pretreatment can reduces the OS produced by seizures.     

The effects of acute stress and acute corticosterone administration on the immobility response in rats

The immobility response is an innate antipredatory behavior in a broad variety of species. The immobility response varies in its postural components but in general is characterized by an absence of movement and a relative unresponsiveness to stimuli. Experimentally in rats, clamping the neck followed by body inversion and manual restrain elicits a response called “immobility by clamping the neck”. Stress reactions protect animals against predators and are characterized by activation of the sympathetic and hypothalamic–pituitary–adrenal systems. However, in mammals, the role of acute stress as a modulator of immobility response has been less studied. The aim of our study was to assess the effects of acute stress and the injection of corticosterone (5 mg/kg, ip) on immobility by clamping the neck in rats. We observed that either previous acute stress caused by forced exposure to elevated open platform or application of a heat-pain stimulus to the rat's tail during the immobility increased the duration of the immobility response caused by clamping the neck. Also, the corticosterone produced a rapid increase (15 min after injection) in the duration of this immobility response. Our results show that the acute stress, in rats, is a facilitator of the immobility response and suggest a possible nongenomic rapid action of corticosterone over brain structures that control this behavior.     

Changes in lipid peroxidation in the hippocampus and neocortex after severe hypobaric hypoxia in rats

We studied the effects of severe hypobaric hypoxia followed by reoxygenation at the level and the time course of changes in free radical lipid oxidation in the hippocampus, neocortex, and mitochondriaenriched neocortical fraction of rats. We found that severe hypobaric hypoxia induced long-term changes in lipid peroxidation in the brain structures susceptible to hypoxia, the hippocampus and the neocortex.     

Effects of chronic stress and corticosterone on sialidase activity in the rat hippocampus

Sialidases are acid exoglycosidases that catalyse the removal of sialic acid from non-reducing end of sialoglucoconjugated substrates. Synaptic plasticity depends on sialylation state of proteins and lipids mediated by sialic acid-metabolizing enzymes. Since chronic stress causes both, hippocampal atrophy and impairment of learning, it is reasonable to investigate whether sialidase is implicated in these processes. In this study, we tested effects of chronic stress (immobilization, 2 h daily, 21 days) or chronic corticosterone administration (5 mg/kg, sc, daily) on sialidase activity and sialylated NCAMs expression in rat hippocampus.The results showed that chronic stress affects hippocampus-depended spatial learning in the Barnes maze. Both, stress (p > 0.05) and corticosterone (p < 0.001), increased latencies to enter the escape tunnel of the maze in comparison to control animals. Similar but not significant differences between control and other experimental groups were observed in the numbers of errors. Chronic stress (p > 0.05) and corticosterone (p < 0.05) decreased sialidase activity in the brain homogenates and synaptosomes (p < 0.05, both). In the stressed animals, these changes were related to significantly higher expression of polysialic acid. These results indicate that changes in sialidase activity caused by stress and chronic corticosterone administration reflect disturbances of polysialylated glycoconjugates known to be related to synaptic plasticity in hippocampus.     

Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats

Recent in vivo and in vitro experiments have demonstrated that second-generation antipsychotic drugs (SGAs) might have neuroprotective effects. Ziprasidone is a SGA that is efficacious in the treatment of schizophrenia. In this study, we sought to analyze the effects of ziprasidone on the expression of the neuroprotective protein brain-derived neurotrophic factor (BDNF) in the rat hippocampus and neocortex, with or without immobilization stress. The effect of ziprasidone (2.5 mg/kg) on the expression of BDNF mRNA was determined by in situ hybridization in tissue sections from the rat hippocampus and neocortex. Haloperidol (1.0 mg/kg) was used for comparison. Haloperidol strongly decreased the expression of BDNF mRNA in both the hippocampal and cortical regions, with or without immobilization stress (p < 0.01). In contrast, the administration of ziprasidone significantly attenuated the immobilization stress-induced decrease in BDNF mRNA expression in the rat hippocampus and neocortex (p < 0.01). Ziprasidone exhibited differential effects on BDNF mRNA expression in the rat hippocampus and neocortex. These results suggest that ziprasidone might have a neuroprotective effect by recovering stress-induced decreases in BDNF mRNA expression.     

