Vitamin E protects against alcohol-induced cell loss and oxidative stress in the neonatal rat hippocampus

Oxidative stress has been proposed as a possible mechanism underlying nervous system deficits associated with Fetal Alcohol Syndrome (FAS). Current research suggests that antioxidant therapy may afford some level of protection against the teratogenic effects of alcohol. This study examined the effectiveness of antioxidant treatment in alleviating biochemical, neuroanatomical, and behavioral effects of neonatal alcohol exposure. Neonatal rats were administered alcohol (5.25 g/kg) by intragastric intubation on postnatal days 7, 8, and 9. A subset of alcohol-exposed pups were co-administered a high dose of Vitamin E (2 g/kg, or 71.9 IU/g). Controls consisted of a non-treated group, a group given the administration procedure only, and a group given the administration procedure plus the Vitamin E dose. Ethanol-exposed animals showed impaired spatial navigation in the Morris water maze, a decreased number of hippocampal CA1 pyramidal cells, and higher protein carbonyl formation in the hippocampus than controls. Vitamin E treatment alleviated the increase in protein carbonyls and the reduction in CA1 pyramidal cells seen in the ethanol-exposed group. However, the treatment did not improve spatial learning in the ethanol-exposed animals. These results suggest that while oxidative stress-related neurodegeneration may be a contributing factor in FAS, the antioxidant protection against alcohol-induced oxidative stress and neuronal cell loss in the rat hippocampus does not appear to be sufficient to prevent the behavioral impairments associated with FAS. Our findings underscore the complexity of the pathogenesis of behavioral deficits in FAS and suggest that additional mechanisms beyond oxidative damage of hippocampal neurons also contribute to the disorder.     

Middle-aged, but not young, rats develop cognitive impairment and cortical neurodegeneration following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion

Permanent, stepwise occlusion of the vertebral arteries (VAs) and internal carotid arteries (ICAs) following the sequence VA→ICA→ICA, with an interstage interval (ISI, →) of 7 days, has been investigated as a four-vessel occlusion (4-VO)/ICA model of chronic cerebral hypoperfusion. This model has the advantage of not causing retinal damage. In young rats, however, 4-VO/ICA with an ISI of 7 days fails to cause behavioral sequelae. We hypothesized that such a long ISI would allow the brain to efficiently compensate for cerebral hypoperfusion, preventing the occurrence of cognitive impairment and neurodegeneration. The present study evaluated whether brain neurodegeneration and learning/memory deficits can be expressed by reducing the length of the ISI and whether aging influences the outcome. Young, male Wistar rats were subjected to 4-VO/ICA with different ISIs (5, 4, 3 or 2 days). An ISI of 4 days was used in middle-aged rats. Ninety days after 4-VO/ICA, the rats were tested for learning/memory impairment in a modified radial maze and then examined for neurodegeneration of the hippocampus and cerebral cortex. Regardless of the ISI, young rats were not cognitively impaired, although hippocampal damage was evident. Learning/memory deficits and hippocampal and cortical neurodegeneration occurred in middle-aged rats. The data indicate that 4-VO/ICA has no impact on the capacity of young rats to learn the radial maze task, despite 51% hippocampal cell death. Such resistance is lost in middle-aged animals, for which the most extensive neurodegeneration observed in both the hippocampus and cerebral cortex may be responsible.     

Flupirtine reduces functional deficits and neuronal damage after global ischemia in rats

Global cerebral ischemia leads to selective neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum. In addition, it results in deficits in spatial learning and memory as shown by an increase in escape latency and swim distance during the escape trials and a reduction of time spent in the quadrant of the former platform position during the probe trial of the water maze. Flupirtine is a non-opioid, centrally acting analgesic which has been shown to be neuroprotective against N-methyl-

