Delayed sodium pyruvate treatment improves working memory following experimental traumatic brain injury

Prior work indicates that cerebral glycolysis is impaired following traumatic brain injury (TBI) and that pyruvate treatment acutely after TBI can improve cerebral metabolism and is neuroprotective. Since extracellular levels of glucose decrease during periods of increased cognitive demand and exogenous glucose improves cognitive performance, we hypothesized that pyruvate treatment prior to testing could ameliorate cognitive deficits in rats with TBI. Based on pre-surgical spatial alternation performance in a 4-arm plus-maze, adult male rats were randomized to receive either sham injury or unilateral (left) cortical contusion injury (CCI). On days 4, 9 and 14 after surgery animals received an intraperitoneal injection of either vehicle (Sham-Veh, n = 6; CCI-Veh, n = 7) or 1000 mg/kg of sodium pyruvate (CCI-SP, n = 7). One hour after each injection rats were retested for spatial alternation performance. Animals in the CCI-SP group showed no significant working memory deficits in the spatial alternation task compared to Sham-Veh controls. The percent four/five alternation scores for CCI-Veh rats were significantly decreased from Sham-Veh scores on days 4 and 9 (p < 0.01) and from CCI-SP scores on days 4, 9 and 14 (p < 0.05). Measures of cortical contusion volume, regional cerebral metabolic rates of glucose and regional cytochrome oxidase activity at day 15 post-injury did not differ between CCI-SP and CCI-Veh groups. These results show that spatial alternation testing can reliably detect temporal deficits and recovery of working memory after TBI and that delayed pyruvate treatment can ameliorate TBI-induced cognitive impairments.     

Protective effect of the heparin-derived oligosaccharide C3, on AF64A-induced cholinergic lesion in rats

Alzheimer's disease (AD) literature indicates that glycosaminoglycans (GAGs) may prevent proteoglycan-induced amyloid-beta (Abeta) aggregation, decrease Abeta-induced tau-2 immunoreactivity, and increase the axonal growth and arborization of hippocampal neurons. However, there is no information about the impact of GAGs on cholinergic lesions. Here, AF64A was administered stereotaxically into the lateral ventricles of rats, at doses that are selective for cholinotoxicity (1 and 2 nmol). The heparin-derived oligosaccharide (HDO), C3 (25mg/kg), was administered orally, once daily for 7 days before, and 7 days after AF64A administration. Choline acetyltransferase (ChAT) immunohistochemistry revealed that C3 administration reduced AF64A-induced cholinergic damage in the septum and cingulum bundle. Quantitative neuronal cell counts showed that C3 attenuated, by 60%, the decrease in cell number in the medial septum. Enzyme analysis showed that C3 also significantly restored ChAT (30%) and acetylcholinesterase (AChE) enzyme activity (45%), which had been diminished by AF64A. Our data suggest that, in addition to its effects of anti-Abeta aggregation, anti-Abeta-induced tau-2 immunoreactivity, and neurotrophic effects, C3 also effectively reduces AF64A-induced cholinergic damage; hence it may have potential therapeutic value in AD patients.     

Water T-maze,an improved method to assess spatial working memory in rats: Pharmacological validation

The present study was performed to validate a spatial working memory task using pharmacological manipulations. The water escape T-maze combines the advantages of the Morris water maze and the T-maze while minimizing the disadvantages. Scopolamine (1 mg/kg), a drug that affects cognitive function in spatial working memory tasks, significantly decreased the rats’ performance in the present delayed alternation task. Glutamate neurotransmission plays an important role in the maintenance of working memory; rats treated with dizocilpine (MK-801; 0.125–0.25 mg/kg), a N-methyl-d-aspartate (NMDA) receptor antagonist, were impaired in this task. In agreement with evidence showing a functional interaction between ionotropic and metabotropic glutamatergic receptors, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a mGlu₅ receptor antagonist, at a dose (1 mg/kg) which by itself had no significant effects, enhanced MK-801-induced impairments of spatial working memory. These evidences suggest that the water escape T-maze might be a valid method to assess spatial working memory, sensitive to pharmacological manipulations.     

Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: Involvement of estrogen receptors and oxidative stress

This study examined neuroprotective effect of silymarin (SM) in a model of Parkinson's disease (PD). Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated i.p. with SM (100 and 200 mg/kg) 1 h before neurotoxin injection. Fulvestrant was used to evaluate the involvement of estrogen receptors. Net apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted in addition to measurement of oxidative stress markers. SM administration only at a dose of 200 mg/kg attenuated the rotational behavior in 6-OHDA-lesioned rats and protected the neurons of SNC against its toxicity and fulvestrant partially attenuated this beneficial effect of SM. In addition, pretreatment with SM at a dose of 200 mg/kg significantly decreased the 6-OHDA-induced thiobarbituric acid reactive substances (TBARS) formation. SM exhibits a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress and via an estrogenic pathway.     

Effects of beta-adrenergic antagonist,propranolol on spatial memory and exploratory behavior in mice

The beta-adrenergic system has been suggested to be involved in novelty detection and memory modulation. The present study aimed to investigate the role of beta-adrenergic receptors on novelty-based spatial recognition memory and exploratory behavior in mice using Y-maze test and open-field respectively. Mice were injected with three doses of beta-adrenergic receptor antagonist, propranolol (2, 10 and 20 mg/kg) or saline at three different time points (15 min prior to training, immediately after training and 15 min before test). The results showed that higher doses of propranolol (10 and 20 mg/kg) given before the training trial impaired spatial recognition memory while those injected at other two time points did not. A detailed analysis of exploratory behavior in open-field showed that lower dose (2 mg/kg) of propranolol reduced exploratory behavior of mice. Our findings indicate that higher dose of propranolol can impair acquisition of spatial information in the Y-maze without altering locomotion, suggesting that the beta-adrenergic system may be involved in modulating memory processes at the time of learning.     

Chronic prenatal lead exposure impairs long-term memory in day old chicks

Environmental exposure to lead during developmental stages has been established as a potential cause of intellectual deficits. The high susceptibility of rapidly developing fetal and infant brains to external factors suggests that impairment of later cognitive functions may arise from relatively minor prenatal exposure to environmental lead levels. In this study, we used the one-trial passive avoidance learning paradigm with day old chicks to evaluate memory function and memory consolidation in response to prenatal lead exposure. Lead acetate (5.5 mg/kg, 11 mg/kg, 16.5 mg/kg) was administered daily from E9 to E16 via direct injection into the airspace in chick eggs. Higher doses of lead acetate (11 mg/kg, 16.5 mg/kg) administration had significant effects on the hatching success (23.4 and 17, respectively) and hatch weight (∼10% decrease) of chicks when compared to equivalent treatments of sodium acetate (11 mg/kg, 16.5 mg/kg) (p < 0.001). Low doses of lead acetate (5.5 mg/kg) did not significantly affect chick hatching, weight or morphology compared to equivalent sodium acetate treatments (5.5 mg/kg) and controls. However, lead acetate (5.5 mg/kg) was found to significantly impair long-term memory after 120 min following training in the one-trial passive avoidance learning task (p < 0.05). These findings add to a growing body of evidence that suggests lead toxicity during fetal development leads to impairment in cognitive and memory processes.     

Parietal and frontal object areas underlie perception of object orientation in depth

Attention deficit/hyperactivity disorder (ADHD) is a developmental disorder of cognition. Behavioral symptoms of ADHD are inattention, hyperactivity, and impulsivity. We investigated the effects of treadmill exercise and methylphenidate (MPH) on activity and spatial learning memory in relation to dopamine synthesis and brain-derived neurotrophic factor (BDNF) expression using spontaneously hypertensive adult male rats. The rats in the MPH-treated group received 1 mg/kg MPH orally once a day for 28 days. The rats in the treadmill exercise group were made to run on a treadmill for 30 min once a day, five times a week, for 28 days. Activity was determined by an open-field test and spatial learning memory was evaluated by an 8-arm maze test. Immunohistochemistry and Western blotting were conducted to examine the levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine, and BDNF. The rats in the ADHD group showed hyperactivity and spatial learning memory deficit. Reduction of TH in the striatum and substantia nigra and BDNF in the hippocampus was observed of the rats in the ADHD group. Treadmill exercise and MPH alleviated the ADHD-induced hyperactivity and spatial learning memory impairment. Expressions of TH and BDNF in the ADHD rats were also increased by both treadmill exercise and MPH. These findings provide a possibility that exercise may be used as an effective therapeutic intervention for ADHD patients as MPH treatment.     

