Short-term glucocorticoid manipulations affect neuronal morphology and survival in the adult dentate gyrus

In order to determine whether short-term glucocorticoid manipulations influence the morphology and survival of neurons in the adult mammalian hippocampal formation, we performed quantitative analyses of Golgi-impregnated and Nissl-stained tissue from the brains of sham operated male rats, adrenalectomized male rats and adrenalectomized male rats which received corticosterone replacement. Three days after adrenalectomy, massive cell death, as detected by a dramatic increase in number of pyknotic cells, was observed in the granule cell layer of the dentate gyrus. By seven days following adrenalectomy, the numbers of pyknotic cells were even greater. Moreover, significant decreases in cross-sectional cell body area and numbers of dendritic branch points of Golgi-impregnated dentate gyrus granule cells were detected at seven days after adrenalectomy. Replacement of corticosterone to adrenalectomized rats prevented the appearance of large numbers of pyknotic cells as well as the decrease in granule cell cross-sectional cell body area and the numbers of dendritic branch points. In contrast, no obvious signs of degeneration were detected in the pyramidal cell layers of the CA1 and CA3 regions of the hippocampus at either three or seven days following adrenalectomy. In addition, no significant changes in morphological characteristics were observed in CA1 or CA3 pyramidal cells with adrenalectomy. These results show that dentate gyrus granule cells require glucocorticoids for their survival and for the maintenance of normal morphology and suggest that granule cell morphology and/or survival may undergo constant fluctuation in response to diurnal rhythms or stress-induced changes in glucocorticoid levels.     

Adrenalectomy and corticosterone replacement differentially alter CA3 dendritic morphology and new cell survival in the adult rat hippocampus

Plastic changes in the adult mammal hippocampus can be altered by many factors and perhaps the most well-documented is stress. Stress and elevated corticosterone levels have been shown to decrease hippocampal neurogenesis and decrease the complexity of CA3 pyramidal neurons. However, the extent of these changes in relation to low and moderately elevated levels of corticosterone has yet to be fully investigated. Therefore, the aim of the present study was to determine how low to moderately elevated circulating corticosterone levels affect dendritic morphology of CA3 pyramidal cells and hippocampal neurogenesis in adult male rats. To do this, three groups of adult male Wistar rats were used: (1) Sham-operated, (2) Adrenalectomized (ADX), and (3) ADX + corticosterone replacement. Primary results show that adrenalectomy, but not moderately elevated levels of corticosterone replacement, resulted in significant atrophy of CA3 pyramidal neurons. Interestingly, moderate corticosterone replacement resulted in significantly more surviving new cells in the dentate gyrus when compared to sham controls. This work shows that circulating levels of corticosterone differentially affect plasticity in the CA3 region and the dentate gyrus.     

缺血后适应减轻树鼩缺血性脑水肿及脑梗死的机制

目的 观察缺血后适应对树鼩血栓性脑缺血时大脑皮层脑水含量、局部脑血流、梗塞面积及神经元超微结构的影响,探讨其对树鼩脑缺血时神经保护的可能机制。 方法 将88只健康成年树鼩随机分为对照组、脑缺血4 h组、脑缺血24 h组、后适应4 h组及后适应24 h组（每组n=8）,另取8只动物做HE染色（n=3）及电子显微镜观察（n=5）。本实验采用光化学反应诱导树鼩血栓性脑缺血而建立脑缺血动物模型,在脑缺血模型建成后4 h夹闭缺血侧颈总动脉5 min,再灌注5 min,如此交替进行3个循环以建立缺血后适应模型。测定大脑皮层局部脑血流,脑组织含水量,脑梗死范围,并观察皮层及海马CA1区神经元超微结构改变。 结果 脑缺血时神经元固缩,线粒体肿胀,嵴溶解或形成空泡,内质网肿胀,内质网池形成。缺血后适应能使海马CA1区神经元固缩减少,线粒体和内质网的病理改变减轻,细胞水肿改善。随着缺血时间的延长,缺血24h组脑水含量明显增加86.81%±1.08%,此时脑梗塞面积明显扩大33.00%±3.03%,局部脑血流明显降低（134.27±28.75）ml/min。缺血后适应24h组脑组织含水量明显减少（81.04%±1.04%,P＜0.01）;脑梗塞面积缩小（16.79%±1.29%,P＜0.01）;而局部脑血流明显增加［（195.25±21.18）ml/min,P＜0.01］。 结论 缺血后适应可缓解树鼩缺血性脑水肿并缩小梗死范围,其机制可能与改善局部脑血流有关。     

Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats

BACKGROUND: Sensorimotor gating, as measured by prepulse inhibition of the startle reflex, is deficient in schizophrenia patients, and in rats after specific manipulations of limbic cortico-striato-pallido-thalamic circuitry. For example, prepulse inhibition in rats is disrupted after D1 blockade in the medial prefrontal cortex, and after N-methyl-D-aspartate infusion into the ventral hippocampus. In the present study, we examined whether these two substrates form part of an integrated circuit regulating sensorimotor gating, which might contribute to the loss of prepulse inhibition in patient populations. METHODS: Prepulse inhibition was assessed in male Sprague-Dawley rats after systemic or intra-medial prefrontal cortex administration of the D1 antagonist, SCH 23390. Separate rats received intra-medial prefrontal cortex infusion of the retrograde transported label Fluoro-Gold. In rats with sham or electrolytic lesions of the medial prefrontal cortex, prepulse inhibition was tested after infusion of N-methyl-D-aspartate or vehicle into ventral hippocampus regions that were determined to send projections to the medial prefrontal cortex. RESULTS: Prepulse inhibition was disrupted after systemic SCH 23390 treatment and after infusion of SCH 23390 into medial prefrontal cortex sites within the prelimbic and cingulate cortices. Fluoro-Gold infusion into these medial prefrontal cortex sites labeled cells in the ventral hippocampus complex, including regions CA1 and entorhinal cortex. N-methyl-D-aspartate infusions into these ventral hippocampus regions disrupted prepulse inhibition in rats after sham but not electrolytic lesions of the medial prefrontal cortex. CONCLUSIONS: Prepulse inhibition appears to be regulated by interacting substrates within the ventral hippocampus and MPFC. Specifically, NMDA activation of the ventral hippocampus appears to disrupt prepulse inhibition in a manner that is dependent on the integrity of infralimbic or cingulate cortical regions that also support a D1-mediated regulation of prepulse inhibition. Conceivably, dysfunction within these hippocampal-frontal circuits may contribute to sensorimotor gating deficits in schizophrenia.     

Temporal and region-dependent changes in muscarinic M4 receptors in the hippocampus and entorhinal cortex of adrenalectomized rats

Long-term adrenalectomy induces a dramatic loss of cells in the dentate gyrus and CA1-CA4 fields of the hippocampus resulting in an impairment of cognitive functions such as spatial learning, memory and exploratory behaviour. Muscarinic M₁ and M₄ receptor levels in the hippocampus and entorhinal cortex of adult male Wistar rats were examined 3, 14, 30, 90, and 150 days after adrenalectomy. Receptor levels in the entorhinal cortex and the hippocampus were determined by quantitative autoradiography using ¹²⁵I-M₁-toxin-1 and ¹²⁵I-M₄-toxin-1, M₁ and M₄ subtype selective antagonists, respectively. Moreover, the level of hippocampal M₁ and M₄ muscarinic receptors were evaluated 1 month after adrenalectomy by immunoblot analysis. Adrenalectomy induced apoptotic processes were examined by analysing apoptotic markers using Western blot analysis. No significant changes were observed in the level of muscarinic M₁ receptors in the entorhinal cortex, the dentate gyrus and in the different CA fields of the hippocampus of adrenalectomized (ADX) rats. However, M₄ receptors showed a significant decrease in the entorhinal cortex (at 3 days), dentate gyrus and CA4 (at 14 days), CA3 (at 30 days), and CA2 and CA1 (at 90 days) after adrenalectomy. Moreover, a decrease in the level of M₄ receptors was detected in ADX rats 1 month after adrenalectomy as compared with sham groups using M₄ specific antibody. Apoptotic markers such as PARP and p53 were significantly increased whereas Bcl-2 marker was decreased in ADX rat brain homogenates compared to controls. Our results show that M₁ and M₄ receptors are differentially affected by adrenalectomy and indicate that these subtypes have different functions in the hippocampus. Our data on time and region-dependent decreases in hippocampal M₄ receptors indicate that the M₄ receptor subtype is influenced by adrenal hormones and suggest that the M₄ receptor might be linked to memory function in the hippocampus.     

