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PubMed2004

Selective rotation of egocentric spatial representation following right putaminal hemorrhage.

Although the role of frontoparietal cortex in spatial egocentric processing is well established, recent animal-lesion and human functional imaging studies have suggested that the neostriatum may also be a critical modulator in the processing of body-centred spatial orientation. We describe here a patient with right putamen-centred hemorrhage who exhibited a consistent counterclockwise rotation of approximately 90 degrees when drawing and writing from memory. A more detailed assessment with a series of representational clock tests demonstrated that the rotation was present only in tasks requiring the use of egocentric cues. In the absence of external cues the patient would adopt and maintain a stable but incorrectly-oriented egocentric representation of the imagined or recollected object. By contrast, performance could be rectified by presentation of correctly-oriented stimuli. These findings suggest that the putamen is part of a circuit underlying egocentric, as opposed to allocentric, representation of space in humans.

Adult↗
PubMed2004

Cognitive and motor effects of dopaminergic medication withdrawal in Parkinson's disease.

AIMS: Recent evidence points towards dissociable effects of dopaminergic medication on motor function and cognitive function mediated by different fronto-striatal neural circuits. This study aimed to clarify the role of dopaminergic medication in spatial working memory, and reinforcement-based associative learning in relation to clinical changes in motor function in early Parkinson's disease (PD). METHOD: We tested 14 patients with mild to moderate PD on and off dopaminergic medication, on a spatial delayed-response working memory task, and on spatial and non-spatial (visual) trial-and-error learning tasks based on reinforcement, carefully matched for motor requirements. In addition, we explored relationships between the effects of withdrawal on motor symptom expression and performance on the cognitive tasks. RESULTS: Withdrawal from dopaminergic medication significantly exacerbated motor symptoms. This was related to spatial learning, but not visual learning, or delayed response accuracy. Moreover, medication withdrawal led to dissociable effects of response latency on the spatial learning and spatial delayed response tasks, with patients becoming faster after spatial learning, but relatively slower on the delayed response task. These changes in response latency were unrelated to motor symptom impairment. CONCLUSION: Our findings suggest dissociable effects of dopamine medication withdrawal on cognitive processes putatively mediated by dorsal and ventral striatal regions.

Aged↗
PubMed2005

The cerebellum's involvement in the judgment of spatial orientation: a functional magnetic resonance imaging study.

A functional magnetic resonance imaging (fMRI) study was conducted to integrate the clinical observations of the impaired judgment of spatial orientation of cerebellar patients with recent theoretical discoveries about the role of the cerebellum in cognitive functions. Ten normal healthy male right-handed Chinese postgraduates consented to participate in this study. The experimental task employed was a modified version of Benton's Judgment of Line Orientation Test, administered in a blocked fMRI study. The findings indicated activation of the cerebellar regions, the Hemisphere Lobules IV, VI and Crus I, while the subjects were performing the experimental task of the judgment of the orientation of lines. Furthermore, cortical regions were activated, including the bilateral precuneus (BA 7), the extrastriate regions (BA 19), and the bilateral prefrontal regions (BA 9, 10, 44, 46). The imaging data confirmed that the activity of the cerebellum is associated with judging spatial orientation. The theoretical and clinical implications of the findings are discussed.

Adult↗
PubMed2005

Frontal lobe involvement in spatial span: converging studies of normal and impaired function.

Although monkey lesion studies involving the prefrontal cortex commonly report working memory deficits, and neuroimaging studies consistently show prefrontal involvement in such tasks, patients with damage to this region commonly fail to show any working memory impairment. Such a discrepancy may be due to insensitive testing measures for patients, as well as small, yet critical differences between working memory tasks in imaging and patient studies. The current study utilised a more sensitive measure of spatial working memory spans, based either on structured or unstructured spatial arrays. A PET study in normal subjects confirmed that both variants did indeed activate prefrontal cortex. The same tasks were given to frontal lobe patients and closely matched controls. Patients with large frontal lesions were significantly impaired on this task, with those patients with damage to the right dorsolateral prefrontal cortex appearing particularly impaired. This result demonstrates that prefrontal cortex is necessary for normal working memory, even in simple tasks, such as spatial span. It is suggested, however, that the patient deficit reflects strategic or goal-based dysfunction, rather than storage limitations.

Adult↗
PubMed2006

Modulation of spatial bias in the dual task paradigm: evidence from patients with unilateral parietal lesions and controls.