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-aspartate (NMDA)-mediated toxicity in vitro. The purpose of the present study was to investigate the potential protective effect of flupirtine in vivo with both behavioural and histological measures of global cerebral ischemia. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Flupirtine was administered at a dose of 5 mg/kg i.p. either 20 min before and 50 min after occlusion (pre-treatment) or directly and 70 min after occlusion (post-treatment). 1 week after surgery, spatial learning and memory was tested in the Morris water maze. Pre-treatment with flupirtine reduced the increase in escape latency and in swim distance induced by 4VO. It also diminished the deficit in spatial memory as revealed by an increase in time spent in the quadrant of the former platform position during the probe trial which was reduced by 4VO. Post-treatment with flupirtine had no effect on the deficits in spatial learning and memory induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated with pre-treatment of flupirtine whereas post-treatment did not affect this neuronal damage. The present data demonstrate that pre-treatment with flupirtine exerts a protective effect on hippocampal and striatal neuronal damage and on deficits in spatial learning induced by 4VO. © 1997 Elsevier Science B.V. All rights reserved.     

Protective effects of brain hypothermia on behavior and histopathology following global cerebral ischemia in rats

The present experiments were designed to assess whether brain hypothermia can reduce the behavioral and histopathological deficits associated with global forebrain ischemia. Animals were subjected to 12.5 min of four vessel occlusion (4VO) with moderate hypotension, and brain temperature maintained at either 37°C (4VO-37) or 30°C (4VO-30). Behavioral tests designed to assess forelimb reflexes and sensorimotor function were given on post-operative weeks 2 and 4. Beginning in week 5, the rats were trained on a variety of navigation problems in the Morris water maze. Histopathological examination of the tissue 2 months following reperfusion revealed that 4VO-30 animals sustained substantial cell death in hippocampal region CA1 and moderate damage to the dorsolateral neostriatum. 4VO-30 animals showed minimal cell death in CA1 and neostriatum. There were no group differences for any of the sensorimotor measures, or for acquisition performance on either the simple place task or visible platform version of the water maze. In contrast, during acquisition of the learning set performance of 4VO-37 animals was impaired relative to either of the other groups, whereas the performance of 4VO-30 animals was not significantly different from the sham controls. These data suggest that moderate intra-ischemic brain hypothermia provides long-lasting protection from behavioral deficits as well as neuronal injury following transient global ischemia.     

Rat models of dementia based on reductions in regional glucose metabolism,cerebral blood flow and cytochrome oxidase activity

Summary. Three models are described in rats which attempt to mimic morphological and behavioural pathology of Alzheimers dementia; intracerebroventricular injection of streptozotocin (STZ), permanent bilateral carotid artery occlusion (2VO) and brain mitochondrial cytochrome oxidase inhibition by sodium azide. Learning and memory are impaired within 4 weeks in all models. This probably involves a reduction in cortical and/or hippocampal cholinergic neurotransmission. STZ causes microglial activation and specific damage to myelinated tracts in the fornix through generation of oxidative stress, thereby disrupting connections between the septum and hippocampus. 2VO results in damage to myelin and CA1 cells in hippocampus and in abnormal processing of APP to -amyloid. It is not known if microglial activation and neuronal damage occur after sodium azide administration. Memory and learning can be improved in the STZ and 2VO models by estradiol, melatonin and cholinesterase inhibitors. Antioxidants and neuroprotective agents may also decrease memory deficits by preventing inflammation and neurodegeneration.     

Long‐lasting modulation of synaptic plasticity in rat hippocampus after early‐life complex febrile seizures