Long-term lack of endogenous glucocorticoids down-regulates glucocorticoid receptor levels in the rat forebrain

To understand the effect of a chronic lack of endogenous glucocorticoids on glucocorticoid receptor levels, the changes of glucocorticoid receptor content in the rat forebrain five months after adrenalectomy were investigated. In the long-term adrenalectomized rats that showed a hormone deficiency and loss of glucocorticoid receptor immunoreactivity in the forebrain, an intraperitoneal injection of corticosterone was used to elevate the serum hormone levels and recover glucocorticoid receptor immunoreactivity in the forebrain. One hour later, when the blood corticosterone returned to the normal level, the recovery of glucocorticoid receptor immunoreactivity in the forebrain was examined by immunohistochemistry. Since the complete restoration of glucocorticoid receptor immunoreactivity was shown to depend on the presence of normal levels of both serum hormone and intracellular glucocorticoid receptors, the weak reappearance of glucocorticoid receptor immunoreactivity in any forebrain area of the long-term adrenalectomized rats that had normal serum corticosterone might reflect the low intracellular glucocorticoid receptor levels there. Our results revealed a weak reappearance of glucocorticoid receptor immunoreactivity in some forebrain areas of the long-term adrenalectomized rats after corticosterone treatment; the hippocampal granule cell layer and cerebral cortex in particular showed very weak recovery of glucocorticoid receptor immunoreactivity. Conversely, neurons in the CA1/CA2 subfields of the hippocampal pyramidal cell layer, immediately adjacent to the granule cell layer on the same brain section, exhibited a strong reappearance of glucocorticoid receptor immunoreactivity, to near normal levels.

These results suggest that, five months after adrenalectomy, the intracellular glucocorticoid receptor content decreased in the rat granule cell layer and cerebral cortex. Therefore, the long-term lack of endogenous glucocorticoids after adrenalectomy might down-regulate but not up-regulate the intracellular glucocorticoid receptor level, and the presence of glucocorticoids is important for the continued synthesis of glucocorticoid receptors.     

Corticosteroids and ACTH are not required for compensatory adrenal growth.

We have tested the hypothesis that unilateral adrenalectomy results in decreased glucocorticoid secretion, reflexly elevated ACTH secretion, and consequently, compensatory adrenal growth. Plasma ACTH and corticosterone and right adrenal weight were measured during the first 10 days after left adrenalectomy or sham adrenalectomy in young male rats. There is a decrease in plasma corticosterone after unilateral adrenalectomy compared to sham adrenalectomy that persists for 1 h. ACTH is elevated only at 2 h after unilateral adrenalectomy compared to shamoperated rats. Treatment with dexamethasone, shown to abolish the ACTH and corticosterone responses to laparotomy with intestinal traction, resulted in significantly increased adrenal weight after unilateral adrenalectomy by 6 h (wet or dry weight), and at 24 h. Compensatory adrenal growth also occurs after unilateral adrenalectomy in hypophysectomized rats (wet or dry weight). We conclude the compensatory adrenal growth after unilateral adrenalectomy requires neither a virtual decrease in circulating corticosterone levels nor elevated ACTH levels, and speculate that the phenomenon is neurally mediated.     

Chronic stress exposure influences local cerebral blood flow in the rat hippocampus.

To examine the influence of chronic stress on the brain, we measured local cerebral blood flow in the hippocampus of rats which had been exposed to chronic stress by the hydrogen clearance method in the freely moving status. Rats were exposed, once a day for 12 weeks, to stress of a 15-min immersion in cold water at 4 degrees C (the stress group) or slightly handled for about 1 min (the control group). Local cerebral blood flow values in the hippocampus, which were measured after a 12-week recovery period, were lower in rats in the stress group than those of rats in the control group only in the dark cycle, but not in the light cycle. Accordingly, local cerebral blood flow in the hippocampus of rats in the stress group did not have a daily fluctuation, i.e. lower in the light cycle and higher in the dark cycle, as was shown in rats in the control group. There were no significant changes in motor activity in rats in the stress group as compared to those in the control group. Severe structural damages were observed in the CA2 and CA3 cell fields of the hippocampus of rats in the stress group. We found that an increase in local cerebral blood flow in the hippocampus in the dark cycle was blunted following chronic stress exposure, suggesting that chronic stress exposure caused hippocampal neurons to be less responsive to environmental stimuli derived from motor activity during the dark cycle.     

