Visuospatial Learning Deficits Research Articles

Aromatic Bromination Abolishes Deficits in Visuospatial Learning Induced by MDMA (“Ecstasy”) in Rats While Preserving the Ability to Increase LTP in the Prefrontal Cortex

It has recently been demonstrated that aromatic bromination at C(2) abolishes all typical psychomotor, and some key prosocial effects of the entactogen MDMA in rats. Nevertheless, the influence of aromatic bromination on MDMA-like effects on higher cognitive functions remains unexplored. In the present work, the effects of MDMA and its brominated analog 2Br-4,5-MDMA (1 mg/kg and 10 mg/kg i.p. each) on visuospatial learning, using a radial, octagonal Olton maze (4 × 4) which may discriminate between short-term and long-term memory, were compared with their influence on in vivo long-term potentiation (LTP) in the prefrontal cortex in rats. The results obtained indicate that MDMA diminishes both short- and long-term visuospatial memory but increases LTP. In contrast, 2Br-4,5-MDMA preserves long-term visuospatial memory and slightly accelerates the occurrence of short-term memory compared to controls, but increases LTP, like MDMA. Taken together, these data are consistent with the notion that the modulatory effects induced by the aromatic bromination of the MDMA template, which abolishes typical entactogenic-like responses, might be extended to those effects affecting higher cognitive functions, such as visuospatial learning. This effect seems not to be associated with the increase of LTP in the prefrontal cortex.

Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits.

Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.

Chronic Calcineurin Inhibition via Cyclosporine A Impairs Visuospatial Learning After Isoflurane Anesthesia.

Clinical studies implicate the perioperative period in cognitive complications, and increasing experimental evidence shows that the anesthetic agents can affect neuronal processes that underpin learning and memory. Calcineurin, a Ca-dependent phosphatase critically involved in synaptic plasticity, is activated after isoflurane exposure, but its role in the neurological response to anesthesia is unclear. We investigated the effect of chronic calcineurin inhibition on postanesthetic cognitive function. Mice were treated with 30 minutes of isoflurane anesthesia during a chronic cyclosporine A regimen. Behavioral end points during the perianesthesia period were quantified. Visuospatial learning was assessed with the water radial arm maze. Total and biotinylated surface protein expression of the α5β3γ2 γ-aminobutyric acid (GABA) type A receptors was measured. Expression of the GABA synthesis enzyme glutamate decarboxylase (GAD)-67 was also measured. Mice treated with cyclosporine A before anesthesia showed significant deficits in visuospatial learning compared to sham and cyclosporine A-treated mice (n = 10 per group, P = .0152, Tukey post hoc test). Induction and emergence were unaltered by cyclosporine A. Analysis of hippocampal protein expression revealed an increased surface expression of the α5 GABA type A receptor subunit after isoflurane treatment (P = .019, Dunnett post hoc testing), as well as a decrease in GAD-67 expression. Cyclosporine A did not rescue either effect. Our results confirm the work of others that isoflurane induces changes to inhibitory network function and exclude calcineurin inhibition via cyclosporine A as an intervention. Further, our studies suggest that calcineurin mediates a protective role in the neurological response to anesthesia, and patients receiving cyclosporine A may be an at-risk group for memory problems related to anesthesia.

Alpha-synuclein targets GluN2A NMDA receptor subunit causing striatal synaptic dysfunction and visuospatial memory alteration.

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease.