A subset of μ-opioid receptor-expressing cells in the rostral ventromedial medulla contribute to thermal hyperalgesia in experimental neuropathic pain

Stimulation of the immune system has been found to enhance, impair, or have no effect on various memory tasks. In the present study, male Wistar rats received saline, lipopolysaccharide (LPS, 250 μg/kg in saline, 7 consecutive days), intranigral 6-hydroxydopamine (6-OHDA, 2 μg/μl saline; 5 μl/site) and intranigral 6-OHDA plus 7 consecutive days of LPS injections and then tested in two cognitive tasks (Y-maze and radial arm-maze). Altered behavioral responses in Y-maze and radial arm-maze tasks were observed in LPS- and LPS + 6-OHDA-treated rats compared to control group. Notably, positive correlations were detected among LPS and LPS + 6-OHDA-treated rats when behavioral deficits were correlated with indicators of oxidative stress. Taken together, we demonstrated that activation of the immune system with LPS administration induced memory impairment and brain oxidative stress, significantly correlated with nigral lesion promoted by 6-OHDA.     

Post-learning REM sleep deprivation impairs long-term memory: Reversal by acute nicotine treatment

Rapid eye movement sleep deprivation (REM-SD) is associated with spatial learning and memory impairment. During REM-SD, an increase in nicotine consumption among habitual smokers and initiation of tobacco use by non-smokers have been reported. We have shown recently that nicotine treatment prevented learning and memory impairments associated with REM-SD. We now report the interactive effects of post-learning REM-SD and/or nicotine. The animals were first trained on the radial arm water maze (RAWM) task, then they were REM-sleep deprived using the modified multiple platform paradigm for 24 h. During REM-SD period, the rats were injected with saline or nicotine (1 mg/kg s.c. every 12 h: a total of 3 injections). The animals were tested for long-term memory in the RAWM at the end of the REM-SD period. The 24 h post-learning REM-SD significantly impaired long-term memory. However, nicotine treatment reversed the post-learning REM-SD-induced impairment of long-term memory. On the other hand, post-learning treatment of normal rats with nicotine for 24 h enhanced long-term memory. These results indicate that post-learning acute nicotine treatment prevented the deleterious effect of REM-SD on cognitive abilities.     

Tetrahydroaminoacridine alleviates medial septal lesion-induced and age-related spatial reference but not working memory deficits

This study examined the effects of tetrahydroaminoacridine (THA, an anticholinesterase) on water-maze (WM) spatial reference (stable platform location during training) and spatial working memory (reversal of platform location) learning in young intact/medial septal (MS)-lesioned and aged rats. THA (1 or 3 mg/kg, IP) had no effect on reference or working memory performance of young intact rats. MS lesions decreased cholineacetyltransferase activity in the hippocampus and also impaired spatial reference and working memory. THA at 3 mg/kg stabilized MS lesion-induced reference memory performance deficit (path length increase), but was ineffective at 1 mg/kg. THA had no effect on the working memory performance of MS-lesioned rats. Aged rats were impaired in spatial reference and working memory tasks. THA at 3 mg/kg partially stabilized the age-induced spatial reference memory deficits, but was ineffective at 1 mg/kg. THA at either 1 or 3 mg/kg did not alleviate the age-related deficit in the working memory version of WM. The present results suggest that some of the age-related WM deficits may be related to the degeneration of the MS-hippocampus cholinergic system and that THA may be effective in stabilizing the reference memory deficits induced by hippocampal cholinergic dysfunction.     