The effects of losartan and immobilization stress on heart rate variability and plasma corticosterone levels in rats

In this study, the effects of losartan, an angiotensin II receptor antagonist, on heart rate variability and the changes of plasma corticosterone levels caused by immobilization stress were investigated. Losartan (3 mg/kg, p.o.) significantly prevented increases in plasma corticosterone levels in both losartan+acute stress and losartan+chronic stress groups. But, losartan did not prevent the diminution of the power of heart rate variability caused by stress. Our results supported the idea that the renin-angiotensin system is also involved in the stress- induced cardiovascular response, besides the autonomic nervous system. But, the effects of losartan on heart rate variability remained controversial.     

发育期大鼠海马氨基酸类神经递质的研究

目的用高效液相色谱法检测大鼠海马组织中氨基酸类神经递质,研究它们在发育期大鼠海马中含量的变化.方法采用安捷伦反相高效液相色谱柱(ZORBAX,XDB,C18,4.6mm×250mm,5μm,Agilent),异硫氰酸苯酯为柱前衍生剂,在柱温38℃下采用二元梯度洗脱,于254 nm波长处用VARIAN-Prostar 325紫外检测器和LC-WORKSTATION-V6.2色谱数据处理系统检测和处理对照品和大鼠海马样品的氨基酸色谱数据,并计算乳鼠、幼鼠和成鼠海马氨基酸含量.结果氨基酸含量在Asp0.036～0.586 mg/ml、Glu0.027～0.4336 mg/ml、Gly0.053～0.8438 mg/ml、Tau0.039～0.6312 mg/ml和GABA0.0268～0.4288 mg/ml时,其峰面积与氨基酸含量的线性相关系数均大于0.9995;五种氨基酸回收率在96.0%～106%之间.三组样品间五种氨基酸含量的差别均有极显著性意义(P<0.01).结论该法检测大鼠海马组织中氨基酸类神经递质灵敏,特异性好,且分析时间短.氨基酸类神经递质含量随大鼠海马的发育而增高.     

慢性冷水游泳应激对大鼠海马、前脑皮层神经颗粒素含量的影响

目的探讨慢性应激对大鼠海马和前脑皮层神经颗粒素(NG)含量的影响。方法将雄性SD大鼠随机分为应激组(予10℃冷水游泳应激,共2周)、装置对照组和正常对照组,每组10只。于应激前后测量三组大鼠的体质量变化情况,并记录每天应激过程中应激组和装置对照组的排便量以考察应激的强度,应激后以Westernblotting方法测定海马和前脑皮层中的NG含量(以NG含量与βActin含量的比值表示)。结果(1)应激前后,三组大鼠的体质量比较,差异均无统计学意义(P>0.05),但应激组的体质量增长相对缓慢;(2)应激第4—14天应激组的排便量多于装置对照组(P<0.01);(3)应激组和装置对照组海马的NG含量[分别为(0.66±0.13)和(0.94±0.26)]低于正常对照组[(1.93±0.53)],差异有统计学意义(P<0.01);(4)应激组前脑皮层的NG含量[(0.45±0.00)]低于装置对照组和正常对照组[分别为(2.76±1.74)和(2.87±1.63)],差异有统计学意义(P<0.01);(5)应激组海马NG含量高于前脑皮层(P<0.01);装置对照组海马NG含量低于前脑皮层(P<0.01);正常对照组海马与前脑皮层NG含量的差异无统计学意义。结论慢性应激导致海马和前脑皮层NG含量显著下降;对于时程长、程度严重、适应不良的冷水游泳应激,前脑皮层受损比海马更为严重;而对于时程长、程度微弱的装置应激,海马则比前脑皮层更为敏感。     

The development of long-term potentiation in hippocampus and neocortex

The development of long-term potentiation (LTP), an enduring alteration in synaptic efficacy following afferent activation, was examined in CA1 hippocampus and primary visual cortex of rat. Both regions show little LTP prior to postnatal day 5, demonstrate a maximal potentiated response around postnatal day 15, and a subsequent decline to adult levels. These results are discussed with respect to the underlying mechanism of action and behavioral significance of these critical-period phenomena.     

Changes in total serum immunoreactive neurophysins and corticosterone levels after restraint stress in rats

This study indicates that total immunoreactive circulating neurophysins (IRN) increased in male rats submitted to acute restraint stress. Total immunoreactive serum corticosterone levels also were elevated, confirming the stressful character of the restraint situation. It is speculatively suggested that IRN elevations due to stress are the reflection of a corticotropin releasing factor (CRF)-IRN product.     