A small fraction of children with febrile seizures appears to develop cognitive impairments. Recent studies in a rat model of hyperthermia‐induced febrile seizures indicate that prolonged febrile seizures early in life have long‐lasting effects on the hippocampus and induce cognitive deficits. However, data on network plasticity and the nature of cognitive deficits are conflicting. We examined three specific measures of hippocampal plasticity in adult rats with a prior history of experimental febrile seizures: (i) activity‐dependent synaptic plasticity (long‐term potentiation and depression) by electrophysiological recordings of Schaffer collateral/commissural‐evoked field excitatory synaptic potentials in CA1 of acute hippocampal slices; (ii) Morris water maze spatial learning and memory; and (iii) hippocampal mossy fiber plasticity by Timm histochemistry and quantification of terminal sprouting in CA3 and the dentate gyrus. We found enhanced hippocampal CA1 long‐term potentiation and reduced long‐term depression but normal spatial learning and memory in adult rats that were subjected to experimental febrile seizures on postnatal day 10. Furthermore, rats with experimental febrile seizures showed modest but significant sprouting of mossy fiber collaterals into the inner molecular layer of the dentate gyrus in adulthood. We conclude that enhanced CA1 long‐term potentiation and mild mossy fiber sprouting occur after experimental febrile seizures, without affecting spatial learning and memory in the Morris water maze. These long‐term functional and structural alterations in hippocampal plasticity are likely to play a role in the enhanced seizure susceptibility in this model of prolonged human febrile seizures but do not correlate with overt cognitive deficits.     

The antioxidant LY 231617 ameliorates functional and morphological sequelate induced by global ischemia in rats

In this study the effect of LY 231617, an antioxidant, on spatial learning deficit on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. LY 231617 (20 mg/kg i.p.) was administered after onset of reperfusion. One week after surgery spatial learning was tested in the Morris water maze. LY 231617 reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus produced by 4VO was significantly attenuated by LY 231617. The present data demonstrate that posttreatment with LY 231617 exerts a protective effect on hippocampal neuronal damage and deficits in spatial learning induced by 4VO.     

Differential effects of tumor necrosis factor-alpha co-administered with amyloid beta-peptide (25-35) on memory function and hippocampal damage in rat

Effects of concurrent intracerebroventricular administration of amyloid-beta peptide 25-35 (Abeta(25-35)) and the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) to rats were investigated. A battery of behavioral tests including radial arm maze, passive avoidance, elevated plus-maze and forced swim test as well as histological methods were used. A single administration of Abeta(25-35) induced delayed behavioral deficits manifested in reference and working memory disturbances in the radial maze task involving spatial memory. However, no effects of Abeta(25-35) on learning or retention in a passive avoidance test could be revealed. Abeta(25-35) appeared to decrease anxiety without affecting depression-like behavior in the rats. Abeta(25-35)-induced cognitive deficits could be related to the moderate neuronal cell loss found in the hippocampal CA1 field. Though administration of TNFalpha did not impair learning and memory of rats in the radial maze, it induced gross changes in their behavior during passive avoidance training. Though TNFalpha did not protect against Abeta(25-35)-induced neuronal cell loss in the CA1 field of hippocampus, co-administration of TNFalpha with Abeta(25-35) resulted in an improvement of reference memory impaired by the amyloid peptide, but not of working memory.     

Does neuronal damage of CA1 relate to spatial memory performance of rats subjected to transient forebrain ischemia?

The effect of ischemia-induced hippocampal neuronal damage on acquisition and performance in the Morris water maze task was investigated in male Wistar rats, subjected to 8 min of transient forebrain ischemia, induced by the 4-vessel occlusion (4-VO) method. After a morphological scoring of the neuronal damage within the CA1, CA2, and CA3 subfields of the anterior-dorsal part of hippocampus we found that rats with a total neuronal cell loss of the anterior-dorsal CA1 region showed memory performance impairments in the acquisition trials, in a probe trial, and in a reversal experiment. However, rats with only partial damage to the CA1 region did not exhibit significant impairments during the acquisition trials of the water maze test or in the probe trial and the reversal experiment. In conclusion, these results suggest that it is possible to relate the histological damage score of CA1 in the anterior-dorsal hippocampus to impaired memory performance in the present water maze setup.     

