Deficits in cortico-striatal synaptic plasticity and behavioral habituation in rats with portacaval anastomosis

Hepatic encephalopathy is characterized by disturbances of motor and cognitive functions involving the basal ganglia. So far no standards for assessment of neuropsychiatric abnormalities (disorders of sleep, mood, anxiety and personality) in subclinical hepatic encephalopathy have been defined. Using an animal model of mild (subclinical) hepatic encephalopathy we investigated now striatum-related behaviors and cortico-striatal synaptic plasticity in rats 2 months after introduction of a portacaval shunt and sham-operated matched controls. In a novel open field portacaval shunt rats displayed less locomotor activity; unlike controls they also showed no habituation to the field and no recall of the field environment after 24 h, indicative of cognitive deficit. The elevated-plus maze test indicated no differences in fear/anxiety in the portacaval shunt animals. Tetanic stimulation of cortical afferents in magnesium-free solution evoked an N-methyl-D-aspartate-dependent long-term potentiation in sham-operated animals. In portacaval shunt animals long-term potentiation was significantly impaired. Histamine, a potent modulator of cortico-striatal transmission, induced a larger long-term depression of field potentials in control compared with portacaval shunt rats. In conclusion, a combination of electrophysiological and behavioral approaches has revealed functional changes in cortico-striatal transmission. These data are relevant for understanding the mechanisms of motor and cognitive dysfunctions in hepatic encephalopathy patients and for the development of precise psychometric tests, evaluating cognitive deficits in subclinical hepatic encephalopathy.     

Neonatal rat hypoxia-ischemia: long-term rescue of striatal neurons and motor skills by combined antioxidant-hypothermia treatment

Perinatal hypoxia-ischemia can cause long-term neurological and behavioral disability. Recent multicenter clinical trials suggest that moderate hypothermia, within 6 h of birth, offers significant yet incomplete protection. We investigated the effect of combined treatment with the antioxidant N-tert-butyl-(2-sulfophenyl)-nitrone (S-PBN) and moderate hypothermia on long-term neuronal injury and behavioral disability. S-PBN or its diluent was administered 12-hourly to rats from postnatal day (PN) 7 to 10. On PN8, hypoxia-ischemia was induced. Immediately post-hypoxia, additional S-PBN and 6 h of moderate hypothermia or additional diluent and 6 h of normothermia were administered. At 1 week, and at 11 weeks, after hypoxia-ischemia, the absolute number of surviving medium-spiny neurons was measured in the coded right striatum. In a separate experiment, skilled forepaw ability was investigated in coded 9- to 11-week-old rats. Normal, uninjured animals were also tested for motor skills at 9- to 11-weeks-of-age. The combination of S-PBN and moderate hypothermia provided statistically significant short- and long-term protection of the striatal medium-spiny neurons to normal control levels. This combinatorial treatment also preserved fine motor skills to normal control levels. The impressive histological and functional preservation suggests that S-PBN and moderate hypothermia is a safe and attractive combination therapy for perinatal hypoxia-ischemia.     

Effects of sensorimotor restriction and anoxia on gait and motor cortex organization: implications for a rodent model of cerebral palsy

Chronic or acute perinatal asphyxia (PA) has been correlated with the subsequent development of cerebral palsy (CP), a developmental neurological disorder characterized by spasticity and motor abnormalities often associated with cognitive deficits. Despite the prevalence of CP, an animal model that mimics the lifetime hypertonic motor deficits is still not available. In the present study, the consequences of PA on motor behavior, gait and organization of the primary motor cortex were examined in rats, and compared with the behavioral and neurological consequences of early postnatal movement-restriction with or without oxygen deprivation. Rats subjected to PA had mild increases in muscular tone accompanied by subtle differences in walking patterns, paralleled by significantly altered but relatively modest disorganization of their primary motor cortices. Movement-restricted rats, suffering PA or not, had reduced body growth rate, markedly increased muscular tone at rest and with active flexion and extension around movement-restricted joints that resulted in abnormal walking patterns and in a profoundly distorted representation of the hind limbs in the primary motor cortex. Within the sensorimotor-restricted groups, non-anoxic rats presented the most abnormal pattern and the greatest cortical representational degradation. This outcome further supports the argument that PA per se may represent a substrate for subtle altered motor behaviors, and that PA alone is sufficient to alter the organization of the primary motor cortex. At the same time, they also show that early experience-dependent movements play a crucial role in shaping normal behavioral motor abilities, and can make a powerful contribution to the genesis of aberrant movement abilities.     