Combined treatment with pantothenic acid derivatives and memantine alleviates scopolamine-induced amnesia in rats: The involvement of the thiol redox state and coenzyme A

Free-radical-mediated processes are involved in a variety of physiological events, while oxidative stress and related redox deregulation are implicated in various pathological events. Tripeptide glutathione plays an important role in the antioxidant defense of the brain, particularly in the maintenance of the optimal redox state in neurons and glial cells. We studied the combined effects of pantothenic acid derivatives, pantothenol and calcium pantothenate, and memantine, which is a glutamate receptor antagonist that is widely used for the treatment of dementia, on amnesia induced by scopolamine in rats. Scopolamine induced amnesia in rats; however, unexpectedly, this effect was even more expressed in the memantine-pretreated animals. Memory impairments were less manifested in the rats that were pretreated with memantine in combination with panthenol or calcium pantothenate. The detrimental scopolamine effect on memory was accompanied by significant depletions of glutathione and coenzyme A in the brain. While memantine recovered the glutathione status to some extent, it nevertheless further aggravated the scopolamine influence on coenzyme A levels. An alleviation of scopolamine-induced memory impairments that was observed after combined pretreatment with memantine and panthenol or calcium pantothenate was accompanied by a normalization of coenzyme A levels, while the effects on glutathione redox did not correlate with the behavioral data.     

Computational principles of learning in the neocortex and hippocampus

We present an overview of our computational approach towards understanding the different contributions of the neocortex and hippocampus in learning and memory. The approach is based on a set of principles derived from converging biological, psychological, and computational constraints. The most central principles are that the neocortex employs a slow learning rate and overlapping distributed representations to extract the general statistical structure of the environment, while the hippocampus learns rapidly, using separated representations to encode the details of specific events while suffering minimal interference. Additional principles concern the nature of learning (error-driven and Hebbian), and recall of information via pattern completion. We summarize the results of applying these principles to a wide range of phenomena in conditioning, habituation, contextual learning, recognition memory, recall, and retrograde amnesia, and we point to directions of current development.     

Lymphocyte infiltration of neocortex and hippocampus after a single brief seizure in mice

Various immune responses have been described in epileptic patients and animal models of epilepsy, but immune responses in brain after a single seizure are poorly understood. We studied immune responses in brain after a single brief generalized tonic–clonic seizure in mice. C57bl/6 mice, either unanesthetized or anesthetized (pentobarbital, ethyl chloride) received either electrical (15–30 mA, 100 Hz, 1 s) or sham stimulation (subcutaneous electrodes over frontal lobe, no current). Electrical stimulation of unanesthetized mice resulted in tonic–clonic convulsions with hind-limb extension (maximal seizure), tonic–clonic convulsions without hind-limb extension (submaximal seizure), or no seizure. In contrast, such stimulation of anesthetized mice did not result in seizure. Mice were killed at 1 h–7 days after seizure. Brains or regions dissected from brain (neocortex, hippocampus, midbrain, cerebellum) of each group were pooled, single cell suspensions prepared, and cells separated according to density. CD4⁺ (CD3⁺CD45^Hi) and CD8⁺ (CD3⁺CD45^Hi) T cell and CD45R⁺ (CD45^Hi) B cell numbers were determined by flow cytometry. At 24 h after a maximal seizure, CD4⁺ and CD8⁺ T cells and CD45R⁺ B cells appeared in brain, reaching peak numbers at 48 h, but were no longer detected at 7 days. CD4⁺ T cells and CD45R⁺ B cells were preferentially found in neocortex compared with hippocampus, whereas CD8⁺ T cells were preferentially found in hippocampus at 24 h after a maximal seizure. In contrast, virtually no lymphocytes were detected in brains of unstimulated or sham stimulated mice, unanesthetized stimulated mice after submaximal or no seizure, and anesthetized stimulated mice at 1 h–7 day. Neither Ly6-G+ neutrophils nor erythrocytes were detected in brains of any animals, nor was there any detectable increase of blood–brain barrier permeability by uptake of Evans Blue dye. The results indicate that lymphocyte entry into brain after a single brief seizure is due to a selective process of recruitment into cortical regions.     

