Eight-arm Radial Maze Task Research Articles

Female mice lacking membrane estrogen receptor alpha display impairments in spatial memory

Estrogens exert effects on cognition by acting on estrogen receptors (ER) including ERα. Activation of nuclear ERα results in classical genomic signaling leading to transcriptional changes that occur over hours to days. In contrast, activation of ERα localized to the membrane results in rapid signaling with effects occurring in seconds to minutes. The goal of the current study was to determine the role of membrane ERα in spatial memory. Female wildtype (WT) and transgenic mice that lack membrane ERα and express nuclear only ERα (NOER) were trained on an eight-arm radial-maze task. Following training, mice were tested on delay trials, in which delays ranging from 30 min to 5 h were inserted between the 4th and 5th arm choices. Performance was measured by number of proactive and retroactive errors. Proactive errors are short-term working memory errors defined by reentries into arms previously visited during the post-delay period or errors made during the pre-delay period. Retroactive errors are delay-dependent memory errors, defined as reentries into arms during the post-delay that were previously visited during the pre-delay. Consistent with a role for membrane ERα in rapid signaling, NOER mice made more proactive errors than WTs across all delays. NOER mice made more retroactive errors than WTs only after the 5-h delay. WT and NOER mice performed similarly on elevated plus maze and open field tests indicating no effects of membrane ERα on anxiety-related behavior or locomotor activity. Results reveal that membrane ERα plays important roles in both short-term and longer-term delay-dependent memory either directly or potentially indirectly through a role in the regulation of estradiol levels via the hypothalamic-pituitary-gonadal axis.

Hippocampus-related cognitive disorders develop in the absence of epilepsy and ataxia in the heterozygous Cacna1a mutant mice tottering

ABSTRACT CACNA1A-associated epilepsy and ataxia frequently accompany cognitive impairments as devastating co-morbidities. However, it is unclear whether the cognitive deficits are consequences secondary to the neurological symptoms elicited by CACNA1A mutations. To address this issue, Cacna1a mutant mice tottering (tg), and in particular tg/+ heterozygotes, serve as a suitable model system, given that tg/+ heterozygotes fail to display spontaneous absence epilepsy and ataxia typically observed in tg/tg homozygotes. Here, we examined hippocampus-dependent behaviors and hippocampal learning-related synaptic plasticity in tg mice. In behavioral analyses of tg/+ and tg/tg, acquisition and retention of spatial reference memory were characteristically impaired in the Morris water maze task, while working memory was intact in the eight-arm radial maze and T-maze tasks. tg/+ heterozygotes showed normal motor function in contrast to tg/tg homozygotes. In electrophysiological analyses, Schaffer collateral–CA1 synapses showed a deficit in the maintenance of long-term potentiation in tg/+ and tg/tg mice and an increased paired-pulse facilitation induced by paired pulses with 100 ms in tg/tg mice. Our results indicate that the tg mutation causes a dominant disorder of the hippocampus-related memory and synaptic plasticity, raising the possibility that in CACNA1A-associated human diseases, functionally aberrant CaV2.1 Ca2+ channels actively induce the observed cognitive deficits independently of the neurological symptoms.

Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity.

Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10mg/kg CBD (i.p.) 30min before surgery, 3h after surgery, and then once daily for 14days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.

Effects of Juvenile or Adolescent Working Memory Experience and Inter-Alpha Inhibitor Protein Treatment after Neonatal Hypoxia-Ischemia.

Hypoxic-Ischemic (HI) brain injury in the neonate contributes to life-long cognitive impairment. Early diagnosis and therapeutic interventions are critical but limited. We previously reported in a rat model of HI two interventional approaches that improve cognitive and sensory function: administration of Inter-alpha Inhibitor Proteins (IAIPs) and early experience in an eight-arm radial water maze (RWM) task. Here, we expanded these studies to examine the combined effects of IAIPs and multiple weeks of RWM assessment beginning with juvenile or adolescent rats to evaluate optimal age windows for behavioral interventions. Subjects were divided into treatment groups; HI with vehicle, sham surgery with vehicle, and HI with IAIPs, and received either juvenile (P31 initiation) or adolescent (P52 initiation) RWM testing, followed by adult retesting. Error rates on the RWM decreased across weeks for all conditions. Whereas, HI injury impaired global performance as compared to shams. IAIP-treated HI subjects tested as juveniles made fewer errors as compared to their untreated HI counterparts. The juvenile group made significantly fewer errors on moderate demand trials and showed improved retention as compared to the adolescent group during the first week of adult retesting. Together, results support and extend our previous findings that combining behavioral and anti-inflammatory interventions in the presence of HI improves subsequent learning performance. Results further indicate sensitive periods for behavioral interventions to improve cognitive outcomes. Specifically, early life cognitive experience can improve long-term learning performance even in the presence of HI injury. Results from this study provide insight into typical brain development and the impact of developmentally targeted therapeutics and task-specific experience on subsequent cognitive processing.

