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1.  The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats 
Neurobiology of aging  2009;32(4):698-706.
NMDA Receptor (NMDAR) activity has been strongly implicated in both in-vitro and in-vivo learning models and the decline in cognitive function associated with aging and is linked to a decrease in NMDAR functional expression. GLYX-13 is a tetrapeptide (Thr-Pro-Pro-Thr) which acts as a NMDAR receptor partial agonist at the glycine site. GLYX-13 was administered to young adult (3 month old) and aged (27–32 month old) Fischer 344 X Brown Norway F1 rats (FBNF1), and behavioral learning tested in trace eyeblink conditioning (tEBC), a movable platform version of the Morris water maze (MWM), and alternating t-maze tasks. GLYX-13 (1 mg/kg i.v.) enhanced learning in both young adult and aging animals for MWM and alternating t-maze, and increased tEBC in aging rats. We previously showed optimal enhancement of tEBC in young adult rats given GLYX-13 at the same dose. Of these learning tasks, the MWM showed the most robust age related deficit in learning. In the MWM, GLYX-13 enhancement of learning was greater in the old compared to the young adult animals. Examination of the induction of long-term potentiation (LTP) and depression (LTD) at Schaffer collateral-CA1 synapses in hippocampal slices showed that aged rats showed marked, selective impairment in the magnitude of LTP evoked by a sub-maximal tetanus, and that GLYX-13 significantly enhanced the magnitude of LTP in slices from both young adult and aged rats without affecting LTD. These data, combined with the observation that the GLYX-13 enhancement of learning was greater in old than in young adult animals, suggest that GLYX-13 may be a promising treatment for deficits in cognitive function associated with aging.
PMCID: PMC3035742  PMID: 19446371
learning; memory; aging; rat; hippocampus; eyeblink conditioning, water maze, t-maze, GLYX-13
2.  Effects of chronic adult dietary restriction on spatial learning in the aged F344 X BN hybrid F1 rat 
Physiology & behavior  2007;93(3):560-569.
Dietary restriction (DR) has been shown to increase life span and reduce disease incidence across a variety of species. Recent research suggests that chronic adult DR may also alter age-related cognitive decline. The purpose of this study was twofold: (1) to examine the potential deficits in spatial learning ability in the aged F344 X BN hybrid F1 rat with specific attention to the contributory effects of motoric impairments and (2) to determine the influence of chronic adult DR on any such impairments. The Morris water maze (MWM) task was employed with a 1.8 m diameter tank, 10 cm2 escape platform, 28°C water, and an automated collapsing central starting platform. Spatial learning impairments in the aged rats were evident on all dependent measures during training and the probe test. Motoric function, as reflected in measures of strength and locomotion demonstrated profound age-related performance impairments that were attenuated by chronic adult DR. The present data also replicate previous reports, indicating that DR attenuates the age-related impairments of performance in the MWM as indexed by the latency measure in acquisition, but critically was dissociated from any DR effect on measures of preference and, more critically, accuracy in the probe test. Collectively, the most parsimonious interpretation of DR effects on MWM performance would appear to be the preservation of motoric, and not cognitive, function.
PMCID: PMC4041982  PMID: 18035382
Cognition; Motoric function; Morris water maze
3.  The Peroxisomal Proliferator-Activated Receptor (PPAR) α Agonist, Fenofibrate, Prevents Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment 
Radiation research  2014;181(1):33-44.
We hypothesized that dietary administration of the peroxisomal proliferator-activated receptor α agonist, fenofibrate, to young adult male rats would prevent the fractionated whole-brain irradiation (fWBI)-induced reduction in cognitive function and neurogenesis and prevent the fWBI-induced increase in the total number of activated microglia. Eighty 12–14-week-old young adult male Fischer 344 × Brown Norway rats received either: (1) sham irradiation, (2) 40 Gy of fWBI delivered as two 5 Gy fractions/week for 4 weeks, (3) sham irradiation + dietary fenofibrate (0.2% w/w) starting 7 days prior to irradiation, or (4) fWBI + fenofibrate. Cognitive function was measured 26–29 weeks after irradiation using: (1) the perirhinal cortex (PRh)-dependent novel object recognition task; (2) the hippocampal-dependent standard Morris water maze (MWM) task; (3) the hippocampal-dependent delayed match-to-place version of the MWM task; and (4) a cue strategy preference version of the MWM to distinguish hippocampal from striatal task performance. Neurogenesis was assessed 29 weeks after fWBI in the granular cell layer and subgranular zone of the dentate gyrus using a doublecortin antibody. Microglial activation was assessed using an ED1 antibody in the dentate gyrus and hilus of the hippocampus. A significant impairment in perirhinal cortex-dependent cognitive function was measured after fWBI. In contrast, fWBI failed to alter hippocampal-dependent cognitive function, despite a significant reduction in hippocampal neurogenesis. Continuous administration of fenofibrate prevented the fWBI-induced reduction in perirhinal cortex-dependent cognitive function, but did not prevent the radiation-induced reduction in neurogenesis or the radiation-induced increase in activated microglia. These data suggest that fenofibrate may be a promising therapeutic for the prevention of some modalities of radiation-induced cognitive impairment in brain cancer patients.