Sexually dimorphic cognitive style, female sex hormones, and cortical nitric oxide

Recent studies using the water maze (WM) found marked sex differences in behavioral strategy employed in place learning tasks in adult rats. When a change in the platform position is introduced following learning the place of a platform (visible or hidden) in a different position, female rats escape to the newly positioned visible platform faster than males. Nitric oxide (NO) is implicated in place learning, and there are regional sex differences in its stable metabolites, NO(2)(-)+NO(3)(-), in rat brain. Furthermore, NO(2)(-)+NO(3)(-) levels are sensitive to ovariectomy in female rats. The effect of sex hormones on brain development and function is well documented. The present study was undertaken to study the effects of ovariectomy and hormonal manipulations on cognitive performance in a WM task designed to test differences in behavioral strategy in Sprague-Dawley rats (n=48) of both sexes. Some of the females rats were ovariectomised and received either hormone replacement (estrogen or progesterone alone or in combination) or the vehicle. Cortical and hippocampal NO(2)(-)+NO(3)(-) levels were determined after behavioral testing. There were no group differences in cognitive ability or non-cognitive factors such as motivation or swim speed. Males and intact females differed in their cognitive style, but hormonal manipulations in female rats did not affect this relative use of behavioral strategy. There was a correlation between performance on the trial where sex differences were most prominent and NO(2)(-)+NO(3)(-) levels in the cortex. Our results suggest that the activational effects of circulating gonadal hormones do not play a major role in sexually dimorphic cognitive styles.     

心跳骤停心肺复苏后亚低温治疗的荟萃分析

目的 评价心跳骤停(CA),心肺复苏自主循环恢复(ROSC)后临床亚低温治疗的有效性和安全性.方法 计算机检索PubMed数据库(1966-01至2008-08)、中国学术期刊网全文数据库(CNKI,1994-01至2008-08)、万方数据库(1994-01至2008-08),收集心肺复苏ROSC后亚低温治疗的临床研究文献,并对符合纳入标准的文献结果 进行荟萃(Meta)分析,比较ROSC后亚低温治疗和常温治疗的结果 .结果 7篇文献纳入Meta分析,合并分析表明,与常温治疗组相比,院外CA ROSC后亚低温治疗可提高患者的出院生存率[OR=2.29(95% CI,1.75～2.98),P<0.01]、改善出院时神经功能[OR=2.04(95% CI,1.55～2.67),P<0.01]和远期神经功能[OR=2.17(95% CI,1.44～3.27),P<0.01],但两组总的不良反应发生率差异无统计学意义.结论 心肺复苏ROSC后亚低温治疗安全有效,可改善患者出院时和远期神经功能,提高出院生存率.     

Effects of undernutrition on glutamatergic parameters in the cerebral cortex of young rats

Perinatal undernutrition impairs maturational events in the development of the brain, resulting in a variety of brain dysfunctions, which affect cognitive functions. This study investigated the effects of pre- and post-natal undernutrition (diet: 8% protein; control group: 25% protein) on some glutamatergic and behavioral parameters of 21-day-old rats. In the cerebral cortex, undernutrition reduced the Na-independent [(3)H]Glutamate binding in cellular membranes and [(3)H]Glutamate vesicular uptake, without affecting the [(3)H]Glutamate uptake by slices preparation. Behavioral parameters were affected, showing a strong amnesic effect both in the short- and long-term memory of inhibitory avoidance tasks, and a significant reduction in the number of crossings in an open field. The effects of perinatal undernutrition in 21-day-old rats, which alter some glutamatergic parameters may be related to the impairment of memory in certain behavioral tasks.     