The Japanese Angelica acutiloba root and yokukansan increase hippocampal acetylcholine level, prevent apoptosis and improve memory in a rat model of repeated cerebral ischemia

Ethnopharmacological relevanceJapanese Angelica acutiloba root (Angelica root) is included in several Kampo medicines including Yokukansan (YKS). Angelica root and YKS are used for the treatment of a variety of psychological and neurodegenerative disorders. Development of safe and effective therapeutic agents against cerebrovascular disorders will improve the treatment of patients with dementia. Aim of the studyThe effect of Angelica root and YKS on ischemia-impaired memory has not yet been fully investigated. The present study investigated whether Angelica root is also involved in memory improving and neuroprotective effect of YKS in a model of cerebrovascular ischemia. Materials and methodsMale Wistar rats grouped into sham rats received saline, and other three groups subjected to repeated cerebral ischemia induced by 4-vessel occlusion (4-VO), received a 7-day oral administration of either saline, Angelica root or YKS. Memory was evaluated by eight-arm radial maze task. Acetylcholine release (ACh) in the dorsal hippocampus was investigated by microdialysis-HPLC. Apoptosis was determined by terminal deoxynucleotidyl transferase (TdT)-mediated fluorescein-deoxyuridine triphosphate (dUTP) nick-end labeling. ResultsIschemia induced apoptosis, reduced release of ACh, and impaired the memory (increased error choices and decreased correct choices). Angelica root and YKS improved the memory deficits, upregulated the release of ACh and prevented 4-VO-induced hippocampal apoptosis. ConclusionThe dual ACh-increasing and neuroprotective effect of Angelica root could make it a promising therapeutic agent useful for the treatment of symptoms of cerebrovascular dementia. Angelica root could be one of the components contributing to the memory-improving and neuroprotective effects of YKS.

The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models.

Cognitive deficits in various domains, including recognition memory, attention, impulsivity, working memory, and executive function, substantially affect functional outcomes in patients with schizophrenia. TAK-063 [1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one] is a potent and selective phosphodiesterase 10A inhibitor that produces antipsychotic-like effects in rodent models of schizophrenia. We evaluated the effects of TAK-063 on multiple cognitive functions associated with schizophrenia using naïve and drug-perturbed rodents. TAK-063 at 0.1 and 0.3 mg/kg p.o. improved time-dependent memory decay in object recognition in naïve rats. TAK-063 at 0.1 and 0.3 mg/kg p.o. increased accuracy rate, and TAK-063 at 0.3 mg/kg p.o. reduced impulsivity in a five-choice serial reaction time task in naïve rats. N-methyl-d-aspartate receptor antagonists, such as phencyclidine and MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine], were used to induce working memory deficits relevant to schizophrenia in animals. TAK-063 at 0.3 mg/kg p.o. attenuated both phencyclidine-induced working memory deficits in a Y-maze test in mice and MK-801-induced working memory deficits in an eight-arm radial maze task in rats. An attentional set-shifting task using subchronic phencyclidine-treated rats was used to assess the executive function. TAK-063 at 0.3 mg/kg p.o. reversed cognitive deficits in extradimensional shifts. These findings suggest that TAK-063 has a potential to ameliorate deficits in multiple cognitive domains impaired in schizophrenia.

Systems genetic analysis of hippocampal neuroanatomy and spatial learning in mice.

Variation in hippocampal neuroanatomy correlates well with spatial learning ability in mice. Here, we have studied both hippocampal neuroanatomy and behavior in 53 isogenic BXD recombinant strains derived from C57BL/6J and DBA/2J parents. A combination of experimental, neuroinformatic and systems genetics methods was used to test the genetic bases of variation and covariation among traits. Data were collected on seven hippocampal subregions in CA3 and CA4 after testing spatial memory in an eight-arm radial maze task. Quantitative trait loci were identified for hippocampal structure, including the areas of the intra- and infrapyramidal mossy fibers (IIPMFs), stratum radiatum and stratum pyramidale, and for a spatial learning parameter, error rate. We identified multiple loci and gene variants linked to either structural differences or behavior. Gpc4 and Tenm2 are strong candidate genes that may modulate IIPMF areas. Analysis of gene expression networks and trait correlations highlight several processes influencing morphometrical variation and spatial learning.