PMCID: PMC4144193  PMID: 24397438
4.  Effect of exercise on learning and memory in a rat model of developmental stress 
Metabolic brain disease  2009;24(4):643-657.
Adverse life events occurring in early development can result in long-term effects on behavioural, physiological and cognitive processes. In particular, perinatal stressors impair neurogenesis in the hippocampus which consequently impairs memory formation. Exercise has previously been shown to have antidepressant effects and to increase cognitive functioning by increasing neurogenesis and neurotrophins in the hippocampus. The current study examined the effects of maternal separation, which has been shown to model anxiety in animals, and the effects of exercise on learning and memory.
Forty-five male Sprague-Dawley rats were divided into 4 groups, maternally separated / non-runners, maternally separated / runners, non-separated / runners and non-separated / non-runners. Maternal separation occurred from postnatal day 2 (P2) to 14 (P14) for 3 hours per day. Exercised rats were given voluntary access to individual running wheels attached to their cages from P29 to P49. Behavioural testing (Morris water maze (MWM) and object recognition tests) took place from P49 to P63.
Maternally separated rats showed no significant difference in anxiety levels in the elevated plus maze and the open field compared to the normally reared controls. However, rats that were allowed voluntary access to running wheels showed increased levels of anxiety in the elevated plus maze and in the open field. Maternal separation did not have any effect on memory performance in the MWM or the object recognition tasks. Exercise increased spatial learning and memory in the MWM with the exercised rats displaying a decreased latency in locating the hidden platform than the non-exercised rats. The exercised rats spent significantly less time exploring the most recently encountered object in the temporal order task in comparison to the non-exercised controls, therefore showing improved temporal recognition memory. All groups performed the same on the other recognition tasks, with all rats showing intact memory performance.
Results indicate that maternal separation had little effect on the rats whereas exercise enhanced both spatial and recognition memory.
PMCID: PMC2857751  PMID: 19821018
Maternal separation; stress; exercise; learning and memory
5.  Aging masks detection of radiation-induced brain injury 
Brain research  2011;1385:307-316.
Fractionated partial or whole-brain irradiation (fWBI) is a widely used, effective treatment for primary and metastatic brain tumors, but it also produces radiation-induced brain injury, including cognitive impairment. Radiation-induced neural changes are particularly problematic for elderly brain tumor survivors who also experience age-dependent cognitive impairment. Accordingly, we investigated, i] radiation-induced cognitive impairment, and ii] potential biomarkers of radiation-induced brain injury in a rat model of aging. Fischer 344 × Brown Norway rats received fractionated whole-brain irradiation (fWBI rats, 40 Gy, 8 fractions over 4 wk) or sham-irradiation (Sham-IR rats) at 12 months of age; all analyses were performed at 26–30 months of age. Spatial learning and memory were measured using the Morris water maze (MWM), hippocampal metabolites were measured using proton magnetic resonance spectroscopy (1H MRS), and hippocampal glutamate receptor subunits were evaluated using Western blots. Young rats (7–10 month-old) were included to control for age effects. The results revealed that both Sham-IR and fWBI rats exhibited age-dependent impairments in MWM performance; fWBI induced additional impairments in the reversal MWM. 1H MRS revealed age-dependent decreases in neuronal markers, increases in glial markers, but no detectable fWBI-dependent changes. Western blot analysis revealed age-dependent, but not fWBI-dependent, glutamate subunit declines. Although previous studies demonstrated fWBI-induced changes in cognition, glutamate subunits, and brain metabolites in younger rats, age-dependent changes in these parameters appear to mask their detection in old rats, a phenomenon also likely to occur in elderly fWBI patients >70 years of age.
PMCID: PMC3065504  PMID: 21338580
MRS; fractionated whole brain irradiation; cognition
6.  Effect of a water-maze procedure on the redox mechanisms in brain parts of aged rats 
The Morris water maze (MWM) is a tool for assessment of age-related modulations spatial learning and memory in laboratory rats. In our work was investigated the age-related decline of MWM performance in 11-month-old rats and the effect exerted by training in the MWM on the redox mechanisms in rat brain parts. Young adult (3-month-old) and aged (11-month-old) male rats were trained in the MWM. Intact animals of the corresponding age were used as the reference groups. The level of pro- and antioxidant capacity in brain tissue homogenates was assessed using the chemiluminescence method. A reduced performance in the MWM test was found in 11-month-old rats: at the first day of training they showed only 30% of successful MWM trials. However, at the last training day the percentage of successful trials was equal for young adult and aged animals. This indicates that the aged 11-month-old rats can successfully learn in MWM. Therewith, the MWM spatial learning procedure itself produces changes in different processes of redox homeostasis in 11-month-old and 3-month-old rats as compared to intact animals. Young adult rats showed a decrease in prooxidant capacity in all brain parts, while 11-month-old rats demonstrated an increase in antioxidant capacity in the olfactory bulb, pons + medulla oblongata and frontal lobe cortex. Hence, the MWM procedure activates the mechanisms that restrict the oxidative stress in brain parts. The obtained results may be an argument for further development of the animal training procedures aimed to activate the mechanisms that can prevent the age-related deterioration of performance in the learning test. This may be useful not only for the development of training procedures applicable to human patients with age-related cognitive impairments, but also for their rehabilitation.