Adrenalectomy fails to alter radial maze performance of rats at retention intervals of 24 hours or less

Evidence suggests that the behavioral actions of adrenalectomy and glucocorticoid replacement therapy result from changes in the binding of corticosterone to specific receptors in the hippocampus. Efficient foraging for bait on the radial maze has been demonstrated to require a functionally intact hippocampal system. The present experiment examined the effect of adrenalectomy on the ability of rats to locate unexplored arms in the radial maze after various retention intervals midway through completion of the maze. Rats were very proficient at locating the unexplored arms after retention intervals of 3 hours or less; significantly more trials were required to locate all of the previously unvisited arms at retention intervals of 8 and 24 hours. However, adrenalectomy failed to alter maze performance at any retention interval tested. It was concluded that the neural substrates involved in the performance of this spatial/working memory task are not dependent upon the neuromodulatory effects of physiological levels of adrenal corticosteroids. The results are discussed in terms of behavior/contingency conflicts and innate versus learned responses as factors which may be important for revealing behavioral actions of adrenalectomy or corticosteroid therapy.     

Activation of the intracerebral cholinergic nerve fibers originating in the basal forebrain increases regional cerebral blood flow in the rat's cortex and hippocampus

In the rat, activation of the intracerebral cholinergic system originating in the basal forebrain and projecting to the cortex and hippocampus releases acetylcholine in the cortex and hippocampus, which results in vasodilation and an increase in regional cerebral blood flow (rCBF) in the cortex and hippocampus. The augmentation of rCBF is independent of both systemic blood pressure and regional metabolism. The intracerebral cholinergic fibers are able to act as autonomic nerve fibers for the regulation of cortical and hippocampal blood flow.     

Dynamic exercise improves cognitive function in association with increased prefrontal oxygenation

The Stroop test was performed before and after ergometer exercise for 15 min at 20, 40, and 60 % of maximum voluntary exercise (EX_max), in order to examine whether dynamic exercise is capable of improving cognitive function and whether the changes in regional cerebral blood flow of the prefrontal cortex are associated with the cognitive improvement. Subjects were asked to answer the displayed color of incongruent color words as quickly as possible. The total time period and the number of errors for the Stroop test were measured as an index of cognitive function. The concentrations of oxygenated-hemoglobin (Oxy-Hb) and deoxygenated-hemoglobin (Deoxy-Hb) in the cerebral prefrontal area were measured with near-infrared spectroscopy to determine the changes in regional cerebral blood flow. Ergometer exercise at 40 % of EX_max, but not 20 and 60 % of EX_max, shortened (P < 0.05) the total time period for the Stroop test by 6.6 ± 1.5 % as compared to the time control. In contrast, the number of errors was not altered by exercise at any intensity. The Oxy-Hb in bilateral prefrontal cortices increased during the Stroop test, while the Deoxy-Hb in those areas was unchanged. Ergometer exercise at 40 % of EX_max, but not at 20 and 60 % of EX_max, significantly augmented the response in the prefrontal Oxy-Hb during the Stroop test. The magnitude of the increased prefrontal Oxy-Hb response tended to correlate with the reduction in total time period for the Stroop test. Thus, it is likely that ergometer exercise at moderate intensity for 15 min may improve cognitive function through the increased neural activity in the prefrontal cortex.     

Effects of NMDA and calcium channel antagonists on regional cerebral blood flow.

N-Methyl-D-aspartate (NMDA) antagonists and voltage-dependent calcium channel antagonists were tested to determine potential effects on regional cerebral blood flow in the normal rabbit brain. Ketamine had no effects on cortical or hippocampal blood flow, but was found to significantly decrease blood flow in the inferior colliculus. MK-801 decreased blood flow in almost all regions of the brain tested. On the other hand, nimodipine significantly increased flow in the cortex, hippocampus, and tegmentum. Dextromethorphan and dextrorphan, which have been shown to act at the NMDA receptor as well as the dihydropyridine calcium channel, decreased blood flow in the inferior colliculus, but showed no effects in the cortex or hippocampus. These results suggest that the neuroprotective NMDA antagonists do not increase blood flow primarily in the normal brain.     