Lateral attentional bias is common after unilateral brain damage. It has sometimes been proposed that lateral bias is increased by concurrent cognitive demands, perhaps because of lost top-down compensation. However, an important limitation of previous studies is the sole use of right hemisphere patients. Here we employed a dual task paradigm to measure spatial bias on a visual task while manipulating demands of a concurrent auditory task. Bias was examined in patients with left or right parietal lesions and controls. In Experiment 1 the addition of either a non-spatial or spatial auditory task led to a rightward shift in visual bias. This same rightward shift occurred in controls, left parietals and right parietals. Experiment 2 examined whether the participant's response hand affected their bias. In addition, it attempted to distinguish between the hypothesis that modulatory effects are strongly dependent on lateralization of the concurrent task, and the hypothesis that dual tasks cause a general rightward shift. Response hand was found to have no effect on spatial bias. In addition, bias did not differ between left hemisphere (verbal) and right hemisphere (pitch) concurrent tasks, though the trend was for a smaller rightward shift with the verbal task. Our results show that dual tasks do not exacerbate patients' underlying deficits; instead they cause a global shift in attention to the right. This shift may resemble general rightward shifts that have previously been linked to reduced arousal.

Acoustic Stimulation↗
PubMed2004

Gender-dependent alterations in corticosteroid receptor status and spatial performance following 21 days of restraint stress.

The effects of 21-day exposure to restraint stress on hippocampal corticosteroid receptors and on spatial performance of male and female rats were evaluated. Stressed male animals exhibited a decrease in glucocorticoid receptor immunoreactivity in the CA1 area and the dentate gyrus. At the same time, stressed males tested on Morris water maze showed delayed learning and worse memory scores, compared with the control males. By contrast, stressed females exhibited an increase in glucocorticoid receptor immunoreactivity in CA1, similar learning ability and improved memory scores, compared with control females. In addition, stressed females showed a significant increase in mineralocorticoid receptor immunoreactivity in the CA3 area compared with controls. These data show that 21 days of restraint stress affect hippocampal corticosteroid receptors and spatial performance in a gender-specific manner. The observed changes in corticosteroid receptor levels following stress, may be causatively linked to the stress-induced alterations on spatial learning and memory.

Adrenal Glands↗
PubMed2004

Growth hormone treatment attenuates age-related changes in hippocampal short-term plasticity and spatial learning.

Downregulation of the growth hormone/insulin-like growth factor-1 (IGF-1)axis is one of the most robust biomarkers of mammalian aging. Reports have suggested that age-related changes in secretion of growth hormone and IGF-1 contribute to the development of some peripheral characteristics of the aged phenotype including decreased bone density and lean body mass. Recent work has focused on the identification of a role for age-related reductions in growth hormone and IGF-1 in the development of cognitive impairments associated with aging. In the current study, we report that aged (30 month-old) Brown Norway x Fisher rats demonstrate impairments in spatial learning compared with adult (10 month-old) animals, and that 4-month treatment with growth hormone (300 microg twice daily) attenuates age-related learning impairments. After 6 months of treatment, we employed an extracellular paired-pulse protocol to investigate age-related changes in hippocampal short-term plasticity, and found that aged rats exhibit significantly increased paired-pulse ratios (PPRs) at an interpulse interval of 50 ms compared with adult rats. Long-term growth hormone administration restored PPRs in aged animals to values comparable to those observed in adult controls. Since the age-related changes observed in PPR may result from decreases in hippocampal inhibitory tone mediated by GABA(A) receptors, we assessed GABA(A) receptor subunit expression by immunoblot analysis. Data revealed significant age-related decreases in GABA(A) receptor alpha-1 subunit expression which were attenuated by growth hormone treatment. However, hippocampal levels of the gamma2 subunit, glutamic acid decarboxylase (GAD)(65), and GAD(67) protein concentrations were not significantly affected by age or growth hormone treatment. In conclusion, we suggest that age-related decreases in growth hormone and IGF-1 contribute to cognitive decline, in part, via alterations in hippocampal short-term plasticity. Changes in plasticity may reflect a shift in the balance of hippocampal inhibitory and excitatory function.

Aging↗
PubMed2005

Chronic stress enhances spatial memory in ovariectomized female rats despite CA3 dendritic retraction: possible involvement of CA1 neurons.