PMCID: PMC4356083  PMID: 25814952
aging; brain; water-maze procedure; oxidants; antioxidants
7.  Minocycline ameliorates cognitive impairment induced by whole-brain irradiation: an animal study 
It has been long recognized that cranial irradiation used for the treatment of primary and metastatic brain tumor often causes neurological side-effects such as intellectual impairment, memory loss and dementia, especially in children patients. Our previous study has demonstrated that whole-brain irradiation (WBI) can cause cognitive decline in rats. Minocycline is an antibiotic that has shown neuroprotective properties in a variety of experimental models of neurological diseases. However, whether minocycline can ameliorate cognitive impairment induced by ionizing radiation (IR) has not been tested. Thus this study aimed to demonstrate the potential implication of minocycline in the treatment of WBI-induced cognitive deficits by using a rat model.
Sprague Dawley rats were cranial irradiated with electron beams delivered by a linear accelerator with a single dose of 20 Gy. Minocycline was administered via oral gavages directly into the stomach before and after irradiation. The open field test was used to assess the anxiety level of rats. The Morris water maze (MWM) was used to assess the spatial learning and memory of rats. The level of apoptosis in hippocampal neurons was measured using immunohistochemistry for caspase-3 and relative markers for mature neurons (NeuN) or for newborn neurons (Doublecortin (DCX)). Neurogenesis was determined by BrdU incorporation method.
Neither WBI nor minocycline affected the locomotor activity and anxiety level of rats. However, compared with the sham-irradiated controls, WBI caused a significant loss of learning and memory manifest as longer latency to reach the hidden platform in the MWM task. Minocycline intervention significantly improved the memory retention of irradiated rats. Although minocycline did not rescue neurogenesis deficit caused by WBI 2 months post-IR, it did significantly decreased WBI-induced apoptosis in the DCX positive neurons, thereby resulting in less newborn neuron depletion 12 h after irradiation.
Minocycline significantly inhibits WBI-induced neuron apoptosis, leading to less newborn neurons loss shortly after irradiation. In the long run, minocycline improves the cognitive performance of rats post WBI. The results indicate a potential clinical implication of minocycline as an effective adjunct in radiotherapy for brain tumor patients.
PMCID: PMC4271325  PMID: 25498371
Whole-brain irradiation; Cognitive deficit; Minocycline; Newborn neuron; Apoptosis; Neurogenesis
8.  Glutamatergic signaling and low prodynorphin expression are associated with intact memory and reduced anxiety in rat models of healthy aging 
The LOU/C/Jall (LOU) rat strain is considered a model of healthy aging due to its increased longevity, maintenance of stable body weight (BW) throughout life and low incidence of age-related diseases. However, aging LOU rat cognitive and anxiety status has yet to be investigated. In the present study, male and female LOU rat cognitive performances (6–42 months) were assessed using novel object recognition and Morris Water Maze tasks. Recognition memory remained intact in all LOU rats up to 42 months of age. As for spatial memory, old LOU rat performed similarly as young animals for learning acquisition, reversal learning, and retention. While LOU rat BW remained stable despite aging, 20-month-old ad-libitum-fed (OAL) male Sprague Dawley rats become obese. We determined if long-term caloric restriction (LTCR) prevents age-related BW increase and cognitive deficits in this rat strain, as observed in the obesity-resistant LOU rats. Compared to young animals, recognition memory was impaired in OAL but intact in 20-month-old calorie-restricted (OCR) rats. Similarly, OAL spatial learning acquisition was impaired but LTCR prevented the deficits. Exacerbated stress responses may favor age-related cognitive decline. In the elevated plus maze and open field tasks, LOU and OCR rats exhibited high levels of exploratory activity whereas OAL rats displayed anxious behaviors. Expression of prodynorphin (Pdyn), an endogenous peptide involved in stress-related memory impairments, was increased in the hippocampus of OAL rats. Group 1 metabotropic glutamate receptor 5 and immediate early genes Homer 1a and Arc expression, both associated with successful cognitive aging, were unaltered in aging LOU rats but lower in OAL than OCR rats. Altogether, our results, supported by principal component analysis and correlation matrix, suggest that intact memory and low anxiety are associated with glutamatergic signaling and low Pdyn expression in the hippocampus of non-obese aging rats.