Hippocampal AP5 treatment impairs both spatial working and reference memory in radial maze performance in rats

The possible involvement of hippocampal N-methyl-d-aspartate (NMDA) receptors in spatial reference and working memory was investigated. Rats were first trained in a four-baited/four-unbaited version of the eight-arm radial maze task in which only predetermined four arms for each rat were baited with a food pellet. After rats reached the learning criterion, their performance was tested under the treatment of a NMDA antagonist, AP5 (d,l-2-amino-5-phosphonopentanoic acid, 20–40nmol), or vehicle into the dorsal hippocampus through the bilaterally implanted guide cannulae. AP5 produced dose-dependent increments on both reference and working memory errors, but did not have any effect on the running speed. Additionally, there were significant correlations between the number of trials to criterion in acquisition and the number of reference and working memory errors induced by AP5 treatment. The results suggest that hippocampal NMDA receptors are involved in both spatial reference and working memory.

Postnatal MK-801 treatment of female rats impairs acquisition of working memory, but not reference memory in an eight-arm radial maze; no beneficial effects of enriched environment.

Memory impairment has been documented in MK-801 (NMDA receptor antagonist) model of schizophrenia, but less is known on the rescue and/or differential effects of MK-801 on short- and long-term memories. We determined the effects of MK-801 treatment and/or enriched environment (EE) on acquisition of reference and working memory in developing rats. Female Wistar rats were injected with MK-801 (1mg/kg) from postnatal days (P) 6-10. Task acquisition, working memory error (WME), and reference memory error (RME) were assessed in an eight-arm radial maze task. Behavioral performance of rats was also tested in an open field test before (P35-P40) and after (P65-P70) radial maze training to assess anxiety and locomotion. EE was applied from birth up to the end of experiments. MK-801 treatment did not influence task acquisition in the radial maze; however, by the end of training, MK-801-treated rats made significantly more WME, but not RME, compared to control rats. Ratio of WME to total error was also significantly higher in MK-801 group. EE prevented MK-801-associated behaviors in the open field but did not exert beneficial effects on working memory deficit in the radial maze task. EE per se affected behavioral performance of rats only in the open field test. Our results suggest that postnatal MK-801 treatment differentially affects working and reference memory in a young brain. Anxiety and hyperactivity associated with MK-801 are observed more severely in adulthood. Dissociation of the positive effects of EE may suggest selective modification of distinct pathways.

Chronic Administration of <i> Curcuma longa </i>Extract Improves Spatial Memory-Related Learning Ability in Aged Rats by Inhibiting Brain Cortico-Hippocampal Oxidative Stress and TNF<i>α</i>

We studied on the effect of Curcuma longa extract on spatial learning-related memory ability of old rats in eight-arm radial maze task. Rats were randomly divided into two groups: one group was orally administered 100 mg/KgBW/day C. longa extract (CLE) dissolved in deionized water and the other group was administered the vehicle alone for 10 weeks. The rats were tested with the partially baited eight-arm radial maze to evaluate two types of spatial memory-related learning ability displayed by reference memory errors (RMEs) and working memory errors (WMEs). Chronic administration of CLE significantly decreased the number of RMEs and WMEs, concurrently with the decreases in the cortico-hippocampal levels of lipid peroxides (LPO) and tumor necrosis factor alpha (TNF-α). In a parallel set of experiments, CLE-pretreated rats of the same age group were subjected to hypoxia-reperfusion injury by carotid artery occlusion to induce oxidative stress in the brains in order to examine whether such an in vivo hypoxia-induced oxidative stress could be ameliorated by the extract. Again, the levels of LPO were significantly decreased in the cortico-hippocampal tissues of the CLE-fed hypoxic rats. The histology of the brains also revealed that the CLE-pretreated rats had retained improved cellular integrity. Finally, our results provide the evidence that oral administration of C. longa extract increases the defense against oxidative stress and proinflammatory TNF-α, concurrently with the improvement of memory-related brain cognitive ability of the aged rats.