Memory performance and scopolamine: Hypoactivity of the thalamus revealed by cytochrome oxidase histochemistry

Spatial memory learning is related to the functioning of a neuronal circuit composed of cortical, hippocampal and diencephalic brain regions. The Morris water maze (MWM) is frequently used to assess spatial memory in rats. In this study, the neuronal functional activity of some brain limbic system regions after a memory task in adult male Wistar rats injected with scopolamine (1.0 mg/kg, i.p.) was assessed using cytochrome oxidase (COx) histochemistry. The rats were trained following a working memory schedule in the MWM. A trained group injected with saline and an untreated control group were examined to compare changes in COx activity in the dorsal hippocampus, anterior thalamus, mammillary nuclei, prefrontal cortex and ventral tegmental area. The scopolamine-treated group showed an impairment of spatial learning. Also, a decrease in COx activity was found in this group as compared to the saline group in the anteroventral and anteromedial thalamic nuclei. Overall, these findings suggest that memory deficits induced by scopolamine may be due to impairment of the cholinergic function in the anterior thalamic nuclei.     

低剂量木黄酮降低缺血后神经元损伤并改善学习记忆功能

目的探讨染料木黄酮(GEN)对全脑缺血(GCI)大鼠海马CA1区神经元的神经保护作用及其可能的机制。方法建立大鼠4动脉结扎全脑缺血模型,实验动物随机分为假手术组(sham)、缺血再灌注组(I/R)、GEN处理组、ICI 182,780组和溶剂对照组。采用Fluoro-Jade B和神经元特异性核蛋白(NeuN)染色观察海马CA1区神经元存活情况,TUNEL技术观察海马CA1区神经元的凋亡。Morris水迷宫观察大鼠的空间学习和记忆功能。结果 GEN发挥神经保护作用的最佳剂量为1.0 mg/kg;与sham组相比,I/R组和溶剂对照组海马CA1区TUNEL阳性神经元数量显著增多(P0.01),而1.0 mg/kg GEN可显著降低缺血后TUNEL阳性神经元数量(P0.01);与I/R组相比,GEN能明显改善缺血后大鼠的空间学习和记忆能力。缺血前侧脑室给予ICI 182,780可显著降低GEN的神经保护作用(P0.01)。结论低剂量(1.0mg/kg)GEN可显著降低缺血后大鼠海马CA1区神经元损伤,改善认知功能,其分子机制可能与雌激素受体活性密切相关。     

Effects of pre-training morphine on spatial memory acquisition and retrieval in mice

The opioid system plays an important role in memory processess. Morphine mimics endogenous opioids by acting on opioid receptor in brain to regulate memory. However, the effects of morphine on spatial memory acquisition are controversial. Also, little evidence has suggested that morphine could affect the retrieval of spatial memory. In the current study, effects of pre-training morphine and naloxone on the acquisition vs. retrieval of spatial reference vs. working memory were examined using discrete water maze tasks in C57BL/6 mice. Pre-training morphine administration (7.5 and 15 mg/kg, i.p.) impaired the acquisition of both spatial reference memory and working memory. Motivation to escape from the water maze was not affected by morphine. Pre-test morphine also inhibited the retrieval of spatial working memory but not reference memory. The effects of morphine on the acquisition and retrieval of spatial working memory were eliminated by naloxone pretreatment (1 mg/kg). These results indicate that morphine could differentially modulate a variety of aspects of spatial memory and these effects are mediated by the mu-opioid receptor.     

Electroacupuncture combined with clomipramine enhances antidepressant effect in rodents