Emerging data report sex differences in how the brain responds to chronic stress. Here, we investigated the effects of chronic restraint stress (6 h/day/21 days) on hippocampal morphology and function in ovariectomized female rats. Chronic restraint stress caused CA3 apical dendritic retraction in short- and long-shafted neurons, while it reduced basal dendritic arbors in long-shafted neurons only. Chronic restraint did not affect CA1 dendritic arborization, although it increased the proportion of CA1 spine heads compared with controls. Both stressed and control animals performed well on the Y-maze, a spatial memory task. However, chronic stress enhanced Y-maze performance compared with controls, which may reflect facilitated spatial memory or reduced habituation. Y-maze performance correlated with CA1 spine head proportion. This relationship suggests that spatial ability in females may be more tightly coupled with CA1 morphology, which may override the influence of CA3 dendritic retraction. Thus, this research provides additional evidence that CA3 morphology does not always parallel spatial memory.

Animals↗
PubMed2004

Bilateral lesion of the cerebellar-dentate nucleus impairs egocentric sequential learning but not egocentric navigation in the rat.

The involvement of the cerebellum in procedural learning is demonstrated in visuomotor-sequence tasks, as lesion of this area impedes the acquisition of new sequences. Likewise, the lateral cerebellum appears to be involved in the acquisition of new sequences, but not in the execution of learned sequences. In contrast, the dentate nucleus participates only in the execution of learned visuomotor sequences. In previous studies, disruption of the procedural elements of spatial navigation following cerebellar or dentate lesions has been reported. However, as praxic strategies (egocentric learning) are included in the procedural elements of the navigation, the participation of the cerebellar-dentate nucleus in egocentric procedural learning processes has not been evaluated. Therefore, using colchicine, bilateral lesions were made in the cerebellar-dentate nucleus of Sprague-Dawley rats, and these rats were given two tasks: egocentric-based motor sequence learning in the radial maze and egocentric navigation in the Morris water maze. The lesioned rats were unable to use the sequential information in the short term and showed delayed long-term acquisition, which was probably due to the inability to detect the sequence. No effects on the egocentric navigation task were observed. Our results indicate that the cerebellar-dentate nucleus is involved in the detection of egocentric sequential information but not in the use of this information in the navigation process. Further, they show differential involvement of the cerebellar-dentate nucleus in the execution of learned visuomotor sequences, as the dentate lesion disrupted the acquisition of new egocentric-motor-based sequences.

Analysis of Variance↗
PubMed2004

Estrogen replacement in ovariectomized rats affects strategy selection in the Morris water maze.

While estrogen enhances performance on some tasks of learning and memory, it has impairing or no effects on others. It has been proposed that estrogen differentially affects performance on various tasks of learning and memory by influencing the strategy used to solve a task. The goal of the present study was to determine if estrogen would influence strategy selection in the Morris water maze. Long-Evans rats were ovariectomized and implanted with Silastic capsules containing 25% estradiol diluted in cholesterol or 100% cholesterol. Rats were trained in a water maze task in which multiple strategies were available for use to locate a hidden escape platform that was moved to a new location for each set of four daily trials. During 10 days of acquisition trials, a visible floating landmark was always located in a static position relative to the hidden escape platform. Additionally, fixed extramaze cues visible to the animals surrounded the maze. Following acquisition, 2 days of probe trials were conducted in which the static landmark was removed. Estrogen replacement in ovariectomized rats resulted in impaired performance across 10 days of acquisition. Additionally, while removal of the visible landmark during the probe trials had no effect on the performance of the females receiving estrogen, it significantly disrupted performance of females receiving cholesterol treatment. These results indicate that estrogen replacement in ovariectomized rats biases an animal against using a landmark or static cue to aid in the location of a hidden escape platform in the water maze.

Animals↗
PubMed2004

Is the unilateral lesion of the left substantia nigra pars compacta sufficient to induce working memory impairment in rats?

Adult male Wistar rats with a substantia nigra pars compacta (SNc) lesion induced by intranigral administration of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used as a model of early phase Parkinson's disease (PD). This lesion caused a partial depletion of striatal dopamine (DA). The animals were submitted to a spatial working memory version of the water maze task in which they had to find a hidden (submersed) platform using online-maintained information that the platform remains in the same place during four consecutive trials, but that it is moved to another place every training day. Left, but not right SNc-lesioned rats were impaired in finding the platform in the second trial. This result suggests that the left SNc plays a key role in spatial working memory. Control experiments ruled out the possibility that motor impairment, sensory neglect, and/or impairment in the mental representation of the contralateral spatial environment had affected performance of the SNc-lesioned rats.

