Spatial memory deficits in a virtual reality eight-arm radial maze in schizophrenia

Extensive research with laboratory animals indicates that the hippocampus is crucial for the formation and use of spatial memory. Hippocampal lesions in rodents impair spatial memory on radial arm maze tasks. It is unknown whether amnesic patients with hippocampal damage would exhibit similar impairments on a virtual version of a radial arm maze. To evaluate the importance of the hippocampus in spatial learning and memory, we tested amnesic participants with hippocampal damage in a virtual radial arm maze environment. The virtual radial arm maze required participants to learn and remember 4 rewarded arms of 8 total arms. Spatial learning and memory were assessed using the participants' ability to use salient distal cues in the virtual room to remember the 4 rewarded arms. Amnesic participants' latencies were longer and distance traveled was greater to the rewarded arms compared with nonamnesic participants. Amnesic participants made more errors than nonamnesic participants by either entering nonrewarded arms or by revisiting previously entered arms. These data are analogous to previous animal research. Overall, the human hippocampus is necessary for spatial memory and navigation in a virtual radial arm maze task.

BackgroundComparisons between animal and human neurotoxicology studies are a foundation of risk assessment, but are hindered by differences in measured behaviors. The radial arm maze (RAM), a rodent visuospatial learning and memory task, has a computerized version for use in children, which may help improve comparisons between animal and human studies. ObjectiveTo describe the characteristics and correlates of the virtual radial arm maze (VRAM) in 255 children age 10–15 years from Italy. MethodsWe administered the VRAM using a laptop computer and measured children's performance using the latency, distance, and working/reference memory errors during eight trials. Using generalized linear mixed models, we described VRAM performance in relation to demographic factors, child activities, and several standard neuropsychologic tests (Italian translations), including the Conners Parent Rating Scales-Short Version (CPRS), California Verbal Learning Test (CVLT), Wechsler Intelligence Scales for Children, finger tapping speed, reaction time, and motor skills. ResultsChildren's VRAM performance tended to improve between trials 1 and 6 and then plateaued between trials 6 and 8. Males finished the task 14s faster (95% confidence interval [CI]: −20, −9) than females. Children who played 2+h of video games per day finished 16s faster (CI: −26, −6) and with 34% (CI: 5, 54%) fewer working memory errors than children who reported not playing video games. Higher IQ and better CVLT scores were associated with better VRAM performance. Higher cognitive/inattention CPRS scores were associated with more working (11%; CI: 1, 22) and reference memory errors (7%; CI: 1, 12). ConclusionsConsistent with animal studies, VRAM performance improved over the course of test trials and males performed better than females. Better VRAM performance was related to higher IQ, fewer inattentive behaviors, and better verbal memory. The VRAM may help to improve the integration and comparison between animal and epidemiological studies of environmental neurotoxicants.

Introduction: Manganese (Mn) exposure can now be quantified using teeth, which can determine dose and exposure timing. Translation of epidemiologic research can be further facilitated by employing behavioral tasks that parallel animal studies, which in turn have access to neurologic tissue for mechanistic research. We examined associations of Mn exposure among Italian adolescents living near a ferromanganese plant with visuospatial learning assessed using the virtual radial arm maze (VRAM). Methods: We analyzed deciduous teeth from 137 children ages 10-15 years by laser ablation inductively coupled plasma mass spectrometry. Mn levels were measured in prenatal and postnatal exposure periods. We assessed performance on the VRAM, a computerized version of the rodent task, estimating latency, distance, working and reference memory errors. Linear mixed regression and generalized additive mixed regression were used to model associations between tooth Mn and VRAM performance and to assess interactions with sex. Results are compared to rodent research. Results: Adjusting for age, socioeconomic status, video game use, childhood blood lead, and tooth type, we observed sex-specific associations of tooth Mn with VRAM performance: among girls, there was a U-shaped association between prenatal Mn and latency, distance and working memory errors (pGAM=0.009-0.02). This result suggest both lower and higher prenatal tooth Mn predict worse performance among girls. Among boys, no association was observed in the prenatal period, but postnatal Mn was associated with latency, distance and reference memory in a non-linear manner (pGAM=0.004-0.08), which is consistent with a rodent study of Mn that also used a radial arm maze. Conclusions: Our sex specific results parallel a rodent study of postnatal Mn exposure demonstrating the utility of employing parallel phenotyping methods for translational research. Sensitive exposure windows appeared to be sex-specific.