The effects of chronic unpredictable stress on male rats in the water maze

Exposure to chronic stress can affect cognitive processes in a complex manner depending upon the intensity and duration of the stressors. The current study investigated the effects of chronic unpredictable stress (CUS), a procedure thought to use moderate stressors, on acquisition of and performance in the Morris Water Maze (MWM). Separate behavioral tests were also used to determine whether the stress-induced changes in MWM were due to general changes in locomotor activity or preference for a rewarding stimulus. Adult male rats were exposed to 10 days of different stressors applied at various times. Following the last stressor, stressed and non-stressed rats began training in the MWM, were tested in an open field box, or were tested for sucrose preference. In the MWM, rats exposed to stress had shorter latencies to reach the hidden platform during training. The path lengths on day 2 of training, trials 2 and 4, were shorter in CUS rats compared to controls, with the stressed rats traveling less in the outer portion of the maze. During the probe trial, CUS rats also traveled less overall and less in the outer portion of the maze, although all other measures were the same. The facilitation in learning the platform location was not due to a change in other behavioral components that could contribute to the measures, such as general activity, sensorimotor processing or the preference for a 2% sucrose solution. Thus, chronic unpredictable stress selectively appears to affect the search strategies in the water maze.     

Individual differences in aging: behavioral and neurobiological correlates

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.     

局部亚低温对大鼠局灶性脑缺血-再灌注模型NKCC1 mRNA水平的影响

目的:观察局部亚低温对大鼠局灶性脑缺血-再灌注模型NKCC1 mRNA表达水平的影响,探索局部亚低温的脑保护机制.方法:雄性Wistar大鼠50只,随机分成常温组和亚低温组.应用"线栓法"实现大鼠右侧大脑中动脉阻塞,2h后拔出线栓进行再灌注,于再灌注3h、12h、24h和72h处死大鼠.应用RT-PCR方法观察NKCC1 mRNA水平的变化.结果:与假手术亚组相比,缺血-再灌注亚组大鼠缺血区皮质NKCC1 mRNA水平明显升高,开始于再灌注3h,12h～24h达到高峰,72h开始下降,亚低温组各再灌注时间点NKCC1 mRNA水平均低于常温组中相应亚组的水平.结论:局部亚低温通过抑制缺血-再灌注过程中NKCC1 mRNA水平的上调发挥脑保护作用.     

选择性深低温血流阻断猴海马超微结构和波形蛋白表达的变化**

背景：前期研究显示,选择性深低温顺行脑灌注能提高猴脑对缺血缺氧的耐受性。 目的：观察选择性深低温血流阻断对猴海马超微结构和波形蛋白表达的影响。 方法：将8只健康成年恒河猴随机分为两组：深低温组(n=5)在常温下阻断猴双侧颈总动脉及颈内静脉10 min,然后通过一侧颈内动脉灌注4 ℃林格氏液,同侧颈内静脉回流,使脑温维持在18 ℃以下,60 min后恢复脑血流;常温组(n=3)除灌注液改为37 ℃林格氏液外,其余与深低温组相同。 结果与结论：深低温组猴全部成功复苏,海马组织形态及超微结构未见明显异常。常温组猴全部死亡,未能成功复苏,海马组织形态及超微结构有不同程度异常。与常温组比较,深低温组海马波形蛋白表达显著降低(P < 0.01)。说明阻断双侧颈总动脉10 min后行选择性深低温顺行脑灌注可下调海马波形蛋白表达,保护海马组织,减轻脑缺血损害。     

Sex differences in passive avoidance behavior of rats: sex-dependent susceptibility to shock-induced behavioral depression

Male and female Wistar rats were trained in a standard passive avoidance task. One-half of the subjects was shocked (S) upon entering a dark compartment, the other half was not (NS). One hour after S and NS experience subjects were tested. During testing different behavioral elements were observed in order to elucidate the variables which might be responsible for the observation of sex differences in passive avoidance behavior (Experiment Ia). In addition, separate groups of NS and S male and female rats were used to establish effects of sex and shock presentation on locomotor activity (Experiment Ib). One hour after S and NS experience within a passive avoidance procedure these subjects were tested for open field ambulation. Results of both experiments indicated that shock-stress reduces locomotor activity of male and female rats, but to a lesser extent in female rats. Sex differences in behavioral responses to aversive stimuli may thus be a consequence of a sex-dependent susceptability to stress-induced behavioral depression.     