Visuospatial Learning in Traumatic Brain Injury: An Examination of Impairments using the Computerised Austin Maze Task

An important aspect of cognitive functioning that is often impaired following traumatic brain injury (TBI) is visuospatial learning and memory. The Austin Maze task is a measure of visuospatial learning that has a long history in both clinical neuropsychological practice and research, particularly in individuals with TBI. The aim of this study was to evaluate visuospatial learning deficits following TBI using a new computerised version of the Austin Maze task. Twenty-eight individuals with moderate-to-severe TBI were compared to 28 healthy controls on this task, together with alternative neuropsychological measures, including the WAIS-III Digit Symbol and Digit Span subtests, the Trail Making Test, WMS-III Logical Memory, and Rey Osterrieth Complex Figure Test. The results demonstrated that TBI individuals performed significantly more poorly on the Austin Maze task than control participants. The Austin Maze task also demonstrated good convergent and divergent validity with the alternative neuropsychological measures. Thus, the computerised version of the Austin Maze appears to be a sensitive measure that can detect visuospatial learning impairments in individuals with moderate-to-severe TBI. The new computerised version of the task offers much promise in that it is more accessible and easier to administer than the conventional form of the test.

Decision-making impairment in patients with multiple sclerosis: a case–control study

ObjectivesTo assess decision-making under explicit risk conditions in relapsing–remitting multiple sclerosis patients and its relationship to decisions made under conditions of ambiguity. To assess cognitive functions related to decision-making performance...

P.6.d.001 Inhibition-specific prefrontal connectivity after an acute dose of heroin

The cognitive deficits observed in schizophrenia are considered a core feature of the disease. Neuregulin-1 is a risk gene for schizophrenia that is involved in many neurodevelopmental and synaptic plasticity-related processes relevant to schizophrenia. Here, we have utilized a rat model (Nrg1Tn), which is hypomorphic for the neuregulin-1 (Nrg1) gene, to test whether reduced Type II NRG1 in the rat brain leads to cognitive deficits relevant to schizophrenia. Wild-type and homozygous Nrg1Tn male rats were tested in memory tasks that evaluated spatial memory (Morris water maze) and visuospatial working and reference memory (Can Test). Nrg1Tn rats were not impaired on the Morris water maze, but did show a deficit in the appetitive visuospatial discrimination test. Nrg1Tn rats committed more reference and working memory errors in this test. These results indicate that decreased Type II NRG1 in the brain may lead to deficits in visuospatial learning and memory.

The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory

The cognitive deficits observed in schizophrenia are considered a core feature of the disease. Neuregulin-1 is a risk gene for schizophrenia that is involved in many neurodevelopmental and synaptic plasticity-related processes relevant to schizophrenia. Here, we have utilized a rat model (Nrg1Tn), which is hypomorphic for the neuregulin-1 (Nrg1) gene, to test whether reduced Type II NRG1 in the rat brain leads to cognitive deficits relevant to schizophrenia. Wild-type and homozygous Nrg1Tn male rats were tested in memory tasks that evaluated spatial memory (Morris water maze) and visuospatial working and reference memory (Can Test). Nrg1Tn rats were not impaired on the Morris water maze, but did show a deficit in the appetitive visuospatial discrimination test. Nrg1Tn rats committed more reference and working memory errors in this test. These results indicate that decreased Type II NRG1 in the brain may lead to deficits in visuospatial learning and memory.

The effect of apamin, a small conductance calcium activated potassium (SK) channel blocker, on a mouse model of neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a common genetic disorder known to cause a variety of physiological symptoms such as the formation of both benign and malignant tumors, and is also known to cause visuospatial learning deficits. Mouse models of NF1 show increased GTP activation of ras which may alter K+ channels. One candidate K+ channel that may contribute to deficits in NF1 is the SK (small conductance calcium-activated potassium) channel due to its role in regulation of long term potentiation (LTP), a mechanism of learning which has been shown to be impaired in Nf1+/− mice. We found that administration of apamin (SK antagonist) either through i.p. injection or micro-osmotic pump to Nf1+/− mice significantly improved performance on the water maze task in comparison to saline treated Nf1+/− mice on the third day of training and on the corresponding probe test. In this study we demonstrate a possible mechanism for the learning deficits seen in Nf1+/− mice and a possible drug therapy for rescuing these deficits.