Analysis of Variance↗
PubMed2005

Self-organizing continuous attractor network models of hippocampal spatial view cells.

Single neuron recording studies have demonstrated the existence of hippocampal spatial view neurons which encode information about the spatial location at which a primate is looking in the environment. These neurons are able to maintain their firing even in the absence of visual input. The standard neuronal network approach to model networks with memory that represent continuous spaces is that of continuous attractor networks. It has recently been shown how idiothetic (self-motion) inputs could update the activity packet of neuronal firing for a one-dimensional case (head direction cells), and for a two-dimensional case (place cells which represent the place where a rat is located). In this paper, we describe three models of primate hippocampal spatial view cells, which not only maintain their spatial firing in the absence of visual input, but can also be updated in the dark by idiothetic input. The three models presented in this paper represent different ways in which a continuous attractor network could integrate a number of different kinds of velocity signal (e.g., head rotation and eye movement) simultaneously. The first two models use velocity information from head angular velocity and from eye velocity cells, and make use of a continuous attractor network to integrate this information. A fundamental feature of the first two models is their use of a 'memory trace' learning rule which incorporates a form of temporal average of recent cell activity. Rules of this type are able to build associations between different patterns of neural activities that tend to occur in temporal proximity, and are incorporated in the model to enable the recent change in the continuous attractor to be associated with the contemporaneous idiothetic input. The third model uses positional information from head direction cells and eye position cells to update the representation of where the agent is looking in the dark. In this case the integration of idiothetic velocity signals is performed in the earlier layer of head direction cells.

Action Potentials↗
PubMed2005

Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks.

Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or naïve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or naïve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.

Animals↗
PubMed2005

Vitamins E and C pretreatment prevents ovariectomy-induced memory deficits in water maze.

We investigated whether the pretreatment with vitamins E (alpha-tocopherol) and C (ascorbic acid) would act on ovariectomy-induced memory deficits in Morris water maze tasks. Adult female Wistar rats were divided into three groups: (1) naive (control), (2) sham (submitted to surgery without removal of ovaries) and (3) ovariectomized. Thirty days after surgery, they were trained in the Morris water maze in order to verify ovariectomy effects both on reference and working memory tasks. Results show that ovariectomized rats presented impairment in spatial navigation in the acquisition phase, as well as in the time spent in target quadrant and in the latency to cross over the location of the platform in test session, when compared to naive and sham groups (controls), in the reference memory task. Ovariectomy did not affect performance in the working memory task. Confirming our hypothesis, ovariectomized rats pretreated for 30 days with vitamins E and C had those impairments prevented. We conclude that ovariectomy significantly impairs spatial reference learning/memory and that pretreatment with vitamins E and C prevents such effect. Assuming this experimental memory impairment might mimic, at least in part, the cognitive deficit sometimes present in the human condition of lack of reproductive hormones, our findings lend support to a novel therapeutic strategy, based on vitamins E and C, to cognitive impairments in post-menopausal women.

Animals↗
PubMed2005

The effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage.

Clozapine is an atypical antipsychotic drug that has been shown to improve spatial memory in some animal models; however its efficacy in reversing spatial memory impairment in rats with hippocampal lesions is unknown. To address this issue, we tested the effects of clozapine on delayed spatial alternation deficits in rats with hippocampal damage in three separate experiments. In each experiment, adult male rats received sham surgery or direct stereotaxic infusions of the excitotoxin, NMDA, into the hippocampus. In the first study, seven days after surgery, the sham control animals received daily saline injections while the lesioned animals were split into two groups that received daily saline or clozapine (2.0 mg/kg, sc) injections. During the fifth week of injections, all animals were tested in a food-motivated delayed spatial alternation task. Saline-treated rats with excitotoxic hippocampal damage displayed significant deficits in delayed spatial alternation. Daily clozapine injections completely reversed this deficit. In a second experiment, it was found that clozapine treatment limited to the testing days only did not improve alternation performance in lesioned rats. Finally, in a third experiment, chronic clozapine treatment did not improve alternation performance in lesioned rats that were pre-trained in the alternation task prior to surgery. These results suggest that chronic, but not acute, clozapine treatment enables rats with hippocampal damage to develop new spatial learning, but can not rescue old spatial learning established prior to damage. These results may have implications for the treatment of cognitive deficits caused by hippocampal dysfunction in disorders such as schizophrenia, Alzheimer's disease, and others.