PMCID: PMC4019859  PMID: 24847259
aging; cognition; anxiety; caloric restriction; obesity; glutamate receptors
9.  Effects of grape seed proanthocyanidin extract on pentylenetetrazole-induced kindling and associated cognitive impairment in rats 
Numerous studies have demonstrated the antioxidant effects of grape seed proanthocyanidin extract (GSPE). The generation of free radicals and the ensuing apoptosis may contribute to the pathogenesis of epilepsy; therefore, in the present study, we examined the effects of GSPE on cognitive impairment and neuronal damage induced by chronic seizures in rats. Seizures were induced by a daily intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ; 35 mg/kg/day, 36 days). Two other groups were treated with GSPE (100 or 200 mg/kg/day, orally) for 24 days and then for 36 days prior to each PTZ injection. After the final PTZ injection, hippocampus-dependent spatial learning was assessed using the Morris water maze (MWM). The rats were then sacrificed for the measurement of hippocampal malondialdehyde (MDA, a measure of lipid peroxidation) and glutathione (GSH, a measure of endogenous antioxidant capacity) levels, and for the expression of pro-apoptotic factors [cytochrome c (Cyt c), caspase-9 and caspase-3]. The mitochondrial generation of reactive oxygen species (ROS), degree of mitochondrial swelling, neuronal damage and mitochondrial ultrastructure were also examined. Performance in the MWM was markedly impaired by PTZ-induced seizures, as evidenced by longer escape latencies during training and fewer platform crossings during the probe trial. This cognitive decline was accompanied by oxidative stress (MDA accumulation, ROS generation, reduced GSH activity), an increased expression of pro-apoptotic proteins, as well as damage to CA1 pyramidal neurons and the mitochondria. Pre-treatment with GSPE dose-dependently reversed PTZ-induced impaired performance in the MWM, oxidative stress, mitochondrial ROS generation, the expression of pro-apoptotic proteins and neuronal and mitochondrial damage. Thus, GSPE may reverse the hippocampal dysfunction induced by chronic seizures, by reducing oxidative stress and preserving mitochondrial function.
PMCID: PMC4094588  PMID: 24912930
cognitive impairment; proanthocyanidins; pentylenetetrazole; morris water maze; apoptosis; oxidative stress
10.  Tat-induced histopathological alterations mediate hippocampus-associated behavioural impairments in rats 
HIV-1 is a global catastrophe, and is exceedingly prevalent in Sub-Saharan Africa. HIV-associated neurocognitive disorder is characterized by symptoms such as motor impairments, a decline in cognition, and behavioural irregularities. The aim of this study was to provide insight into the fundamental behavioural and histopathological mechanisms underlying the development and progression of HIV-1 neuropathology.
Using stereotaxic techniques, Tat protein Clade B (1 μg/μl, 10 μl) was injected bilaterally into the dorsal hippocampus of male Sprague–Dawley rats. The Morris water maze (MWM) and novel object recognition test (NORT) were used to assess spatial learning and recognition memory, respectively. Haematoxylin and eosin staining was used to identify the histopathological changes.
A highly significant increase in latency to reach the hidden platform in the MWM implied that noteworthy hippocampal damage had occurred. Severe behavioural deficits were also observed in the NORT where the Tat-injected group showed a greater preference for a familiar object over a novel one. This damage was confirmed by the histopathological changes (increased astrogliosis, cells becoming eosinophilic and a significant reduction in the pyramidal cell layer) observed in the hippocampus. Additionally, increases in the hippocampal mass and protein were observed, consistent with the structural alterations.
This study highlights the relationship between hippocampal-associated behavioural changes and histologic alterations following stereotaxic intra-hippocampal administration of Tat protein in rats. The implications of this study may positively impact the fields of immunology and neuroscience by encouraging future researchers to consider novel strategies to understand the complexities of the pathogenesis of HIV-associated neurocognitive disorder.
PMCID: PMC4333156  PMID: 25880773
Tat protein Clade B; Morris water maze; Novel object recognition test; Histopathology; Hippocampus
11.  3,4-Methylenedioxymethamphetamine in Adult Rats Produces Deficits in Path Integration and Spatial Reference Memory 
Biological psychiatry  2005;59(12):1219-1226.
±3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that causes cognitive deficits in humans. A rat model for learning and memory deficits has not been established, although some cognitive deficits have been reported.
Male Sprague-Dawley rats were treated with MDMA (15 mg/kg × 4 doses) or saline (SAL) (n = 20/treatment group) and tested in different learning paradigms: 1) path integration in the Cincinnati water maze (CWM), 2) spatial learning in the Morris water maze (MWM), and 3) novel object recognition (NOR). One week after drug administration, testing began in the CWM, then four phases of MWM, and finally NOR. Following behavioral testing, monoamine levels were assessed.