Deuterium-depleted water has stimulating effects on long-term memory in rats

Deuterium-depleted water (DDW) is a water which has a 6–7-fold less concentration of the naturally occurring deuterium (20–25ppm vs. 150ppm). While administrated for a longer period, it may reduce the concentration of deuterium throughout the body, thus activating cellular mechanisms which are depending on protons (channels, pumps, enzyme proteins). The aim of the present work was to study, for the first time in our knowledge, the possible influence of deuterium-depleted water (DDW) chronic administration in normal Wistar rats, as compared to a control group which received distilled water, on spatial working memory and the locomotor activity (as studied through Y-maze) or both short-term and long-term spatial memory (assed in radial 8 arms-maze task). Our results presented here showed no significant modifications in terms of spatial working memory (assessed through spontaneous alternation percentage) and locomotor activity (expressed through the number of arm entries) in Y-maze, as a result of DDW ingestion. Also, no significant differences between the DDW and control group were found in terms of the number of working memory errors in the eight-arm radial maze, as a parameter of short-term memory. Still, we observed a significant decrease for the number of reference memory errors in the DDW rats. In this way, we could speculate that the administration of DDW may generate an improvement of the reference memory, as an index of long-term memory. Thus, we can reach the conclusion that the change between the deuterium/hydrogen balance may have important consequences for the mechanisms that govern long-term memory, as showed here especially in the behavioral parameters from the eight-arm radial maze task.

The selective noradrenergic reuptake inhibitor reboxetine restores spatial learning deficits, biochemical changes, and hippocampal synaptic plasticity in an animal model of depression.

Depression is a major psychiatric illness that is associated with cognitive dysfunctions. The underlying mechanism of depression-associated memory impairment is unclear. Previously, we showed altered hippocampal synaptic plasticity in an animal model of depression. Although several antidepressants are beneficial in the treatment of depression, very little is known about the effects of these drugs on depression-associated learning and memory deficits. Prolonged antidepressant treatment might contribute to neuroplastic changes required for clinical outcomes. Accordingly, we evaluated the effect of chronic reboxetine (a selective noradrenergic reuptake inhibitor) treatment on depression-induced reduced hippocampal synaptic plasticity, neurotransmitter levels, and spatial learning and memory impairments. Depression was induced in male Wistar rats by the administration of clomipramine from postnatal days 8 to 21, and these rats were treated with reboxetine in adulthood. The neonatal clomipramine administration resulted in impaired hippocampal long-term potentiation (LTP), decreased hippocampal cholinergic activity and monoamine levels, and poor performance in a partially baited eight-arm radial maze task. Chronic reboxetine treatment restored the hippocampal LTP, acetylcholinesterase activity, and levels of biogenic amines and ameliorated spatial learning and memory deficits in the depressed state. Thus, restoration of hippocampal synaptic plasticity might be a cellular mechanism underlying the beneficial effect of reboxetine in depression-associated cognitive deficits. This study furthers the existing understanding of the effects of antidepressants on learning, memory, and synaptic plasticity and could ultimately assist in the development of better therapeutic strategies to treat depression and associated cognitive impairments.

Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion in middle-aged rats

In this study, we tested whether the phosphodiesterase-5 inhibitor sildenafil protects against neurodegeneration and facilitates recovery from learning deficits examined long after chronic cerebral hypoperfusion (CCH) induced by the 4-vessel occlusion/internal carotid artery (4-VO/ICA) model in middle-aged rats. Male Wistar rats (12-15 months of age) were subjected to permanent 3-stage 4-VO/ICA with an interstage interval of 4 days. Sildenafil (3 mg/kg, p.o.) was administered at one dose per day for 10 days, beginning soon after the first occlusion stage. Three months later, learning in a non-food-rewarded, eight-arm radial maze task was tested. Learning performance is expressed as the latency to find a goal box and the number of reference or working memory errors. Histological examination was performed 1-3 days after behavioral testing. In the vehicle-treated group, permanent 4-VO/ICA markedly disrupted learning performance and caused moderate-to-severe neurodegeneration in the CA1-CA4 subfields of the hippocampus (56.2%), dentate gyrus (DG; 19.2%), retrosplenial cortex (RS cortex; 47.4%), and parietal association cortex (PtA cortex; 38.2%). Sildenafil treatment did not prevent 4-VO/ICA-induced learning deficits, whereas neurodegeneration was significantly reduced in the CA1-CA4 subfields (30.5%), DG (7.2%), RS cortex (11.8%), and PtA cortex (6.5%). Advancing previous findings from our laboratory, this study suggests that while sildenafil can provide important neuroprotection in different brain regions of middle-aged rats subjected to CCH, such histological effect does not translate into cognitive recovery.