Analysis of Variance↗
PubMed2006

Visuospatial function in the beagle dog: an early marker of cognitive decline in a model of human aging and dementia.

Visuospatial learning and memory impairments are an early marker for age-related cognitive decline and Alzheimer's disease. Similar to humans, aged dogs show visuospatial learning and memory deficits (). One hundred and nine beagle dogs ranging between 0.25 and 11.99 years were tested on a visuospatial delayed non-matching to position (DNMP) task to better characterize the progression of visuospatial deficits in the dog. Age predicted 48.2% of the variability in learning the DNMP, with dogs ranging from 1 to 11.99 years generally making more errors with increasing age. By contrast, puppies (<1 year) likely were showing developmental deficits, possibly due to an immature prefrontal cortex. Mild visuospatial deficits were detected by 6 years, which precedes the typical onset of amyloid-beta (Abeta) accumulation in the dog brain by two years, and can serve as an early marker for cognitive decline in the dog. These findings suggest that (1) age-related changes in visuospatial function in the dog models that seen in humans, further validating the dog as a model for human aging and dementia; and (2) other mechanisms, such as oxidative stress, soluble Abeta oligomers or cholinergic deficits, are likely contributing to the early impairment.

Aging↗
PubMed2006

Cholinergic activity in the insular cortex is necessary for acquisition and consolidation of contextual memory.

Experiences with a high emotional content (aversive) tend to be stored as long-term memories; however, there are also contextual recollections, which form a significant part of our memories. Different research has shown that the insular cortex (IC) plays an important role during aversive memory formation, yet its role during incidental/non-aversive learning like pre-exposure contextual memory formation has received little attention. The objective of this research was to establish the role of cholinergic activity in the IC through its muscarinic receptors during the formation of inhibitory avoidance (IA) memory, as well as during pre-exposure contextual memory, using a paradigm such as latent inhibition (LI). Rats with bilateral cannulae directed into the IC were trained in the LI paradigm of IA or IA task alone. The muscarinic antagonist receptor scopolamine was infused bilaterally into the IC 5 min before the pre-exposure into the dark chamber of the IA cage, one day before the conventional IA training or during the IA training day. During the IA test, the entrance latency into the dark chamber of the IA cage was measured as an index of contextual memory. The results showed that scopolamine infused before and after IA training disrupts inhibitory avoidance memory. Also, it showed that the pre-exposed saline-infused animals (LI) had a lower entrance latency compared to the group not pre-exposed (IA). However, the group that received scopolamine into the IC before, but not after, the pre-exposure to the dark chamber, presented a similar latency to the IA group, showing a blockade of the latent inhibition of the IA. These results suggest that cholinergic activity in the insular cortex is necessary during the acquisition and consolidation of avoidance memory, but appears necessary only during the acquisition of pre-exposure non-aversive contextual memory.

Analysis of Variance↗
PubMed2007

Pre-training to find a hidden platform in the Morris water maze can compensate for a deficit to find a cued platform in a rat model of Parkinson's disease.

The bilateral intranigral infusion of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in adult male Wistar rats caused a specific and partial loss of substantia nigra pars compacta (SNc) dopamine neurons, a partial depletion of striatal dopamine, and a deficit to learn the intra-maze cued version of the Morris water maze. Pre-training the SNc rats in the spatial version of the water maze or simply maintaining the animals on the water maze platform reversed this deficit. This improvement was even observed when the order of the extra-maze cues presented to the rats during pre-training of the spatial version was changed during training of the intra-maze cued version. However, this deficit was not reversed either by maintaining the animals on the platform if the spatial cues were surrounded and covered with a curtain or by swimming sessions in the maze without the escape platform and the curtain. These findings suggest that none of the following elements alone, learned during the spatial task pre-training, could help SNc rats learn the intra-maze cued task: improvement of swimming skills or knowledge of the existence of the escape platform; distance between the platform and the border of the pool; location of a particular extra-maze cue; relations among extra-maze cues. However, the simultaneous presence of the escape platform and extra-maze cues (irrespective of their relational configuration) during the pre-training sessions proved to be necessary for this improving effect to occur.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