Effects of discrete kainic acid-induced hippocampal lesions on spatial and contextual learning and memory in rats

Substantial information is available concerning the influence of global hippocampal lesions on spatial learning and memory, however the contributions of discrete subregions within the hippocampus to these functions is less well understood. The present investigation utilized kainic acid to bilaterally lesion specific areas of the rat hippocampus. These animals were subsequently tested on a spatial orientation task using a circular water maze, and on an associative/contextual task using passive avoidance conditioning. The results indicate that both the dorsal CA1 and the ventral CA3 subregions play important roles in learning. Specifically, CA1 lesions produced a deficit in the acquisition of the water maze task and a significant memory impairment on the passive avoidance task. CA3 lesions also caused learning deficits in the acquisition of the water maze task, and produced even greater impairments in performance on the passive avoidance task. We conclude that CA1 and CA3 hippocampal subregions each play significant roles in the overall integration of information concerning spatial and associative learning.     

盐酸法舒地尔对慢性脑低灌注损伤大鼠海马细胞的保护作用

目的 观察Rho激酶抑制剂盐酸法舒地尔(hydroxy fasudil, HF)对慢性低灌注脑缺血所致大鼠海马神经细胞损伤的保护作用。方法 采用永久性结扎大鼠双侧颈总动脉(permanent occlusion of the bilateral CCA, 2VO)制备大鼠慢性不完全性全脑缺血模型,将SD大鼠随机分为假手术组、脑缺血模型组和HF治疗组,运用Morris 水迷宫行为学方法检测大鼠空间学习记忆能力; 用HE染色观察海马组织形态学改变。结果 Morris 水迷宫检测发现模型组大鼠学习记忆能力受损,与假手术组比较逃避潜伏期延长、空间辨别能力下降; 组织学观察模型组大鼠海马CA1细胞发生丢失,组织结构异常。连续给予盐酸法舒地尔30 d能改善大鼠学习记忆功能,减少脑缺血所致的大鼠海马神经细胞丢失。结论 盐酸法舒地尔可减少慢性脑缺血所致的大鼠海马神经元的丢失,改善学习记忆功能。     

Degeneration of newly formed CA1 neurons following global ischemia in the rat

The pyramidal neurons of the hippocampal CA1 region are essential for spatial learning and memory and are almost entirely destroyed 7-14 days after transient cerebral ischemia (DAI). Recently, we found that CA1 neurons reappeared at 21-90 DAI, in association with a recovery of ischemia-induced deficits in spatial learning and memory. However, at 125 DAI the number of neurons was fewer than at 90 DAI, suggesting that the new nerve cells undergo neurodegeneration during this time period. We therefore investigated whether neuronal degeneration occurred between 90 and 250 DAI and how this related to learning and memory performance. We found that many of the new CA1 neurons previously seen at 90 DAI had disappeared at 250 DAI. In parallel, large mineralized calcium deposits appeared in the hippocampus and thalamus, in association with neuroinflammatory and astroglial reactions. In spite of the extensive CA1 damage, the ischemic rats showed no deficiencies in spatial learning and memory, as analyzed in the Morris water maze and a complimentary water maze test based on sequential left-right choices. However, ischemia rats showed a general increase in swim length in the Morris water maze suggesting altered search behaviour. Taken together, these results indicate that the CA1 neurons that reappear after transient global ischemia to a large extent degenerate at 125-250 DAI, in parallel with the appearance of a less efficient search strategy.     

Diabetes impairs learning performance through affecting membrane excitability of hippocampal pyramidal neurons

Previous research has demonstrated that diabetes induced learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Sprague-Dawley rats were used in the present study to investigate the effect of streptozotocin (STZ)-induced diabetes on spatial learning and memory with the Morris water maze. The excitability of CA1 pyramidal neurons in hippocampus was also examined. Diabetes impaired spatial learning and memory of rats. Diabetes decreased the membrane excitability of CA1 pyramidal neurons, effects which may contribute to the behavioral deficits. To investigate the further ionic mechanisms, the sodium currents and the potassium currents were detected. Diabetes decreased both transient and persistent sodium currents, and increased both transient and sustained potassium currents, which leads to the reduction of neuron excitability and to the increase of firing accommodation. The results of the present study suggested that sodium and potassium currents contributed to the inhibitory effect of diabetes on neuron excitability, further influencing learning and memory processing. Modulating the ion channels and increasing the membrane excitability are possible candidates for preventing the impairments of diabetes on hippocampal function.     