Diabetic Goto-Kakizaki rats display pronounced hyperglycemia and longer-lasting cognitive impairments following ischemia induced by cortical compression

Hyperglycemia has been shown to worsen the outcome of brain ischemia in several animal models but few experimental studies have investigated impairments in cognition induced by ischemic brain lesions in hyperglycemic animals. The Goto-Kakizaki (GK) rat naturally develops type 2 diabetes characterized by mild hyperglycemia and insulin resistance. We hypothesized that GK rats would display more severe cerebral damage due to hyperglycemia-aggravated brain injury and, accordingly, more severe cognitive impairments. In this study, recovery of motor and cognitive functions of GK and healthy Wistar rats was examined following extradural compression (EC) of the sensorimotor cortex. For this purpose, tests of vestibulomotor function (beam-walking) and combined tests of motor function and learning (locomotor activity from day (D) 1 to D5, operant lever-pressing from D14 to D25) were used. EC consistently reduced cerebral blood flow in both strains. Anesthesia-challenge and EC resulted in pronounced hyperglycemia in GK but not in Wistar rats. Lower beam-walking scores, increased locomotor activity, impairments in long-term habituation and learning of operant lever-pressing were more pronounced and observed at later time-points in GK rats. Fluoro-Jade, a marker of irreversible neuronal degeneration, revealed consistent degeneration in the ipsilateral cortex, hippocampus and thalamus at 2, 7 and 14 days post-compression. The amount of degeneration in these structures was considerably higher in GK rats. Thus, GK rats exhibited marked hyperglycemia during EC, as well as longer-lasting behavioral deficits and increased neurodegeneration during recovery. The GK rat is thus an attractive model for neuropathologic and cognitive studies after ischemic brain injury in hyperglycemic rats.     

Periodic maternal deprivation induces gender-dependent alterations in behavioral and neuroendocrine responses to emotional stress in adult rats.

There is evidence that stressful events during the neonatal "stress hyporesponsive period" may influence both emotional behavior and the maturation of the hypothalamic-pituitary-adrenal (HPA) axis in rats. We tested whether periodic maternal deprivation (180 min daily on postnatal days 3-10, PMD) caused chronic changes in emotional behavior and HPA axis activity in either male or female adult rats, or both. In addition, HPA secretory responses to human/rat corticotropin-releasing factor (CRH, 50 ng/kg i.v.) were determined in the adult males. In the elevated plus-maze test, adult (4-5 months of age) PMD-treated animals of both sexes displayed increased anxiety-related behavior compared to control rats. This was indicated by a reduction in the number of entries (male: 70% reduction, p < 0.01; female: 31% reduction, p < 0.01) and amount of time spent on the open arms (male: 86% reduction, p < 0.01; female: 40% reduction, NS). Neuroendocrine parameters were also altered in PMD-treated rats in a gender-dependent manner. Whereas basal plasma adrenocorticotropin (ACTH) and corticosterone levels did not differ significantly between PMD and control groups of either sex, the ACTH response to elevated plus-maze exposure, a predominantly emotional stressor, was higher in male (p < 0.01), but not female, PMD animals than in the respective controls. In contrast, PMD had no effect on behavioral (duration of struggling) or HPA axis responses to forced swimming (90 s, 19 degrees C), a complex and predominantly physical stressor, in either male or female rats. In response to CRH stimulation, PMD-treated males did not show differences in the ACTH secretion compared to controls, indicating alterations in HPA axis regulation at a suprapituitary level. Thus, PMD caused long-term changes in the emotional behavior of adult rats of both sexes, although to a differing degree in males and females, whereas it appeared to cause predominantly alterations in the HPA axis response in males, depending on the characteristics of the stressor used.     