Cholinergic Involvement and Synaptic Dynamin 1 Expression in Yokukansan‐mediated Improvement of Spatial Memory in a Rat Model of Early Alzheimer's Disease

The aim of this study was to investigate the effect of Yokukansan (YKS) on the impairment of spatial memory and cholinergic involvement in a rat model of early-phase Alzheimer's disease (AD). In this model, rats underwent four-vessel transient cerebral ischemia and then were treated with beta amyloid oligomers injected intracerebroventricularly once daily for 7 days. These animals showed memory impairment in an eight-arm radial maze task without histological evidence of apoptosis but with a decrease in expression of hippocampal dynamin 1, an important factor in synaptic vesicle endocytosis. Oral administration of YKS for 2 weeks significantly increased the number of correct choices and decreased the number of error choices in the eight-arm radial maze task (P < 0.05). Moreover, YKS significantly increased high K⁺-evoked potentiation of acetylcholine (ACh) release (P < 0.05) and significantly increased the expression of dynamin 1 (P < 0.01) in the hippocampus. The ameliorative effect of YKS on spatial memory impairment in our rat model of early-phase AD may be mediated in part by an increase in ACh release and modulation of dynamin 1 expression, leading to improved synaptic function. Future studies will determine whether YKS is similarly useful in the treatment of memory defects in patients diagnosed with early-stage AD.

T-maze Forced Alternation and Left-right Discrimination Tasks for Assessing Working and Reference Memory in Mice

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in rodents. In our laboratory, we evaluated the two types of memory in more than 30 strains of genetically engineered mice using the automated version of this apparatus. Here, we present the modified T-maze apparatus operated by a computer with a video-tracking system and our protocols in a movie format. The T-maze apparatus consists of runways partitioned off by sliding doors that can automatically open downward, each with a start box, a T-shaped alley, two boxes with automatic pellet dispensers at one side of the box, and two L-shaped alleys. Each L-shaped alley is connected to the start box so that mice can return to the start box, which excludes the effects of experimenter handling on mouse behavior. This apparatus also has an advantage that in vivo microdialysis, in vivo electrophysiology, and optogenetics techniques can be performed during T-maze performance because the doors are designed to go down into the floor. In this movie article, we describe T-maze tasks using the automated apparatus and the T-maze performance of α-CaMKII+/- mice, which are reported to show working memory deficits in the eight-arm radial maze task. Our data indicated that α-CaMKII+/- mice showed a working memory deficit, but no impairment of reference memory, and are consistent with previous findings using the eight-arm radial maze task, which supports the validity of our protocol. In addition, our data indicate that mutants tended to exhibit reversal learning deficits, suggesting that α-CaMKII deficiency causes reduced behavioral flexibility. Thus, the T-maze test using the modified automatic apparatus is useful for assessing working and reference memory and behavioral flexibility in mice.

T-maze Forced Alternation and Left-right Discrimination Tasks for Assessing Working and Reference Memory in Mice

Forced alternation and left-right discrimination tasks using the T-maze have been widely used to assess working and reference memory, respectively, in rodents. In our laboratory, we evaluated the two types of memory in more than 30 strains of genetically engineered mice using the automated version of this apparatus. Here, we present the modified T-maze apparatus operated by a computer with a video-tracking system and our protocols in a movie format. The T-maze apparatus consists of runways partitioned off by sliding doors that can automatically open downward, each with a start box, a T-shaped alley, two boxes with automatic pellet dispensers at one side of the box, and two L-shaped alleys. Each L-shaped alley is connected to the start box so that mice can return to the start box, which excludes the effects of experimenter handling on mouse behavior. This apparatus also has an advantage that in vivo microdialysis, in vivo electrophysiology, and optogenetics techniques can be performed during T-maze performance because the doors are designed to go down into the floor. In this movie article, we describe T-maze tasks using the automated apparatus and the T-maze performance of α-CaMKII+/- mice, which are reported to show working memory deficits in the eight-arm radial maze task. Our data indicated that α-CaMKII+/- mice showed a working memory deficit, but no impairment of reference memory, and are consistent with previous findings using the eight-arm radial maze task, which supports the validity of our protocol. In addition, our data indicate that mutants tended to exhibit reversal learning deficits, suggesting that α-CaMKII deficiency causes reduced behavioral flexibility. Thus, the T-maze test using the modified automatic apparatus is useful for assessing working and reference memory and behavioral flexibility in mice.