The present study was designed to evaluate the antidepressant effect of electroacupuncture (EA) and the potential additive or synergistic effects of EA and clomipramine (CLO, a tricyclic antidepressant) in the mouse forced swimming test (FST) and chronic mild stress (CMS) induced depression-model rats. The FST is an antidepressant screening procedure performed initially to observe the immediate effects of EA and/or CLO on the immobility time. CLO (2.5, 5, 10, 20 and 60 mg/kg intraperitoneally) were administered at 23, 6 and 1h respectively prior to each test. EA was given at the ‘Bai-Hui’ (Du 20) and unilateral ‘An-Mian’ (EX 17) acupoints 1 h before each test. Immobility time was significantly reduced by EA and CLO at 2.5, 5, 10, 20 or 60 mg/kg, respectively. EA combined with 2.5 mg/kg CLO exhibited additive effects on the immobility time. In addition, rats were exposed chronically (1st–11th week) to a variety of mild unpredictable stressors. Depressed mood and anhedonia were recognized as a decrease in sucrose intake in the CMS rats. CLO at 2.5, 5 mg/kg and EA at the same acupoints and parameters were administrated on the CMS rats once every other day for 6 weeks (5th–11th week). The intake of 1% sucrose solution was reduced by CMS, which was restored to normal level after 6 weeks treatment with 5 mg/kg CLO or EA combined with 2.5 mg/kg CLO. However, neither the sucrose intake nor the sucrose preference in the depressive rats was significantly changed by the treatment with EA or 2.5 mg/kg CLO alone. These results demonstrated that EA combined with CLO at low doses has an additive or synergistic antidepressant action, and this combination may provide an effective strategy for depression management.     

Differential effects of osmotic and SSR149415 challenges in maternally separated and control rats: The role of vasopressin on spatial learning

Maternal separation (MS) has been demonstrated to up-regulate the hypothalamic vasopressin (VP) system. Intracerebrally released VP has been demonstrated to affect several types of animal behaviour, such as active/passive avoidance, social recognition, and learning and memory. However, the role of VP in spatial learning remains unclear. In the present study, we investigated the effects of an osmotic challenge and a V1b receptor-specific (V1bR) antagonist, SSR149415, on spatial learning of maternally separated and animal facility reared (AFR) adult male Wistar rats. The osmotic challenge was applied by injecting a hypertonic saline solution, 1 h before the Morris water maze test (MWM). V1bR antagonist SSR149415 (5 mg/kg) was injected i.p. twice (1 h and 30 min) previous to the MWM. A combined treatment with both osmotic challenge and the SSR149415 was applied to the third group whereas rats for basal condition were injected with isotonic saline. Under basal condition no differences between AFR and MS groups were observed. MS rats showed severe impairment during the MWM after the osmotic challenge, but not after the administration of SSR149415. For AFR rats, the opposite phenomenon was observed. The joint application of SSR149415 and osmotic challenge restored the spatial learning ability for both groups. The differential impairment produced by osmotic stress-induced up-regulation and SSR149415 induced V1bR blockage in MS and control rats suggested that VP involvement in spatial learning depends on the individual intrinsic ligand-receptor functional state.     

Neuroprotective effects of resveratrol against traumatic brain injury in immature rats

Childhood trauma resulting in traumatic brain injury (TBI) due to accidents and abuse is the major cause of death and dysfunction in the young. Since there are no approved specific pharmacological agents that block the progression of the secondary injury, the current management of TBI is mainly supportive. We aimed to determine the effect of resveratrol on hippocampal damage and behavioral deficits in 7-day-old rat pups subjected to contusion injury. Resveratrol was injected intraperitoneally at the doses of 100 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining and behavioral alterations were evaluated using open field and novel object recognition tests 2 weeks after trauma. Histopathological evaluation showed that treatment with a single dose of 100 mg/kg resveratrol (i.p.) after the trauma significantly ameliorated the trauma induced hippocampal neuron loss at ipsilateral and contralateral hippocampal brain regions of rats. Additionally, treatment with resveratrol decreased anxiety and increased cortex/hippocampus dependent memory of animals subjected to blunt head trauma. These results show that acute treatment of resveratrol has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in rats.     

Inverse benzodiazepine agonist β-CCM does not reverse learning deficit induced by sleep deprivation

Increasing evidence indicates that sleep deprivation (SD) alters responses to pharmacological agents by affecting specific transmitter systems. The present work addressed deficits in passive avoidance (PA) performance that are seen after SD, and investigated whether treatment with the inverse benzodiazepine agonist β-CCM could prevent such deficits. Male Wistar rats were deprived of sleep for 96 h using the platform method (SD group), or were sleep deprived and then allowed to recover sleep for 24 h (SR group). Animals were treated with saline or 0.5 mg/kg β-CCM before PA training, and were tested 30 min or 24 h later. A separate set of animals was sacrificed for [³H]Ro 15-4513 binding analysis. β-CCM increased PA performance in control animals in both short and long term retention tests, whereas SD and SR animals were unaffected by the drug treatment. Interestingly, [³H]Ro 15-4513 binding was reduced in the entorhinal cortex in both SD and SR groups. These findings suggest that the lack of promnesic effects of β-CCM after SD and SR may be associated with benzodiazepine receptor downregulation in specific brain regions related to memory formation.     