±3,4-Methylenedioxymethamphetamine-treated rats committed more CWM errors than did SAL-treated rats. ±3,4-Methylenedioxymethamphetamine-treated animals were further from the former platform position during each 30-second MWM probe trial but showed no differences during learning trials with the platform present. There were no group differences in NOR. ± 3,4-Methylenedioxymethamphetamine depleted serotonin in all brain regions and dopamine in the striatum.
±3,4-Methylenedioxymethamphetamine produced MWM reference memory deficits even after complex learning in the CWM, where deficits in path integration learning occurred. Assessment of path integration may provide a sensitive index of MDMA-induced learning deficits.
PMCID: PMC2888296  PMID: 16324685
MDMA; Morris water maze; Cincinnati water maze; sequential learning; spatial learning
12.  Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models 
The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.
PMCID: PMC4005958  PMID: 24795750
Alzheimer's disease; mouse models; neuropsychological assessment; behavior; cognition; APP mice; APP/PS1 mice; 3×TG-AD mice
13.  Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease 
Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg+/− rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg+/− rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in early AD.
PMCID: PMC4165352  PMID: 25278855
Alzheimer's disease; cognitive impairment; anxiety; amyloid β; transgenic rat models
14.  Learning and memory impairments in a neuroendocrine mouse model of anxiety/depression 
Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders (MDDs). Such deficits have been observed in various animal models based on environmental stress. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression based on a chronic (4 weeks) corticosterone administration (CORT). Cognitive performances were assessed using behavioral tests measuring episodic (novel object recognition test, NORT), associative (one-trial contextual fear conditioning, CFC), and visuo-spatial (Morris water maze, MWM; Barnes maze, BM) learning/memory. Altered emotional phenotype after chronic corticosterone treatment was confirmed in mice using tests predictive of anxiety or depression-related behaviors. In the NORT, CORT-treated mice showed a decrease in time exploring the novel object during the test session and a lower discrimination index compared to control mice, characteristic of recognition memory impairment. Associative memory was also impaired, as observed with a decrease in freezing duration in CORT-treated mice in the CFC, thus pointing out the cognitive alterations in this model. In the MWM and in the BM, spatial learning performance but also short-term spatial memory were altered in CORT-treated mice. In the MWM, unlike control animals, CORT-treated animals failed to learn a new location during the reversal phase, suggesting a loss of cognitive flexibility. Finally, in the BM, the lack of preference for the target quadrant during the recall probe trial in animals receiving corticosterone regimen demonstrates that long-term retention was also affected in this paradigm. Taken together, our results highlight that CORT-induced anxio-depressive-like phenotype is associated with a cognitive deficit affecting all aspects of memory tested.
PMCID: PMC4013464  PMID: 24822041
depression; anxiety/depression model; corticosterone; recognition memory; spatial learning maze; associative memory; cognitive impairments; cognitive flexibility
15.  Protective Effects of Borago officinalis Extract on Amyloid β-Peptide(25–35)-Induced Memory Impairment in Male Rats: A Behavioral Study 
BioMed Research International  2014;2014:798535.
Alzheimer's disease (AD) is a neurodegenerative disorder and most common form of dementia that leads to memory impairment. In the present study we have examined the protective effects of Borago officinalis (borage) extract on Amyloid β (Aβ)-Induced memory impairment. Wistar male rats received intrahippocampal (IHP) injection of the Aβ(25–35) and borage extract throughout gestation (100 mg/kg). Learning and memory functions in the rats were examined by the passive avoidance and the Morris water maze (MWM) tasks. Finally, the antioxidant capacity of hippocampus was measured using ferric ion reducing antioxidant power (FRAP) assay. The results showed that Aβ(25–35) impaired step-through latency and time in dark compartment in passive avoidance task. In the MWM, Aβ(25–35) significantly increased escape latency and traveled distance. Borage administration attenuated the Aβ-induced memory impairment in both the passive avoidance and the MWM tasks. Aβ induced a remarkable decrease in antioxidant power (FRAP value) of hippocampus and borage prevented the decrease of the hippocampal antioxidant status. This data suggests that borage could improve the learning impairment and oxidative damage in the hippocampal tissue following Aβ treatment and that borage consumption may lead to an improvement of AD-induced cognitive dysfunction.
PMCID: PMC4071970  PMID: 25013802
16.  Effects of training in the Morris water maze on the spatial learning acquisition and VAChT expression in male rats 
Background and the purpose of the study
It has been well established that cholinergic pathway plays an important role in learning and memory processes. The present study was designed to evaluate the effects of Morris water maze (MWM) training on spatial memory acquisition and expression of the vesicular acetylcholine transporter (VAChT) in male rats.
In this study, training trials of all groups of animals were conducted in the MWM task. Rats received one training session consisting of four trials per day which continued for another four consecutive days. Controls received visible platform MWM training. The escape latency, the traveled distance and swimming speed for each rat were recorded and used to evaluate the performance of the animal during training period. For evaluation of expression of VAChT protein levels, brain tissues from animals in each experiment were obtained immediately after the last trial on the related experimental day and processed for immunohistochemistry staining and western blotting analysis.