Paired associate learning in children with neurofibromatosis type 1: implications for clinical trials

Studies investigating behavior in mice with a heterozygous null mutation of the NF1 gene (Nf1 (+/-)) have provided critical insights into the molecular and cellular mechanisms underlying cognitive impairments associated with neurofibromatosis type 1 (NF1). Hyperactivation of the Ras-MAPK signaling cascade, which results in increased GABA-mediated inhibition and significantly reduced long-term potentiation, has been proposed as a core mechanism underlying Nf1 (+/-) mice deficits in visuospatial learning and attention. This assertion has been reinforced by preclinical trials that reveal that these impairments can be rescued both at a cognitive and cellular level. We attempted to demonstrate a phenotypic parallel between Nf1 (+/-) mice and children with NF1 using a well-validated measure of visuospatial learning. Children with NF1 (n = 71) and healthy controls (n = 29) were assessed on a computerized paired associate learning task. Interrelationships between visuospatial learning and other cognitive abilities that may influence performance, such as intelligence, attention and visuospatial function, were explored. Children with NF1 displayed significant impairments in visuospatial learning, with reduced initial retention and poorer learning across repeated trials. Importantly, we demonstrated that visuospatial learning was inferior in NF1 even after accounting for group differences in intelligence, sustained attention and visuospatial abilities. We have thus identified impaired visuospatial learning as a core phenotypic feature in children with NF1. These findings imply that hippocampal-based learning networks are dysfunctional in children with NF1 and provide validation for a primary outcome measure for clinical trials aiming to correct aberrant Ras signaling.

Age-related changes in visual acuity, learning and memory in the APPswe/PS1dE9 mouse model of Alzheimer's disease

Mouse models of Alzheimer's disease (AD) are often tested for learning and memory deficits using visuo-spatial tasks such as the Morris water maze. Performance on these tasks is dependent on vision and the APPswe/PS1dE9 mouse model has amyloid beta plaques in their retinas which might influence their performance in these tasks. In a visual learning task, old (20–26 months) transgenic mice and their wildtype littermates of both sexes had poorer visual ability than young (5–8 months) mice and old transgenic mice had poorer visual acuity than old wildtype mice. Old transgenic mice also had deficits in visuo-spatial learning and memory on the Morris water maze. The transgenic mice had no deficits in the conditioned odour preference or conditioned taste aversion memory tests at any age. These results indicate that the old APPswe/PS1dE9 mice and their wildtype littermates both have a deficit in their visual ability and that visually dependent measures alone should not be used to assess learning and memory in this strain.

The Nitrone Free Radical Scavenger NXY-059 Is Neuroprotective when Administered after Traumatic Brain Injury in the Rat

Reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI. NXY-059, a nitrone free radical trapping compound, has been shown to be neuroprotective in models of ischemic stroke but has not been evaluated in experimental TBI. In the present study, a continuous 24-h intravenous infusion of NXY-059 or vehicle was initiated 30 min following a severe lateral fluid percussion brain injury (FPI) in adult rats (n=22), and histological and behavioral outcomes were evaluated. Sham-injured animals (n=22) receiving identical drug infusion were used as controls. Visuospatial learning was evaluated in the Morris water maze at post-injury days 11-14, followed by a probe trial (memory test) at day 18. The animals were sacrificed at day 18, and loss of hemispheric brain tissue was measured in microtubule-associated protein (MAP)-2 stained sections. Brain-injured, NXY-059-treated animals showed a significant reduction of visuospatial learning deficits when compared to the brain-injured, vehicle-treated control animals (p < 0.05). NXY-059-treated animals significantly reduced the loss of hemispheric tissue compared to brain-injured controls (43.0 +/- 11 mm3 versus 74.4 +/- 19 mm3, respectively; p < 0.01). The results show that post-injury treatment with NXY-059 significantly attenuated the loss of injured brain tissue and improved cognitive outcome, suggesting a major role for ROS in the pathophysiology of TBI.