Eag1, Eag2, and SK3 potassium channel expression in the rat hippocampus after global transient brain ischemia

Transient global brain ischemia causes delayed neuronal death in the hippocampus that has been associated with impairments in hippocampus-dependent brain function, such as mood, learning, and memory. We investigated the expression of voltage-dependent Kcnh1 and Kcnh5, ether à go-go-related Eag1 and Eag2 (K(V) 10.1 and K(V) 10.2), and small-conductance calcium-activated SK3 (K(Ca) 2.3, Kcnn3) K(+) channels in the hippocampus in rats after transient global brain ischemia. We tested whether the expression of these channels is associated with behavioral changes by evaluating the animals in the elevated plus maze and step-down inhibitory avoidance task. Seven or tweny-eight days after transient global brain ischemia, one group of rats had the hippocampus bilaterally dissected, and mRNA levels were determined. Seven days after transient global brain ischemia, the rats exhibited a decrease in anxiety-like behavior and memory impairments. An increase in anxiety levels was detected 28 days after ischemia. Eag2 mRNA downregulation was observed in the hippocampus 7 days after transient global brain ischemia, whereas Eag1 and SK3 mRNA expression remained unaltered. This is the first experimental evidence that transient global brain ischemia temporarily alters Eag2. The number of intact-appearing pyramidal neurons was substantially decreased in CA1 and statistically measurable in CA2, CA3, and CA4 hippocampal subfields compared with sham control animals 7 or 28 days after ischemia. mRNA expression in the rat hippocampus. The present results provide further information for the characterization of the physiological role of Eag2 channels in the central nervous system.     

Persistent behavioral impairments and neuroinflammation following global ischemia in the rat

Cognitive deficits associated with cardiac arrest have been well documented; however, the corresponding deficits in animal models of global ischemia have not been comprehensively assessed, particularly after long‐term, clinically relevant survival times. We exposed male Sprague–Dawley rats to 10 min of bilateral carotid artery occlusion + systemic hypotension (40–45 mmHg) or sham surgery, and used histopathological assessments for short‐term survival animals (16 days) and both behavioral and histopathological assessments for long‐term survival animals (270 days). Analyses revealed significant long‐term deficits in ischemic animals’ learning, memory (T‐maze, radial arm maze), working memory (radial arm maze), and reference memory (Morris water maze, radial arm maze) abilities that were not associated with a general cognitive decline. Histological results showed significant increases in glial fibrillary acidic protein, neuron glia 2, OX‐42 and ED‐1 staining, as well as significant decreases in microtubule‐associated protein 2 staining and cornu ammonis area 1 (CA1) cell counts 16 days post‐ischemia. The pattern at 270 days was similar, but notably there was a persistent elevation of ED‐1 staining, suggesting recent cell death as well as significant atrophy of CA1. Whereas previous work has primarily reported transient changes in behavior after global ischemia, this study describes disturbances in several different functional domains following CA1 cell loss at clinically relevant survival times. Moreover, the histopathological outcome is suggestive of a spontaneous repopulation of CA1, but this was not sufficient to offset the behavioral impairments arising from the ischemic insult.     

Gestational protein restriction induces CA3 dendritic atrophy in dorsal hippocampal neurons but does not alter learning and memory performance in adult offspring

Studies have demonstrated that nutrient deficiency during pregnancy or in early postnatal life results in structural abnormalities in the offspring hippocampus and in cognitive impairment. In an attempt to analyze whether gestational protein restriction might induce learning and memory impairments associated with structural changes in the hippocampus, we carried out a detailed morphometric analysis of the hippocampus of male adult rats together with the behavioral characterization of these animals in the Morris water maze (MWM). Our results demonstrate that gestational protein restriction leads to a decrease in total basal dendritic length and in the number of intersections of CA3 pyramidal neurons whereas the cytoarchitecture of CA1 and dentate gyrus remained unchanged. Despite presenting significant structural rearrangements, we did not observe impairments in the MWM test. Considering the clear dissociation between the behavioral profile and the hippocampus neuronal changes, the functional significance of dendritic remodeling in fetal processing remains undisclosed.     