Neonatal hippocampal lesions in rhesus macaques alter the monitoring, but not maintenance, of information in working memory

Neonatal hippocampal damage in rodents impairs medial prefrontal working memory functions. To examine whether similar impairment will follow the same damage in primates, adult monkeys with neonatal hippocampal lesions and sham-operated controls were trained on two working memory tasks. The session-unique delayed nonmatch-to-sample (SU-DNMS) task measures maintenance of information in working memory mediated by the ventral lateral prefrontal cortex. The object self-ordered (Obj-SO) task measures monitoring of information in working memory mediated by the dorsolateral prefrontal cortex. Adult monkeys with neonatal hippocampal lesions performed as well as sham-operated controls on the SU-DNMS task at either the 5- or 30-s delays but were severely impaired on the Obj-SO task. These results extend the earlier findings in rodents by demonstrating that early lesions of the hippocampus in monkeys impair working memory processes known to require the integrity of the dorsolateral prefrontal cortex while sparing lower order working memory processes such as recency. Although the present results suggest that the lack of functional hippocampal inputs may have altered the maturation of the dorsolateral prefrontal cortex, future studies will be needed to determine whether the nature of the observed working memory deficit is due to an absence of the hippocampus, a maldevelopment of the dorsolateral prefrontal cortex, or both.     

Localization and glucocorticoid regulation of 11beta-hydroxysteroid dehydrogenase type 1 mRNA in the male mouse forebrain

The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone. There is accumulating evidence indicating widespread expression of 11beta-HSD1 in the brain. However, there is little information about regulation of 11beta-HSD1 expression in this tissue. Using in situ hybridization involving use of 35S-labeled cRNA probe, we have studied the distribution of cells expressing 11beta-HSD1 mRNA in the male mouse forebrain as well as the effects of adrenalectomy (ADX) and acute administration of corticosterone (3 and 24 h) on 11beta-HSD1 mRNA levels. Cells expressing 11beta-HSD1 mRNA were mostly detected in the cerebral cortex, hippocampus, amygdala and medial preoptic area, with the highest expression in the cerebral cortex (retrosplenial granular area) and hippocampus (CA3 and granular layer of the gyrus dentatus). Seven days following ADX, 11beta-HSD mRNA levels were increased by 50% in the gyrus dentatus, by 100% in the CA3 area, and 105% in the cerebral cortex. Administration of corticosterone to ADX mice induced a significant decrease in mRNA, in both the hippocampus and cerebral cortex so that, at the 24 h time interval, the levels were similar to those observed in intact mice. These results clearly indicate that circulating corticosterone is downregulating the expression of 11beta-HSD1 mRNA in the two forebrain areas studied. This downregulation might contribute to maintain low intracellular corticosterone levels in central regions and then prevent the deleterious effects induced by high glucocorticoid levels.     

Effects of nicotine on blood flow and delayed neuronal death following intermittent transient ischemia in rat hippocampus

A cholinergic neural vasodilative response in the cerebral cortex and hippocampus, independent of metabolic vasodilation, was recently demonstrated by activating the nicotinic acetylcholine receptors (nAChRs) via activation of cholinergic neurons originating in the nucleus basalis of Meynert and septal complex in the basal forebrain and projecting to the cortex and hippocampus (see reviews by Sato A and Sato Y: Neurosci Res 14: 242--274, 1992; Sato A and Sato Y: Alzheimer Dis Assoc Disord 9: 28--38, 1995). In the present study, we aimed to examine whether an increase in regional blood flow in the hippocampus (Hpc-BF) following stimulation of the nAChRs by i.v. injection of nicotine could improve the delayed death of the hippocampal neurons following transient ischemia in rats. Hpc-BF was measured by using a laser Doppler flowmeter. During intermittent (every 2 min) transient occlusion for a total of 6 min of bilateral carotid arteries besides permanent ligation of bilateral vertebral arteries, Hpc-BF decreased to about 16% of the preocclusion level, and 5 or 7 d later, after the occlusion, delayed neuronal death occurred in approximately 70% of the CA1 hippocampal neurons. Hpc-BF was increased dose-dependently by injection of nicotine (30--100 microg/kg, i.v.), independent of mean arterial pressure. Nicotine (30--100 microg/kg) administered 5 min before occlusion slightly but significantly attenuated the occlusion-induced decrease in Hpc-BF. The delayed death of the CA1 hippocampal neurons occurring after transient occlusion was attenuated by pretreatment with nicotine (30--100 microg/kg) to approximately 50% of the total neurons. The results indicate that nAChR stimulation-induced increases in Hpc-BF can protect against ischemia-induced delayed death of hippocampal neurons.     