Analysis of sensitivity to MK-801 treatment in a novel active allothetic place avoidance task and in the working memory version of the Morris water maze reveals differences between Long-Evans and Wistar rats

The aims of the present study were to compare the effect of subchronic administration of MK-801 on performance in the active allothetic place avoidance (AAPA) task and in the working version of Morris water maze (MWM) in Long-Evans and Wistar rats. Animals were trained for four daily sessions either in the AAPA or in the working memory version of the MWM. Wistar rats treated by MK-801 (0.1 mg/kg) showed a cognitive deficit in the AAPA task without a significant hyperlocomotion, whereas they were not impaired in the working memory version of the MWM compared to controls. Long-Evans rats treated by MK-801 (0.1 mg/kg) were not impaired either in the AAPA task or in the MWM task. Higher doses of MK-801 (0.2 and 0.3 mg/kg) produced hyperlocomotion in both strains which corresponded to an inability to solve both spatial tasks. Long-Evans rats were superior in the MWM to the Wistar rats in the groups treated with the low dose of MK-801. In conclusion, intact Wistar rats can efficiently solve both spatial tasks; however, they are more sensitive to MK-801-induced behavioural deficit. This has relevance for modeling of the schizophrenia-related deficits and for screening substances for their therapeutic potential.     

Dynamic changes in cortical NADH fluorescence in rat focal ischemia: evaluation of the effects of hypothermia on propagation of peri-infarct depolarization by temporal and spatial analysis

Suppression of peri-infarct depolarizations (PIDs) is one of the major mechanisms of hypothermic protection against transient focal cerebral ischemia. Previous studies have shown the lack of hypothermic protection against permanent focal ischemia. We hypothesized the lack of hypothermic protection was due to the poor efficacy in suppression of PIDs. To examine the hypothesis, we elucidated the effects of hypothermia on the manner of propagation of PIDs with temporal and spatial resolutions using NADH (reduced nicotinamide adenine dinucleotide) fluorescence images by illuminating the parietal-temporal cortex with ultraviolet light. Spontaneously hypertensive rats (n=14) were subjected to permanent focal ischemia by occlusion of the middle cerebral and left common carotid arteries. 2-h hypothermia (30 degrees C) was initiated before ischemia. Although hypothermia delayed the appearance of PIDs, it did not suppress their appearance. Furthermore, 54% of the PIDs enlarged the high-intensity area of NADH fluorescence in the hypothermia group, similar to the normothermia group (53%). The high-intensity area of NADH fluorescence widened by each PID was larger in the hypothermia group than in the normothermia group. These findings suggest that PIDs even in hypothermia are one of the major factors causing growth of infarction, emphasizing the importance of therapy that targets suppression of PIDs even during hypothermia.     

Sex differences in the effects of early experience on the development of behavioral and brain asymmetries in rats

The influence of early experience (preweaning handling) on the development of several postural/motor asymmetries (side bias in an open field, turn preference in a T-maze, amphetamine-induced rotational behavior, tail pinch-induced asymmetries) and the lateralization of brain dopamine was studied in adult male and female rats. In many cases the adult patterns of behavioral and brain asymmetries were modified by early handling in a sexually dimorphic manner. In addition, the direction of postural/motor asymmetries was very much task-dependent, especially in females. We conclude that: early experience may modify the development of behavioral and brain asymmetries; sex differences in asymmetries are very common; early handling may affect males and females differently; and different measures of postural/motor asymmetries may reflect different and multiple brain asymmetries.     

Protective effect of treatment with black cumin oil on spatial cognitive functions of rats that suffered global cerebrovascular hypoperfusion