Assessment of the effects of the cyclooxygenase-2 inhibitor rofecoxib on visuospatial learning and hippocampal cell death following kainate-induced seizures in the rat

Kainate-induced seizures result in hippocampal neurodegeneration and spatial learning deficits in rodents. Previous studies show that rofecoxib, a selective cyclooxygenase-2 inhibitor, protects against kainate-induced hippocampal cell death 3 days after seizures. Our aim was to determine whether rofecoxib attenuates visuospatial learning deficits and late neuronal death after kainate-induced seizures. Seizures were induced in Sprague–Dawley rats with kainic acid (10 mg/kg, i.p.). Eight hours later, animals received rofecoxib (10 mg/kg; n = 15) or vehicle (dimethylsulfoxide, n = 11). Animals were then treated daily for additional 2 or 9 days. Visuospatial learning was assessed in the Morris water maze (MWM) on days 5–9 after seizures. Seizure animals learned the MWM task significantly slower than non-seizure controls, but seizure animals showed higher swim speed ( P < 0.05). Seizure animals receiving rofecoxib for 2 days showed no significant improvement in acquisition of the task compared to the vehicle group, even though mean latencies in the rofecoxib group were shorter from the third trial day onwards. This tendency was lost when rofecoxib was given for 9 days. TdT-mediated dUTP nick end labelling showed cell death in limbic structures 9 days after seizures. The time course of kainate-induced hippocampal cell death might be delayed by rofecoxib treatment, as the attenuation of cell death observed 3 days after seizures was no longer present after 9 days. We conclude that even though increasing evidence points to an injurious role of cyclooxygenase-2 products in acute brain injury processes, rofecoxib treatment failed to attenuate seizure-induced visuospatial learning deficits and the late phase of hippocampal neurodegeneration.

Effects of creatine and cyclocreatine supplementation on kainate induced injury in pre-pubescent rats

Purpose: To investigate if energy precursor supplementation is neuroprotective in two neuroexcitotoxicity models; the kainate and the kainate followed by chronic phenobarbital models.Methods: Rats in experiment 1 received 1% creatine or cyclocreatine chow from age (P) 21–65 days, underwent kainate induced status epilepticus on P35 and were compared, as adults, to kainate alone rats and to normal controls. Rats in experiment 2 received 1% creatine chow (P21–P85), underwent kainate status epilepticus on P35, received daily phenobarbital (or saline) injections (P36–P85) and were compared, as adults, to kainate, kainate-phenobarbital and to normal control rats that received regular chow.Results: In experiment 1, the cyclocreatine-kainate group had increased emotionality and visuospatial learning deficits on the handling and watermaze tests as compared to all other groups. Creatine supplementation did not have any effects. In experiment 2, creatine supplementation did not prevent spontaneous recurrent seizures, aggressivity on the handling test or hippocampal histologic injury.Conclusion: Energy precursor supplementation in the doses used did not have neuroprotective effects in the kainate or kainate-phenobarbital models in pre-pubescent rats.

Neuropsychological Performance of Patients Following Mold Exposure

This study investigated the effects of mold exposure (ME) on human cognition by analyzing neuropsychological data from patients who were exposed to mold in their homes or workplaces. Compared to normative data, ME patients were impaired (< 10th percentile) on a number of cognitive measures, with the most consistent deficits in visuospatial learning, visuospatial memory, verbal learning, and psychomotor speed. We also examined emotional functioning and found that a number of ME patients showed evidence of both Axis I and Axis II pathology. Interestingly, there was a significant correlation among patients' scores on the Beck Depression Inventory-Second Edition and the number of neuropsychological tests falling within the impaired range. Given the limited understanding of ME and its effect on the human central nervous system, we provide a working model that attempts to capture the complex interactions of impaired cognition, psychosocial stressors, poor physical health, and emotional functioning in patients following ME.