脑络欣通及其拆方对脑缺血再灌注大鼠海马CA1区Fas、Fas L蛋白及皮质Fas mRNA表达影响的实验研究

目的： 探讨脑络欣通及其拆方对局灶性脑缺血再灌注大鼠海马CA1区Fas、FasL蛋白及皮质Fas mRNA表达的影响。方法： 采用线栓法大鼠大脑中动脉阻塞复制局部脑缺血再灌注模型,缺血2 h分别再灌注 1 d、3 d、7 d，随机分为假手术组、模型组、益气药组、活血药组和脑络欣通组。应用免疫组化和原位杂交法,观察缺血侧海马CA1区Fas、FasL蛋白及额顶叶皮质Fas mRNA表达。结果： 局灶性脑缺血再灌注后,缺血侧海马CA1区Fas、FasL蛋白表达平均吸光度值比假手术组增强(P＜0.01），额顶叶皮质Fas mRNA表达平均吸光度和阳性面积值强于假手术组(P＜0.01），脑络欣通组Fas、FasL蛋白和Fas mRNA表达各时段均显著低于模型组(P＜0.05或P＜0.01)；其拆方益气药、活血药组于3 d、7 d显著低于模型组(P＜0.05或P＜0.01)；脑络欣通组于3 d或/和 7 d 显著低于其拆方益气药、活血药组(P＜0.05或P＜0.01)。结论： 脑络欣通及其拆方益气药、活血药可通过抑制海马CA1区Fas、FasL蛋白和Fas mRNA表达，抗局部脑缺血再灌注神经细胞的凋亡，减轻病理性损伤。     

Intracerebroventricular injection of Aβ1-42 combined with two-vessel occlusion accelerate Alzheimer’s disease development in rats

Numerous experimental studies and clinical observations suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer’s disease (AD). Two-vessel occlusion caused cerebral ischemia model is often used in the study of vascular dementia (VaD). But how cerebral ischemia works on AD rat model which induced by intracerebroventricular injection of Aβ_1-42 remains unclear. In the following study, we investigated the characteristics of rat model caused by intracerebroventricular injection of Aβ_1-42 or two-vessel occlusion (2-VO) only and by both of the two operations. The animal cognitive functions were accessed by the Morris water maze. Regional cerebral blood flow was detected by Laser Doppler Blood Flowmeter. HE&Nissl staining, Congo red staining and immunohistochemistry were used to observe the status of neuronal loss, Aβ deposition and the phosphorylated tau expression in hippocampus, respectively. We also measured the contents of AchE and ChAT in serum and hippocampus by Enzyme Linked Immunosorbent Assay. The MWM results showed that rats of Aβ_1–42+2-VO group had a disorder in cognitive functions, at an early stage of one week after modeling, comparing with rats of sham group. The regional cerebral blood flow (rCBF) was significantly reduced in Aβ_1-42+2-VO and 2-VO group one week after modeling, and still maintained low perfusion levels four weeks after modeling. HE and Nissl staining showed that Aβ_1-42+2-VO rats’ hippocampal CA1 neurons were in disorder, degeneration and necrosis, severe neuronal loss from the first week to the fourth week, while this phenomenon only appeared in the fourth week after modeling in rats of Aβ_1-42 group and 2-VO group. Congo red staining showed that Aβ_1-42 + 2-VO group rats’ hippocampus CA1 had amyloid deposits from the first week to the fourth week, Aβ_1-42 group were not find amyloid deposition significantly until four weeks after modeling, however, 2-VO group had no significant amyloid deposition all the time. Notably, IHC showed that, two weeks after modeling, the p-tau positive total area and integrated optical density of hippocampal CA1 region were significantly increased in Aβ_1-42 + 2-VO group rats, while 2-VO group and Aβ_1-42 group rats had no significantly changes all the time. We also found that the content of AchE was increased both in serum and hippocampus of Aβ_1-42 + 2-VO group rats, and ChAT was decreased. However, there was no significantly change in cortex of content of AchE: acetylcholinesterase (AchE) and choline acetylase (ChAT) all three groups. Together, our study suggest that intracerebroventricular injection of Aβ_1-42 combined with two-vessel occlusion may accelerate Alzheimer’s disease development in rats. Also, this may serve as a less-time consuming new model to study the Alzheimer’s disease and especially AD accompanied by cerebral ischemia.     