The fixed oil of black cumin seeds, Nigella sativa L. (NSO), has shown considerable antioxidant and anti-inflammatory activities. Chronic cerebral hypoperfusion has been linked to neurodegenerative disorders including Alzheimer's disease (AD) and its subsequent cognitive impairment in which oxidative stress and neuroinflammation are the principal culprits. Cerebrovascular hypoperfusion was experimentally achieved by bilateral common carotid arteries occlusion (2VO) in rats. Morris water maze (MWM) test was employed to assess the effects of NSO on spatial cognitive function before and after 2VO intervention. Rats were divided into long-term memory (LTM) and short-term memory (STM) groups, each was further subdivided into 3 subgroups: sham control, untreated 2VO and NSO treated 2VO group. All subgroups were tested with MWM at the tenth postoperative week. Working memory test results for both sham control and NSO treated groups showed significantly lower escape latency time and total distance travelled than untreated 2VO group. Similarly, LTM and STM MWM tests for sham control and NSO treated groups revealed significantly better maze test performance as compared to untreated 2VO group. Sham control and NSO treated 2VO groups demonstrated superior probe memory test performance as compared to untreated 2VO group. The fixed oil of Nigella sativa seeds has demonstrated noticeable spatial cognitive preservation in rats challenged with chronic cerebral hypoperfusion which indicates a promising prospective neuroprotective effect.     

Psychological prenatal stress reduced the number of BrdU immunopositive cells in the dorsal hippocampus without affecting the open field behavior of male and female rats at one month of age

We examined whether prenatal psychological stress with little physical stress causes changes in the behavior and neurogenesis of the offspring of Sprague–Dawley rats at one month. Dams in the last trimester of gestation were psychologically stressed by placing them in a social communication box and shocking a rat on the other side of a transparent wall. They suffered little physical stress. Male and female offspring from the dams showed little change in an open field test at postnatal day (PND) 30. To evaluate neurogenesis in the brain, BrdU was intraperitoneally injected at PND 35 into offspring not used in the open field test. Immunohistochemical examinations of BrdU in their dorsal hippocampus at PNDs 42 and 112 revealed that the number of BrdU immunopositive cells in the offspring of prenatally stressed rats was significantly smaller than in the offspring of unstressed ones. These results together with our previous finding that prenatal psychological stress can alter specific behaviors suggest that prenatal psychological stress can suppress neurogenesis in the dorsal hippocampus of rats of both sexes at PND 35 even though impairment in the behavioral task has not yet appeared.     

Effects of maternal separation on hypothalamic-pituitary-adrenal responses, cognition and vulnerability to stress in adult female rats

We studied the long term effects of neonatal stress in female rats and subsequent responses to stress when adults. Female rats that experienced maternal separation (MS) showed in adulthood depressive-like behavior in the forced swimming test and cognitive impairments in the novel object recognition test, which were reverted by the glucocorticoid receptor antagonist mifepristone or the beta-adrenoceptor antagonist propranolol. Markers of HPA axis (corticosterone levels, CRF mRNA levels in the paraventricular nucleus and glucocorticoid receptor density in the hippocampus) were altered by MS, suggesting that an altered HPA axis function may be associated to behavioral and cognitive deficits in MS female rats. In addition, MS rats were found to be more vulnerable to chronic stress than controls as shown by decreases in open field activity, increases in immobility time in the forced swim test, and changes in markers of HPA axis (decreases in the density of glucocorticoid receptors). These present findings are discussed in terms of gender differences in adulthood.     

Low and moderate doses of acute ethanol do not impair spatial cognition but facilitate accelerating rotarod performance in adolescent and adult rats

Adolescents and adult rodents have differing sensitivities to the acute effects of ethanol on a variety of behavioral and electrophysiological measures. Often, these differences are revealed using high ethanol doses and consequently little is known about these age-related effects using lower ethanol doses. We sought to determine if low-dose ethanol produces differential effects on cognition and motor behavior in adolescent and adult rats. Adolescent (postnatal day PD 30–32) and adult (PD 70–72) male Sprague Dawley rats were trained on the standard version of the Morris Water Maze (MWM) for 5 days or received 5 training trials on an accelerating rotarod (ARR). Adolescents learned the location of the submerged platform in the MWM significantly slower than adults during training and, acute ethanol administration (0.5 g/kg, 0.75 g/kg, or 1.0 g/kg) 30 min before testing did not impair spatial memory in either age group. On the ARR test, adolescent rats spent significantly more time on the rotarod compared to adults and, alcohol exposure (1.0 g/kg) significantly increased ARR performance 30 min following administration. Our findings address the utility of investigating low and moderate doses of ethanol during different developmental stages in rats.