There was a significant difference between animals subjected to one day training and those receiving four days of training in escape latency and travel distance. There were an apparent increase in VAChT immunoreactivity in the medial septal area (MSA) and CA1 region of the hippocampus in one day and four day trained animals compared with controls (visible group). Quantitative immunostaining analysis by optical density measurements in the CA1 region and evaluation of immunopositive neurons in medial septal area of brain sections confirmed qualitative findings. Assessment of VAChT protein level expression in hippocampus by western blotting evaluation showed the same pattern of immunohistochemistry results.
Overall, results of this study reveal changes in cholinergic neuron activity in different stages of training in the MWM task. Data suggest that there is a significant level of cholinergic neuronal activity during early stages of the training especially in the hippocampus region that may contribute to the apparent increase in VAChT expression.
PMCID: PMC3232098  PMID: 22615654
Acquisition phase; Cholinergic markers; Hippocampus; Medial septal area; Immunohistochenistry; Western blottig
17.  Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury 
Journal of Neurotrauma  2012;29(15):2475-2489.
Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail-suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14–23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms.
PMCID: PMC3471125  PMID: 22924665
behavior; composite score; controlled cortical impact; correlation; traumatic brain injury
18.  Acupuncture stimulation improves scopolamine-induced cognitive impairment via activation of cholinergic system and regulation of BDNF and CREB expressions in rats 
Acupuncture is an alternative therapy that is widely used to treat various neurodegenerative diseases and effectively improve cognitive and memory impairment. The aim of this study was to examine whether acupuncture stimulation at the Baihui (GV20) acupoint improves memory defects caused by scopolamine (SCO) administration in rats. We also investigated the effects of acupuncture stimulation at GV20 on the cholinergic system as well as the expression of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) in the hippocampus.
SCO (2 mg/kg, i.p.) was administered to male rats once daily for 14 days. Acupuncture stimulation at GV20 was performed for 5 min before SCO injection. After inducing cognitive impairment via SCO administration, we conducted a passive avoidance test (PAT) and the Morris water maze (MWM) test to assess behavior.
Acupuncture stimulation at GV20 improved memory impairment as measured by the PAT and reduced the escape latency for finding the platform in the MWM test. Acupuncture stimulation at GV20 significantly alleviated memory-associated decreases in the levels of choline acetyltransferase (ChAT), BDNF and CREB proteins in the hippocampus. Additionally, acupuncture stimulation at GV20 significantly restored the expression of choline transporter 1 (CHT1), vesicular acetylcholine transporter (VAChT), BDNF and CREB mRNA in the hippocampus. These results demonstrate that acupuncture stimulation at GV20 exerts significant neuroprotective effects against SCO-induced neuronal impairment and memory dysfunction in rats.
These findings suggest that acupuncture stimulation at GV20 might be useful in various neurodegenerative diseases to improve cognitive functioning via stimulating cholinergic enzyme activities and regulating BDNF and CREB expression in the brain.
PMCID: PMC4180318  PMID: 25231482
Scopolamine; Memory; Cholinergic neurons; Brain-derived neurotrophic factor; cAMP-response element-binding protein
19.  Gender difference in motor impairments induced by chronic administration of vinblastine 
Neurotoxicity of anticancer drugs complicates treatment of cancer patients. Vinblastine (VBL) is reported to induce motor and cognitive impairments in patients receiving chronic low-dose regimen.
Materials and Methods:
The effects of VBL treatment on motor, learning and memory functions of male and female Wistar rats were studied by behavioral related tests. Animals were given chronic intraperitoneal injections of VBL (0.2 mg/kg/week for 5 weeks) from postnatal day 23 to 52. Motor function was evaluated using grasping test and balancing was evaluated by the rotarod. Spatial learning and memory and anxiety-like behavior were determined using Morris water maze (MWM) task and open field test, respectively.
Administration of VBL caused severe damage to motor and balance function of male rats in comparison to female rats treated with VBL and rats treated with saline. Memory and locomotion were affected in both male and female rats compared with saline treated rats, while a sex difference was also observed in these parameters; male rats showed more impairment compared with female ones. Both male and female rats showed cognitive impairments in MWM task and no sex differences were observed in these functions.
Results revealed that VBL is a potent neurotoxic agent and despite the profound effect of VBL on motor and cognitive functions, it seems that male rats are more susceptible to motor deficits induced by VBL.
PMCID: PMC4137941  PMID: 25140205
Anticancer; Learning and memory; Motor function; Vinblastine
20.  Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers 
Annals of neurology  2010;68(2):220-230.