ObjectiveThis study aims to apply the virtual radial arm maze (VRAM) task to find spatial working memory and reference memory impairments in patients of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Spatial memory functions between aMCI converters and nonconverters are also compared using VRAM results.MethodsWe assessed the spatial memory in 20 normal controls, 20 aMCI, and 20 mild AD subjects using VRAM. The Mini-Mental State Examination, Clinical Dementia Rating scale, and other neuropsychological tests were given to the subjects in conjunction with the VRAM test. Scores in working memory errors and reference memory errors were compared among the three groups using repeated measures analysis of variance. In addition, aMCI patients were followed-up after 5 years and surveyed for AD conversion rate.ResultsIn AD patients, both spatial working and reference memory were impaired. However, in aMCI subjects, only spatial reference memory was impaired. Significant spatial reference memory impairment was found in the aMCI converter group when compared to the nonconverter group.ConclusionSpatial working memory is less impaired in aMCI while reference memory is similarly damaged in AD. In aMCI patients, more severe spatial reference memory deficit is a neuropsychological marker for AD conversion. VRAM may be well utilized in humans to assess spatial memory in normal aging, in aMCI, and in AD.

Isolation stress during the third postnatal week alters radial arm maze performance and corticosterone levels in adulthood

Sex differences and correlations in a virtual Morris water task, a virtual radial arm maze, and mental rotation

Radial arm maze performance was examined in juvenile and adult rats prenatally exposed to alcohol for the relatively brief period of Gestational Days 7–13. When juvenile animals (26 days of age) were trained in the radial arm maze, alcohol-exposed offspring made significantly more errors than did animals in either nutritional or ad-lib control groups during the second and third blocks of trials. However, by the end of training, alcohol-exposed offspring performed the task at the same level as control animals. When these animals were retested at 90 days of age, radial arm maze performance was comparable to that of control animals, suggesting that once acquired, radial arm maze performance is retained into adulthood in animals prenatally exposed to alcohol. When radial arm maze training began in adulthood (90 days of age), rats prenatally exposed to alcohol demonstrated deficient radial arm maze performance. Thus, early behavioral experience may be useful for treating prenatal-alcohol-exposure-induced deficits in learning and memory.

OPS 40: Metals: neurological effects, Room 412, Floor 4, August 28, 2019, 10:30 AM - 12:00 PM Background/Aim: In rodents, visuospatial memory deficits following metal exposure have been measured with the radial arm maze (RAM) task. In humans, the virtual radial arm maze (VRAM), is the computerized analogue developed to assess visuospatial memory in children. The goal of this study was to examine associations between exposure to metals and performance on the VRAM among adolecents that can be utilized to plan future translational studies using RAM. Methods: Manganese (Mn), lead (Pb), chromium (Cr) and copper (Cu) were measured in blood, urine, hair, nails and saliva of 184 participants (84 girls; 11-15 years of age) enrolled in the PHIME study (Public Health Impact of Manganese Exposure) who resided near a ferroalloy plant in Italy. VRAM performance was assessed as the time required to complete the task. Using generalized weighted quartile sum (gWQS) regression, we investigated associations between a mixture of four metals in all matrices and VRAM performance, controlling for covariates. We estimated metal mixture weights and effects for the whole cohort and for each sex individually. Results: A higher metal mixture index was associated with poorer VRAM performance (β: 0.28; p=0.02). Upon stratification, this association was observed in girls (β: 0.65; p<0.001) and not boys. Urine Mn and blood Cu contributed 27% and 13% respectively to the overall mixture effect. Mn in all 5 matrices combined contributed to 54% to the overall mixture effect. In post-hoc analyses, no associations were observed between exposure to each metal separately and VRAM performance. Conclusions: Exposure to this metal mixture during adolescence may disrupt visuospatial skill acquisition in females. Our results can inform translational research that may address underlying neurotoxic mechanisms and guide additional studies on which metals to focus in future research.