Two phases of behavioral plasticity in rats following unilateral excitotoxic lesion of the hippocampus.

We investigated the effects of dizocilpine, a non-competitive N-methyl-D-aspartate receptor antagonist, on spatial reference and working memory in a radial arm maze task in rats with a unilateral hippocampal lesion. At a dose of 0.2 mg/kg to intact rats, dizocilpine significantly impaired both reference and working memory, and produced ataxia and impairment of food intake; at 0.1 mg/kg, dizocilpine had no effect on performance. Unilateral hippocampal lesion induced by quinolinic acid produced a marked working memory deficit concomitant with a slight but significant impairment of reference memory when mnemonic ability was examined one week after the lesion. The spatial memory deficits in the rats with a unilateral hippocampal lesion were ameliorated by repeated daily trainings over a 21-day period. Following recovery of the spatial memory deficits produced by the brain lesion (four weeks after the brain lesion), dizocilpine (0.1 mg/kg) significantly impaired both reference and working memory, without affecting general behavior or food intake in the brain-lesioned rats. An impairment of working memory, but not reference memory, by dizocilpine was observed six weeks after the brain lesion. However, the disrupting effect of dizocilpine at 0.1 mg/kg on spatial working memory had disappeared at eight weeks after the lesion. Ten weeks after the brain lesion, dizocilpine at 0.2 mg/kg was necessary to induce spatial memory impairment, which was accompanied by motor and food intake deficits, as in intact rats. In sham-operated rats, the dose-response effects of dizocilpine did not differ from those in intact rats at any time after the operation. These results suggest that two phases of behavioral plasticity take place, depending on demand, to compensate for brain dysfunction after the unilateral lesion of the hippocampus in rats.     

Effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval in mice using the elevated plus maze test

Clozapine and olanzapine are antipsychotic drugs commonly used to treat schizophrenia and psychosis; however, few studies have investigated their effects on cognitive function using animal models. Thus, the effects of olanzapine and clozapine on memory acquisition, consolidation and retrieval were investigated in naive mice using a modified elevated plus maze (mEPM) task. Olanzapine (0.15 and 0.30 mg/kg) and clozapine (0.5 and 1 mg/kg) were injected intraperitoneally (i.p.) into male Balb-c mice before training, immediately after training or before the second day of the trial. Our results showed that both olanzapine and clozapine disrupted the acquisition of spatial memory. In addition, clozapine impaired the consolidation of spatial memory, while olanzapine had no effect. Furthermore, olanzapine and clozapine significantly disrupted memory retrieval in naive mice. Thus, these results at least suggest that olanzapine can be a superior treatment for schizophrenia compared to clozapine.     

Ladostigil prevents age-related glial activation and spatial memory deficits in rats

Oxidative stress and glial activation occur in the aging brain. Ladostigil is a new monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitor designed for the treatment of Alzheimer's disease. It has neuroprotective and antioxidant activities in cellular models at much lower concentrations than those inhibiting MAO or AChE. When ladostigil (1 mg/kg/day) was given for 6 months to 16-month-old rats it prevented the age-related increase in activated astrocytes and microglia in several hippocampal and white matter regions and increased proNGF immunoreactivity in the hippocampus towards the levels in young rats. Ladostigil also prevented the age-related reduction in cortical AChE activity and the increase in butyrylcholinesterase activity in the hippocampus, in association with the reduction in gliosis. The immunological and enzymatic changes in aged rats were associated with improved spatial memory. Ladostigil treatment had no effect on memory, glial or proNGF immunoreactivity in young rats. Early treatment with ladostigil could slow disease progression in conditions like Alzheimer's disease in which oxidative stress and inflammatory processes are present.