Early changes in neurons of the hippocampus and neocortex in transgenic rats expressing intracellular human a-beta

Alzheimer's disease (AD) studies typically focus on the extracellular impact of the amyloid-beta (Abeta) protein, however recent findings also implicate intracellular Abeta (iAbeta) accumulation in the disease's molecular neuropathology. In a double mutant transgenic rat model (AbetaPP and PS1 mutations, UKUR25), stably expressing intracellular human Abeta fragments in an environment devoid of both amyloid plaques and neurofibrillary tangles, we investigated the impact of iAbeta burden on both the incidence and relative cross sectional areas of the Golgi apparatus, lysosomes and lipofuscin bodies. Pyramidal cells within the hippocampus and neocortex of both transgenic and non-transgenic age matched controls were compared. This comparison revealed a significant increase in both the proportional area occupied by Golgi apparatus elements as well as in the mean individual cross sectional area of Golgi compartments in the hippocampus of transgenic rats as compared to controls. Elevated lysosome and lipofuscin elements in the hippocampi of transgenic rats were observed, as was an increase in the mean individual, cross sectional area of lipofuscin bodies in the cortex of transgenic rats as compared to controls. These findings support the hypothesis that intracellular Abeta accumulation not only has an impact on subcellular compartments but also potentially contributes to the neuronal cell pathology observed in AD.     

Electrical activity of the hippocampus and neocortex in rats depleted of brain dopamine and norepinephrine: Relations to behavior and effects of atropine

Spontaneous behavior and cerebral electroencephalographic (EEG) activity were studied in rats depleted of the brain catecholamines dopamine (DA) and norepinephrine (NE) by intraventricular injections of 6-hydroxydopamine. It was found that there was a direct relation between the amount of DA depleted and degree of adipsia-aphagia, akinesia (lack of spontaneous activity), and sensorimotor neglect. Results from a number of tests as well as 24-h videorecordings showed that the rats with little or no central dopamine did not eat or drink, walk spontaneously, or orient to tactile stimulation, but they did initiate grooming as often as control rats. Video-recordings also showed that the DA-depleted rats made continuous postural adjustments, a behavior which may be similar to the akathisia or motor impatience described as a human Parkinson's disease symptom. EEG recordings revealed that both atropine-resistant (movement-related), and atropine-sensitive (immobility-related) forms of neocortical low-voltage, fast activity (LVFA) and hippocampal rhythmic slow activity (RSA or theta) survive depletion of brain DA and NE. Furthermore, the amplitude and frequency of theta activity were not changed by DA depletion. It is suggested that neither DA nor NE are critically important for the production of LVFA or RSA although DA may be indirectly involved in regulating the probability of their occurrence by regulating the probability of the occurrence of movement.     

The functions of the preplate in development and evolution of the neocortex and hippocampus

Recently, it has been shown that the early developmental organization of the archicortical hippocampus resembles that of the neocortex. In both cortices at embryonic stages, a preplate is present, which is split by the formation of the cortical plate into a marginal zone and a subplate layer. The pioneer neurons of the preplate are believed to form a phylogenetically ancient cortical structure. Neurons in these preplate layers are the first postmitotic neurons and have important roles in the development of the cerebral cortex. Cajal–Retzius cells in the marginal zone regulate the phenotype of radial glial cells and may direct neuronal migration establishing the inside-out gradient of corticogenesis. Furthermore, pioneer neurons form the initial axonal connections with other (sub)cortical structures. A significant difference between the hippocampus and neocortex, however, is that in the hippocampus, most afferents are guided by the pioneer neurons in the prominent marginal zone, while in the neocortex most ingrowing afferent axons enter via the subplate. At later developmental periods, most pioneer neurons disappear by cell death or transform into other neuronal shapes. Here, we review the early developmental organization of the mammalian cerebral cortex (both neocortex and hippocampus) and discuss the functions and fate of pioneer neurons in cortical development, in particular that of Cajal–Retzius cells. Evaluating the developmental properties of the hippocampus and neocortex, we present the hypothesis that the distribution of the main ingrowing afferent systems in the developing neocortex, which differs from the one in the hippocampal region, may have enabled the specific evolution of the neocortex.     