Recent evidence suggests that high molecular weight soluble oligomeric Aβ (oAβ) assemblies (also known as Aβ-derived diffusible ligands, or ADDLs) may represent a primary neurotoxic basis for cognitive failure in AD. To date, in vivo studies of oAβ/ADDLs have involved injection of assemblies purified from the cerebrospinal fluid (CSF) of human subjects with Alzheimer’s disease or from the conditioned media of Aβ-secreting cells into experimental animals. We sought to study the bioactivities of endogenously formed oAβ/ADDLs generated in situ from the physiological processing of human APP transgenes.
We produced and histologically characterized single transgenic mice overexpressing APPE693Q or APPE693Q X PS1ΔE9 bigenic mice. APPE693Q mice were studied in the Morris water maze (MWM) task at 6 and 12 months of age. Following the second MWM evaluation, mice were sacrificed, and brains were assayed for Aβtotal, Aβ40, Aβ42, and oAβ/ADDL by ELISA and were also histologically examined. Based on results from the oAβ/ADDL ELISA, we assigned individual APPE693Q mice to either an “undetectable oAβ/ADDLs group” or a “readily detectable oAβ/ADDLs group”. A days-to-criterion (DTC) analysis was used to determine delays in acquisition of the MWM task.
Both single transgenic and bigenic mice developed intraneuronal accumulation of APP/Aβ, though only Dutch APPE693Q X PS1Δ9 bigenic mice developed amyloid plaques. The APPE693Q mice did not develop amyloid plaques at any age studied, up to 30 months. APPE693Q mice were tested for spatial learning and memory, and only 12-month old APPE693Q mice with readily detectable oAβ/ADDLs displayed a significant delay in acquisition of the MWM task when compared to NTg littermates.
These data suggest that cerebral oAβ/ADDL assemblies generated in brain in situ from human APP transgenes may be associated with cognitive impairment. We propose that a DTC analysis may be a sensitive method for assessing the cognitive impact in mice of endogenously generated oligomeric human Aβ assemblies.
PMCID: PMC3094694  PMID: 20641005
(1) Amyloid; (2) Alzheimer’s Disease; (3) Spatial Recognition; (4) Days-to-Criterion; (5) Amyloid Precursor Protein
21.  Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior 
Clinical and experimental studies suggest possible risks associated with the repeated administration of benzodiazepines (BZDs) during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP) on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day) was administered from postnatal day (P)7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1) a homing response (HR) test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2) passive avoidance was tested in three trials (at 0, 2 and 24 h intervals) on P12, P15, P18, P25 and P32 rats; (3) within- and between-session habituation was tested in an open field (OF) at P70; and (4) a long-term memory (LTM) version of the Morris water maze (MWM) was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the HR and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test). The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to emotional/motivational responsiveness.
PMCID: PMC3975106  PMID: 24734010
benzodiazepines; clonazepam; cognitive functions; development; rats
Neurobiology of learning and memory  2013;106:10.1016/j.nlm.2013.07.006.
Explicit and implicit learning and memory networks exist where each network can facilitate or inhibit memory. Clinical evidence suggests that implicit networks are relatively preserved after traumatic brain injury (TBI). Non-spatial pre-training (NSPT) in the Morris water maze (MWM) provides the necessary behavioral components to complete the task, while limiting the formation of spatial maps. Our study utilized NSPT in the MWM to assess implicit and explicit learning and memory system deficits in the controlled cortical impact (CCI) model of TBI. 76 adult male Sprague-Dawley rats were divided: CCI vs. sham surgery, NSPT vs. No-NSPT, and cued vs. non-cued groups. NSPT occurred for 4d prior to surgery (dynamic hidden platform location, extra-maze cues covered, static pool entry point). Acquisition (d14–18), Probe/Visible Platform (d19), and Reversal (d20–21) trials were conducted with or without extra-maze cues. Novel time allocation and search strategy selection metrics were utilized. Results indicated implicit and explicit learning/memory networks are distinguishable in the MWM. In the cued condition, NSPT reduced thigmotaxis, improved place learning, and largely eliminated the apparent injury-induced deficits typically observed between untrained CCI and sham rats. However, among NSPT groups, incorporation of cues into search strategy selection for CCI rats was relatively impaired compared to shams. Non-cued condition performance showed sham/NSPT and CCI/NSPT rats perform similarly, suggesting implicit memory networks are largely intact 2 weeks after CCI. Place learning differences between CCI/NSPT and sham/NSPT rats more accurately reflect spatial deficits in our CCI model compared to untrained controls. These data suggest NSPT as a clinically relevant construct for evaluating potential neurorestorative and neuroprotective therapies. These findings also support development of non-spatial cognitive training paradigms for evaluating rehabilitation relevant combination therapies.
PMCID: PMC3851771  PMID: 23871745
traumatic brain injury; controlled cortical impact; implicit memory; water maze; spatial memory; thigmotaxis
23.  Hippocampal expression of myelin-associated inhibitors is induced with age-related cognitive decline and correlates with deficits of spatial learning and memory 
Journal of Neurochemistry  2012;121(1):77-98.