Age-independent and age-related deficits in visuospatial learning, sleep–wake states, thermoregulation and motor activity in PDAPP mice

Recent studies demonstrated that mice overexpressing the human mutant β-amyloid precursor protein (hβAPP; PDAPP mice) show age-independent and age-related deficits in spatial learning. We used behavioral and electrophysiological techniques to determine in young and aged PDAPP mice whether deficits in spatial learning also involve alterations in sleep–wake states, thermoregulation and motor activity. Consistent with earlier studies, young PDAPP mice exhibited selective age-independent deficits using spatial, but not random and serial strategies in the circular maze. Aged PDAPP mice exhibited deficits using all search strategies. The core body temperature (Tb) in young and aged PDAPP mice was significantly lower than in age-matched non-transgenic (non-Tg) littermates. During the dark period, the motor activity (LMA) was significantly increased in young PDAPP mice, but not in aged PDAPP mice. During the light period, young PDAPP mice showed a reduction in the generation of rapid-eye-movement (REM) sleep. In contrast, aged PDAPP mice exhibited a reduction in the amount of time spent in W and an increase in SWS during the light period. Aged PDAPP mice also showed an increase in the amount of time spent in W and a reduction in REM sleep during the dark period. Our findings support previous reports indicating deficits in spatial learning in young and aged PDAPP mice. These data also suggest that PDAPP mice exhibit age-independent and age-related deficits in neural mechanisms regulating visuospatial learning, the total amount and the circadian distribution of sleep–wake states, thermoregulation and motor activity.

Chronic cerebrovascular ischemia in aged rats: effects on brain metabolic capacity and behavior☆

The objective of this study was to model one of the risk factors for the development of late-onset Alzheimer’s disease, decreased cerebral blood flow. Aging rats were tested for visuospatial behavioral deficits after permanent surgical occlusion of both carotid arteries. This was followed after 4 weeks by quantitative cytochrome oxidase histochemical mapping of metabolic capacity throughout the brain. The brain regions affected were related to observed deficits in spatial memory (CA1 and posterior parietal cortex), visually guided movements (superior colliculus and secondary visual cortex), motor coordination (red nucleus), and escape behavior (central gray). The results suggest that deficits in visuospatial learning are not exclusively the result of hippocampal dysfunction, but may be directly correlated with altered oxidative energy metabolism in other integrative visuomotor regions identified in this study. It was concluded that chronic cerebrovascular ischemia in this aged rat model produces neurometabolic and behavioral alterations that may be relevant for an increased risk for the development of Alzheimer’s disease.

Activation, attention, and visuospatial learning in adults with and without a family history of alcoholism.

While recent evidence shows visuospatial information processing deficits to be present in chronic alcoholics, it remains unclear whether such deficits are present prior to alcohol abuse in persons at risk for developing alcoholism. If present, it is also unclear whether the information processing mechanisms underlying these deficits are the same in alcoholics and persons at risk for alcoholism. This study investigated visuospatial information processing psychophysiological activation in adults with and without a family history of alcoholism. Thirty matched nonalcoholics served as participants. Fifteen persons were from families in which at least one biologic parent and one other relative had a history of alcoholism. Another group of 15 persons had no family history of alcoholism. In addition to displaying atypical patterns of learning-contingent physiological activation, participants with a family history of alcoholism displayed visuospatial learning that was significantly poorer than persons with no family history of alcoholism. The learning and physiological activation displayed by the participants with a family history of alcoholism were similar to those displayed by previously studied alcoholics using a similar learning task. The data suggest that visuospatial learning deficits may reflect an antecedent to, rather than a consequence of, chronic alcohol abuse.

Spatial learning deficits in adult children of alcoholic parents.

This study investigated whether the visuospatial deficits displayed by chronic alcoholics are present in persons at risk for alcoholism. Participants were 34 matched social drinkers, half of whom were children of alcoholic parents and half of whom had no family alcoholism history. Ss with a family history of alcoholism displayed visuospatial learning that was significantly poorer than that displayed by Ss with no family alcoholism history. The learning patterns displayed by those with a family alcoholism history were similar to those displayed by previously studied detoxified alcoholics and young children of alcoholics using a similar learning task. Data suggest that visuospatial learning deficits may reflect an antecedent to rather than a consequence of chronic alcohol abuse.