Widespread but regionally specific effects of experimenter- versus self-administered morphine on dendritic spines in the nucleus accumbens,hippocampus, and neocortex of adult rats

We studied the effects of self-administered (SA) vs. experimenter-administered (EA) morphine on dendritic spines in the hippocampal formation (CA1 and dentate), nucleus accumbens shell (NAcc-s), sensory cortex (Par1 and Oc1), medial frontal cortex (Cg3), and orbital frontal cortex (AID) of rats. Animals in the SA group self-administered morphine in 2-h sessions (0.5 mg/kg/infusion, i.v.) for an average of 22 sessions and animals in the EA group were given daily i.v. injections of doses that approximated the total session dose for matched rats in Group SA (average cumulative dose/session of 7.7 mg/kg). Control rats were given daily i.v. infusions of saline. One month after the last treatment the brains were processed for Golgi-Cox staining. In most brain regions (Cg3, Oc1, NAcc-s) morphine decreased the density of dendritic spines, regardless of mode of administration (although to a significantly greater extent in Group SA). However, only SA morphine decreased spine density in the hippocampal formation and only EA morphine decreased spine density in Par1. Interestingly, in the orbital frontal cortex morphine significantly increased spine density in both Groups SA and EA, although to a much greater extent in Group SA. We conclude: 1) Morphine has persistent (at least 1 month) effects on the density of dendritic spines in many brain regions, and on many different types of cells (medium spiny neurons, pyramidal cells, and granule cells); 2) The effect of morphine on spine density (and presumably synaptic organization) varies as a function of both brain region and mode of drug administration; and 3) The ability of morphine to remodel synaptic inputs in a regionally specific manner may account for the many different long-term sequelae associated with opioid use.     

Prolactin and corticosterone secretion in response to acute stress after paraventricular nucleus lesion by ibotenic acid

The cellular organization of the paraventricular nucleus (PVN) is complex and eight distinct regions have been identified by Nissl staining. Three consist of magnocellular neurons and five of parvocellular neurons. Ibotenic acid, a glutamate analogue, is a toxin with neuroexcitatory properties which acts on N-methyl-D-aspartate and metabotropic receptors. Depending on the dose used, ibotenic acid causes extensive damage of parvocellular neurons of the paraventricular nucleus but preserves magnocellular neurons and passage fibers, in contrast to electrolytic lesions, which causes diffuse and nonspecific destruction. We studied the prolactin (PRL) and corticosterone secretion in response to acute stress induced by exposure to the ether, 3 weeks after selective neurotoxic lesion of parvocellular neurons of the paraventricular nucleus by microinjection of ibotenic acid. There was no significant difference in the basal levels of PRL and corticosterone between control and lesioned animals. The plasma PRL increased in the sham and lesioned groups after stress of similar manner. However, the increase in plasma corticosterone in response to stress was significantly higher in lesioned animals. In conclusion, the selective lesion of parvocellular neurons of the PVN did not change basal or stress induced PRL secretion but it caused hypersensitivity of the hypothalamus-pituitary-adrenal axis 3 weeks later, probably by corticotropin releasing hormone (CRH) from hypothalamic areas others than parvocellular neurons of the PVN; hypersensitivity of corticotropes to the secretagogues others than CRH; or hyperresponsiveness of AVP receptors in the adenohypophysis. Furthermore, we cannot rule out a putative inhibitory factor of the hypothalamus-pituitary axis produced by parvocellular neurons of the PVN. This factor modulator of corticotropin secretion could be absent after recuperation of the response of the hypothalamus-pituitary axis to the stress.     

Intraendothelial accumulation of calcium in the hippocampus and thalamus of rats after systemic kainic acid administration

Summary The accumulation of calcium in the hippocampal and thalamic vascular endothelium and the perivascular space was detected histochemically by means of the pyroantimonate technique 30, 60 and 120 min after systemic kainic acid administration. An increased number of calcium pyroantimonate deposits was found in the endothelial mitochondria 60 min after kainate injection. The mitochondria were swollen at this time and vacuoles containing deposits were observed. After 120 min a pronounced perivascular glial swelling was conspicuous, besides the numerouos endothelial mitochondrial deposits. The swollen glial processes contained a large number of pyroantimonate deposits. It seems likely that the transendothelial calcium transport processes are accompanied by intraendothelial calcium accumulation and mitochondrial calcium sequestration.