Impairment of cognitive functions including hippocampus-dependent spatial learning and memory affects nearly half of the aged population. Age-related cognitive decline is associated with synaptic dysfunction that occurs in the absence of neuronal cell loss, suggesting that impaired neuronal signaling and plasticity may underlie age-related deficits of cognitive function. Expression of myelin-associated inhibitors (MAIs) of synaptic plasticity, including the ligands MAG, Nogo-A, and OMgp, and their common receptor, NgR1, was examined in hippocampal synaptosomes and CA1, CA3 and DG subregions derived from adult (12–13 months) and aged (26–28 months) Fischer 344 × Brown Norway rats. Rats were behaviorally phenotyped by Morris water maze testing and classified as aged cognitively intact (n=7–8) or aged cognitively impaired (n=7–10) relative to adults (n=5–7). MAI protein expression was induced in cognitively impaired, but not cognitively intact, aged rats and correlated with cognitive performance in individual rats. Immunohistochemical experiments demonstrated that upregulation of MAIs occurs, in part, in hippocampal neuronal axons and somata. While a number of pathways and processes are altered with brain aging, we report a coordinated induction of myelin-associated inhibitors of functional and structural plasticity only in cognitively impaired aged rats. Induction of MAIs may decrease stimulus-induced synaptic strengthening and structural remodeling, ultimately impairing synaptic mechanisms of spatial learning and memory and resulting in cognitive decline.
PMCID: PMC3341628  PMID: 22269040
myelin-associated glycoprotein; neurite outgrowth inhibitor A; oligodendrocyte myelin glycoprotein; Nogo-66 receptor; Fischer 344 × Brown Norway rat; Morris water maze
24.  Expression of S100A6 in Rat Hippocampus after Traumatic Brain Injury Due to Lateral Head Acceleration 
In a rat model of traumatic brain injury (TBI), we investigated changes in cognitive function and S100A6 expression in the hippocampus. TBI-associated changes in this protein have not previously been reported. Rat S100A6 was studied via immunohistochemical staining, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR) after either lateral head acceleration or sham. Reduced levels of S100A6 protein and mRNA were observed 1 h after TBI, followed by gradual increases over 6, 12, 24, and 72 h, and then a return to sham level at 14 day. Morris water maze (MWM) test was used to evaluate animal spatial cognition. TBI- and sham-rats showed an apparent learning curve, expressed as escape latency. Although TBI-rats displayed a relatively poorer cognitive ability than sham-rats, the disparity was not significant early post-injury. Marked cognitive deficits in TBI-rats were observed at 72 h post-injury compared with sham animals. TBI-rats showed decreased times in platform crossing in the daily MWM test; the performance at 72 h post-injury was the worst. In conclusion, a reduction in S100A6 may be one of the early events that lead to secondary cognitive decline after TBI, and its subsequent elevation is tightly linked with cognitive improvement. S100A6 may play important roles in neuronal degeneration and regeneration in TBI.
PMCID: PMC4013634  PMID: 24739809
S100A6; hippocampus; cognitive deficits; traumatic brain injury (TBI); rats
25.  The Effect of Psilocin on Memory Acquisition, Retrieval, and Consolidation in the Rat 
The involvement of the serotonin system in the pathophysiology of schizophrenia has been elucidated by experiments with hallucinogens. Application of a hallucinogen to humans leads to changes in perception, cognition, emotions, and induction of psychotic-like symptoms that resemble symptoms of schizophrenia. In rodent studies, their acute administration affects sensorimotor gating, locomotor activity, social behavior, and cognition including working memory, the phenotypes are considered as an animal model of schizophrenia. The complexity and singularity of human cognition raises questions about the validity of animal models utilizing agonists of 5-HT2A receptors. The present study thus investigated the effect of psilocin on memory acquisition, reinforced retrieval, and memory consolidation in rats. Psilocin is a main metabolite of psilocybin acting as an agonist at 5-HT2A receptors with a contribution of 5-HT2C and 5-HT1A receptors. First, we tested the effect of psilocin on the acquisition of a Carousel maze, a spatial task requiring navigation using distal cues, attention, and cognitive coordination. Psilocin significantly impaired the acquisition of the Carousel maze at both doses (1 and 4 mg/kg). The higher dose of psilocin blocked the learning processes even in an additional session when the rats received only saline. Next, we examined the effect of psilocin on reinforced retrieval and consolidation in the Morris water maze (MWM). The dose of 4 mg/kg disrupted reinforced retrieval in the MWM. However, the application of a lower dose was without any significant effect. Finally, neither the low nor high dose of psilocin injected post-training caused a deficit in memory consolidation in the MWM. Taken together, the psilocin dose dependently impaired the acquisition of the Carousel maze and reinforced retrieval in MWM; however, it had no effect on memory consolidation.
PMCID: PMC4032947  PMID: 24904332
psilocin; spatial memory; Carousel maze; Morris water maze; allocentric navigation; hallucinogenic alkaloids; learning; memory

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