Effects of chronic restraint stress and estradiol on open field activity, spatial memory, and monoaminergic neurotransmitters in ovariectomized rats

Effect of age on the radial arm water maze—a test of spatial learning and memory

Repeated activation of neural pathways by kindling induces brief seizures, permanent increases in seizure susceptibility, neuronal loss in the hippocampus, and mossy fiber sprouting in the dentate gyrus. Because kindling induces permanent cellular alterations in hippocampal pathways that have been implicated in memory, it was of interest to determine if kindling also induces long-lasting impairments in a spatial memory task in rats. In this study, the effects of kindling on memory were investigated by assessing kindled rats in a radial arm maze behavior that is impaired by hippocampal damage. Kindled rats studied at 1 month after the last of 30-134 evoked generalized tonic-clonic seizures acquired competence in the performance of the radial arm maze task at a rate that was indistinguishable from age-matched normal controls, but demonstrated a deficit in the ability to repeat the task on consecutive days. The repetition deficit was not observed in rats that experienced three afterdischarges or three generalized tonic-clonic seizures, and the severity of the deficit varied directly with the number of evoked kindled seizures. Repeated brief seizures evoked by kindling induced a long-lasting deficit in a radial arm maze task that is a rodent model of memory. The observation of a long-lasting deficit in radial arm maze performance in kindled rats suggests that the cellular alterations induced in the hippocampus by seizures could contribute to the memory dysfunction in human epilepsy.

Numerous studies have shown that the hippocampus is critical for spatial memory. Within nonhuman research, a task often used to assess spatial memory is the radial arm maze. Because of the spatial nature of this task, this maze is often used to assess the function of the hippocampus. Our goal was to extrapolate this task to humans and examine whether healthy undergraduates utilize their hippocampus while performing a virtual reality version of the radial arm maze task. Thirteen undergraduates performed a virtual radial arm maze during functional magnetic resonance imaging. The brain maps of activity reveal bilateral hippocampal BOLD signal changes during the performance of this task. However, paradoxically, this BOLD signal change decreases during the spatial memory component of the task. Additionally, we note frontal cortex activity reflective of working memory circuits. These data reveal that, as predicted by the rodent literature, the hippocampus is involved in performing the virtual radial arm maze in humans. Hence, this virtual reality version may be used to assess the integrity of hippocampus so as to predict risk or severity in a variety of psychiatric disorders.

Chronic restraint stress enhances radial arm maze performance in female rats

Effects of repeated intracerebroventricular administration of the thyrotrophin-releasing hormone (TRH) analogue, RX77368 (3,3'-dimethyl-TRH, 2 μg, once daily), on a scopolamine-induced performance deficit in an eight-arm radial maze were evaluated in adult rats. Scopolamine (0.3 mg/kg i.p.-30 min) pre-treatment produced a significant deficit in the number of unrepeated arm entries and total arm entries and increased the percentage of incorrect arm entries and the total time on the maze, compared with saline-treated controls. Prior treatment with RX77368 (40 min before maze testing) produced a partial but significant attenuation of the scopolamine-induced performance deficit on the maze during the first five trials but RX77368 also enhanced maze performance during the same period when given alone. These results suggest that the observed scopolamine-induced performance deficit on the radial arm maze partly results from a reduction in locomotion and maze exploration rather than solely impairment of memory, and that RX77368 treatment may improve radial maze performance by increasing arousal and exploratory behaviour in rats rather than directly enhancing cognition.

Autism spectrum disorder (ASD) is the fastest-growing child neuropsychiatric condition. Cognitive dysfunctions such as memory impairments are experienced by patients along with social disturbances and repetitive/stereotypic movements. We have used the radial arm maze (RAM), for measurement of working and reference memory errors in an animal model of autism. In addition, the potential effects of agmatine, an endogenous NMDA antagonist, on RAM performance and autistic-like behaviors were assessed. Autism was modeled by valproic acid (VPA) administration at gestational Day 12.5. Autism-associated behaviors in male offspring were examined in an open field test (OFT) and three-chambered test (TCT) on postnatal days 50-51. Thereafter, the animals were trained in the RAM (PND 55) until they attained the criteria of 80% correct choices during five consecutive trials. Forty-eight hours after the acquisition of criteria, agmatine was injected 30 min before subsequent behavioral testing, which included the retention phase of the RAM, OFT, and TCT. VPA-treated and intact rats showed the same performance in RAM, and acute injection of agmatine rescued social and anxiety-like behavior induced by VPA without the effect on RAM. In a rat model of autism, spatial learning, and memory did not change. Agmatine rescued social and anxiety-like behavior in autistic animals.