Neonatal lesions of the ventral hippocampus in rats lead to prefrontal cognitive deficits at two maturational stages

This experiment assessed the effect of neonatal ventral hippocampus lesions in rats, a heuristic approach to model schizophrenia, on continuous delayed alternation and conditional discrimination learning performance before and after complete cerebral maturation. Delays (0, 5, 15, and 30 s) were introduced in the tasks to help dissociate between a hippocampal and a prefrontal cortex dysfunction. At postnatal day (PND) 6 or 7, rats received bilateral microinjections of ibotenic acid or phosphate-buffered saline in the ventral hippocampus. From PND 26 to PND 35, rats were tested on the alternation task in a T-maze; from PND 47 to PND 85, the same rats were tested in the discrimination task where a stimulus and a response location had to be paired. Deficits in ventral hippocampus-lesioned rats were observed in both tasks whether a delay was introduced before a response or not. Impaired performance regardless of delay length, combined with high rates of perseverative errors, suggested a post-lesional prefrontal cortex dysfunction which persisted from the juvenile stage into adulthood. Premature cognitive impairments could not be predicted on the basis of the neurodevelopmental animal model of schizophrenia. Nevertheless, they appear consistent with accounts of premorbidly compromised memory, both immediate and delayed, in subgroups of schizophrenia patients.     

Glucose transporter plasticity during memory processing

Various types of learning, including operant conditioning, induce an increase in cellular activation concomitant with an increase in local cerebral glucose utilization (LCGU). This increase is mediated by increased cerebral blood flow or changes in brain capillary density and diameter. Because glucose transporters are ultimately responsible for glucose uptake, we examined their plastic expression in response to cellular activation. In vitro and in vivo studies have demonstrated that cerebral glucose transporter 1 (GLUT1) expression consistently parallels changes in LCGU. The present study is the first to investigate the effect of memory processing on glucose transporters expression. Changes in GLUT expression produced by training in an operant conditioning task were measured in the brain of CD1 mice. Using semi-quantitative immunohistochemistry, Western blot and real time RT-PCR the cerebral GLUT1 and GLUT3 expression was quantified immediately, 220 min and 24 h following training. Relative to sham-trained and naive controls, operant conditioning training induced an immediate increase in GLUT1 immunoreactivity level in the hippocampus CA1 pyramidal cells as well as in the sensorimotor cortex. At longer post-learning delays, GLUT1 immunoreactivity decreased in the sensorimotor cortex and putamen. Parallel to the changes in protein levels, hippocampus GLUT1 mRNA level also increased immediately following learning. No effect of learning was found on hippocampal GLUT3 protein or mRNA expression. Measures of changes in glucose transporters expression present a link between cellular activation and glucose metabolism. The learning-induced localized increases in GLUT1 protein as well as mRNA levels observed in the present study confirm the previous findings that GLUT1 expression is plastic and respond to changes in cellular metabolic demands.     

Effect of sex and age on brain monoamines and spatial learning in rats

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were measured in the prefrontal cortex, caudate-putamen, and hippocampus in young (3 months) and aged (27–31 months) Wistar rats of both sexes. Age-related changes were found in prefrontal NA and HVA/DA ratio, striatal DA and DOPAC/DA ratio, and striatal and hippocampal 5-HT and 5-HIAA/5-HT ratio. Age and sex dependent changes were found in striatal DA and DOPAC/DA ratio, and hippocampal MHPG-SO₄/NA ratio. The aged rats were tested in spatial discrimination and reversal tasks in a T maze. The effects of α₂-agonist medetomidine (3 μg/kg) on the task performance were assessed in relation to individual variation in monoamine metabolism. Medetomidine impaired spatial discrimination learning of the aged rats by interacting with the hippocampal 5-HT turnover. Medetomidine improved reversal learning through an interaction with the striatal DA turnover and reduced the number of perseverative errors after reversal, mainly due to its interaction with the prefrontal NA turnover. It is concluded that the memory enhancing effect of drugs acting through the brain monoamine systems is highly dependent on the stage of degeneration of these systems that show considerable individual variation in aged animals.