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.     

Age‐related decrease in theta and gamma coherence across dorsal ca1 pyramidale and radiatum layers

In both humans and rodents, aging is linked to impairments in hippocampus dependent learning. Given such deficits, one would expect corresponding changes in hippocampal local field potentials, which represent the integration of multiple inputs onto a given dendritic field within the hippocampus. The current experiment examined coherence of theta and gamma in young and aged rats at sub‐millimeter and millimeter distant locations both within and across layers in CA1 of the dorsal hippocampus. The degree to which different dendritic layers show coherent oscillations indicates the uniformity of the inputs and local circuitry, and may form an important element for processing information. Aged rats had lower coherence in all frequency ranges; this was most marked within a layer as the distance between electrodes increased. Notably, unlike younger rats, in the aged rats coherence was not affected by running on the maze. Furthermore, despite the previously reported effects of cholinergic activation on theta frequency and power, there was no effect of the cholinomimetic physostigmine on coherence. These data indicate an age related fragmentation in hippocampal processing that may underlie some of the observed learning and memory deficits. © 2015 Wiley Periodicals, Inc.     

Effects of test experience and neocortical microgyria on spatial and non-spatial learning in rats

Neocortical neuronal migration anomalies such as microgyria and heterotopia have been associated with developmental language learning impairments in humans, and rapid auditory processing deficits in rodent models. Similar processing impairments have been suggested to play a causal role in human language impairment. Recent data from our group has shown spatial working memory deficits associated with neocortical microgyria in rats. Similar deficits have also been identified in humans with language learning impairments. To further explore the extent of learning deficits associated with cortical neuronal migration anomalies, we evaluated the effects of neocortical microgyria and test order experience using spatial (Morris water maze) and non-spatial water maze learning paradigms. Two independent groups were employed (G1 or G2) incorporating both microgyria and sham conditions. G1 received spatial testing for five days followed by non-spatial testing, while the reverse order was followed for G2. Initial analysis, including both test groups and both maze conditions, revealed a main effect of treatment, with microgyric rats performing significantly worse than shams. Overall analysis also revealed a task by order interaction, indicating that each group performed better on the second task as compared to the first, regardless of which task was presented first. Independent analyses of each task revealed a significant effect of treatment (microgyria worse than sham) only for the spatial water maze condition. Results indicate that prior maze experience (regardless of task type) leads to better subsequent performance. Results suggest that behavioral abnormalities associated with microgyria extend beyond auditory and working memory deficits seen in previous studies, to include spatial but not non-spatial learning impairments and that non-specific test experience may improve behavioral performance.     

Age-related structural changes in the rat hippocampus: correlation with working memory deficiency

Age-related histopathological changes in the hippocampal formation were correlated with cognitive performance, evaluated in rats at the 8-arm radial maze. Experiments were conducted using young (3 months), mature (12 months), middle-aged (17 months) and aged (24 months) Wistar rats. Significant memory impairments were already observed at the age of 12 months in all the measured parameters (correct choices, percent errors and total time). No further decline was observed between 12 and 17 months of age, while at 24 months additional decline was monitored mainly in the percent errors parameter. Morphometric analysis revealed a decrease in the area of cells within the hippocampus and the number of cells in the CA3 subfield. This pattern of morphological changes with age corresponded well with the cognitive impairments, with high correlation especially to lesions at the CA3 subfield. It had also been confirmed in this study that lipofuscin appeared to be a good histochemical marker for CNS cell degeneration. It is concluded that 12-month-old Wistar rats may serve as the animal model of choice for the study of specific age-related behavioral deficits and that the hippocampal CA3 region might play a major role in the age-dependent cognitive decline.