Chronic Administration of Cardanol (Ginkgol) Extracted from Ginkgo biloba Leaves and Cashew Nutshell Liquid Improves Working Memory-Related Learning in Rats

Cardanol (ginkgol) extracted from Ginkgo biloba leaves and cashew nutshell liquid enhances the growth of NSC-34 immortalized motor neuron-like cells and, when chronically administered to young rats, improves working memory-related learning ability as assessed by eight-arm radial maze tasks. These findings suggest that cardanol is one of the components in Ginkgo biloba leaves that improves cognitive learning ability.

Eye tracking, strategies, and sex differences in virtual navigation

Reports of sex differences in wayfinding have typically used paradigms sensitive to the female advantage (navigation by landmarks) or sensitive to the male advantage (navigation by cardinal directions, Euclidian coordinates, environmental geometry, and absolute distances). The current virtual navigation paradigm allowed both men and women an equal advantage. We studied sex differences by systematically varying the number of landmarks. Eye tracking was used to quantify sex differences in landmark utilisation as participants solved an eight-arm radial maze task within different virtual environments. To solve the task, participants were required to remember the locations of target objects within environments containing 0, 2, 4, 6, or 8 landmarks.We found that, as the number of landmarks available in the environment increases, the proportion of time men and women spend looking at landmarks and the number of landmarks they use to find their way increases. Eye tracking confirmed that women rely more on landmarks to navigate, although landmark fixations were also associated with an increase in task completion time. Sex differences in navigational behaviour occurred only in environments devoid of landmarks and disappeared in environments containing multiple landmarks. Moreover, women showed sustained landmark-oriented gaze, while men’s decreased over time. Finally, we found that men and women use spatial and response strategies to the same extent. Together, these results shed new light on the discrepancy in landmark utilisation between men and women and help explain the differences in navigational behaviour previously reported.

Neuroprotective Effects of Citidine-5-diphosphocholine on Impaired Spatial Memory in a Rat Model of Cerebrovascular Dementia

Citidine-5-diphosphocholine or citicoline (CDP-choline) is used as a neuroprotective and memory-enhancing drug in cerebral stroke, Alzheimer's disease, and other neurovascular diseases. Non-clinical studies have demonstrated the neuroprotective effects of CDP-choline in ischemic animal models. However, the relationship between the neuroprotective effect and the memory enhancing effect of CDP-choline is still unknown. No studies have demonstrated the ameliorative effect on impaired spatial memory and the suppressive effect on neuronal cell death of CDP-choline in the same model. In this study, we examined the effect of CDP-choline on impaired spatial memory and hippocampal CA1 neuronal death in rats subjected to repeated cerebral ischemia, and we compared the mechanism of CDP-choline to that of donepezil. Seven days post administration of CDP-choline (100, 300, 1000 mg/kg per day, p.o.) or donepezil increased correct choices and reduced error choices in an eight-arm radial maze task in a dose-dependent manner. Neuronal cell death of caspase-3 protein-positive neurons in the hippocampus were reduced by repeated administration of CDP-choline at the highest dose. These results suggest that CDP-choline has ameliorative effects on the impairment of spatial memory via hippocampal neuronal cell death in a rat model of cerebral ischemia.

Identification of a rapid eye movement sleep window for learning of the win-shift radial arm maze task for male Sprague-Dawley rats

This study identified a rapid eye movement sleep window (RSW) for the eight-arm win-shift radial arm maze (RAM) task. The RSW is defined as a period of time after training during which rapid eye movement (REM) sleep is necessary for efficient learning of a task. Rats were trained over a 15-day period on the win-shift RAM task. After daily training, groups of rats were deprived of REM sleep using the flowerpot technique or were returned to their cages to serve as controls. Groups were deprived of REM sleep during separate 4-h intervals, such that the entire 24-h time-period after training was investigated for the effects of REM sleep deprivation on learning. The results of the analyses of variance that were calculated for latency to completion data and a measure of the rate of performance improvements, and a survival analysis that was calculated using the first day of maze completion as a censoring variable, indicated that the RSW for the win-shift task is 0-4 h post-training.