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Dorsal hippocampal function in unreinforced spatial learning.

This study examined learning about the spatial environment by rats during a single 10 min period of exploration on an eight-arm radial maze. Because no specific behaviors were learned during this procedure, the existence of learned spatial information was inferred from its retarding effect on subsequent conditioned cue preference (CCP) learning on the same maze. Previous experiments have shown that this form of spatial learning, measured in this way, requires an intact fimbriafornix and functional N-methyl-D-aspartate receptors. However, in the present experiments, large neurotoxic lesions of the dorsal hippocampus that impaired win-shift learning failed to eliminate the retarding effect of exploration on CCP learning. This result was obtained in three independent replications. These findings fail to confirm the hypothesis that the hippocampus is involved in spatial learning when that learning occurs in the absence of reinforcers and does not produce any specific learned behaviors. Previous work showed that this form of "pure" spatial learning requires an intact fimbria-fornix for acquisition but not for expression; the present findings suggest that the hippocampus is not required for either of these processes. The fimbria-fornix may interact with other temporal lobe structures in mediating this form of learning. The function of the hippocampus may be limited in some way to situations that involve reinforcers and/or situations in which specific behaviors are learned.

Animals↗

Detecting clinical and balanced selection using spatial autocorrelation analysis under kin-structured migration.

Recently spatial autocorrelation has been employed to infer microevolutionary processes from patterns of genetic variation. In theory, different processes should show characteristic signature correlograms; e.g., clinal selection should produce correlograms decreasing from positive to negative autocorrelation, whereas uniform balanced selection should lead to no spatial autocorrelation. The ability of a statistical method such as spatial autocorrelation analysis to distinguish between these selective regimes or even to detect departures from neutrality is dependent on the strength of the evolutionary force and the population structure. Weak selection or migration will not be apparent against the expected background of stochastic noise. Moreover, the population structure may generate sufficient stochastic variation such that even strong evolutionary forces may fail to be detected. This study uses computer simulation to examine the effects of kin-structured migration and three different selective regimes on the shape of spatial correlograms to assess the ability of this technique to detect different microevolutionary processes. Genetic variation among 8 loci is simulated in a linear set of 25 artificial populations. Kin-structured stepping-stone migration among adjacent populations is modeled; directional, balanced, and clinal selection, as well as neutral loci are considered. These experiments show that strong selection produces correlograms of the predicted shape. However, with an anthropologically reasonable population structure, considerable stochastic variation among correlograms for different alleles may still exist. This suggests the need for caution in inferring genetic process from spatial patterns.

Bias↗

Spatiotemporal activation of the two visual pathways in form discrimination and spatial location: a brain mapping study.

To address the question of the relationship between the two visual pathways, a ventral stream for object and form vision and a dorsal stream for spatial and motion vision, we measured the spatiotemporal activation patterns in the two pathways responding to an integrated visuospatial task to which form discrimination and spatial location were assigned simultaneously. The two cognitive components of form discrimination and spatial location were interwoven in the task; however, the fMRI data demonstrated that such a task still activated both ventral GTi/GF (the inferior temporal gyrus/the fusiform gyrus) and dorsal Ga/PCu (the angular gyrus/Precuneus), which are supposed to mediate form discrimination and spatial location, respectively. In addition, the source waveforms of the fMRI foci based on the source analysis of the fMRI-seeded dipole modeling and the moving dipole modeling indicated that in responding to the task combining simultaneously form perception and spatial location, the activity in Ga/PCu begins earlier than that in GTi/GF, but it peaks later and lasts longer.

Adult↗

Evaluating requirements for spatial resolution of fMRI for neurosurgical planning.

The unambiguous localization of eloquent functional areas is necessary to decrease the neurological morbidity of neurosurgical procedures. We explored the minimum spatial resolution requirements for functional magnetic resonance imaging (fMRI) data acquisition when brain mapping is used in neurosurgical planning and navigation. Using a 1.5 Tesla clinical MRI scanner, eight patients with brain tumors underwent fMRI scans using spatial resolution of approximately 4 x 4 x 4 mm(3) to map the eloquent motor and language areas during the performance of cognitive/sensorimotor tasks. The fMRI results were then used intra-operatively in an open MRI system to delineate eloquent areas. Retrospectively, activation patterns were visually inspected by a neurosurgeon to determine qualitatively whether ambiguity with respect to the activation boundaries, due to low spatial resolution, could be of potential significance for surgical guidance. A significant degree of ambiguity in both the extent and shape of activation was judged to be present in data from six of the eight patients. Analysis of fMRI data at multiple resolutions from a normal volunteer showed that at 3 mm isotropic resolution, eloquent areas were better localized within the gray matter although there was still some potential for ambiguity caused by activations appearing to cross a sulcus. The data acquired with 2-mm isotropic voxels significantly enhanced the spatial localization of activation to within the gray matter. Thus, isotropic spatial resolution on the order of 2 x 2 x 2 mm(3), which is much higher than the resolutions used in typical fMRI examinations, may be needed for the unambiguous identification of cortical activation with respect to tumors and important anatomical landmarks.

Adult↗

Preserved performance in a hippocampal-dependent spatial task despite complete place cell remapping.

The spatially localized firing of hippocampal place cells is thought to underlie the navigational function of the hippocampus. Performance on a spatial task learned using a particular place cell map should therefore deteriorate if the map is disrupted. To test this prediction, we trained rats on a hippocampal-dependent spatial task in a black box and tested them in a white box. Although the change from black to white induced remapping of most place cells, navigational performance remained essentially intact. Furthermore, place cell activity was also unrelated to specific aspects of the task such as tone onset, response, or goal location. Together, these results imply that the spatial information needed to solve this navigation task is represented outside the hippocampus and suggest that the place cells encode some other aspect, such as the spatial context.

Animals↗

Environment-spatial conditional learning in rats with selective lesions of medial septal cholinergic neurons.

Cholinergic medial septal neurons may regulate several aspects of hippocampal function, including place field stability and spatial working memory. Monkeys with damage to septal cholinergic neurons are impaired in visual-spatial conditional learning tasks; however, this candidate function of septal cholinergic neurons has not been studied extensively in the rat. In the present study, rats with selective lesions of cholinergic neurons in the medial septum and vertical limb of the diagonal band of Broca (MS/VDB), made with 192 IgG-saporin, were tested on a conditional associative learning task. In this task, which we term "environment-spatial" conditional learning, the correct location of a spatial response depended on the array of local environmental cues. MS/VDB-lesioned rats were impaired when the two parts of the conditional problem were presented concurrently, but not when one environment had been learned before the full conditional problem was presented. Our findings suggest that cholinergic MS/VDB neurons participate in some aspects of conditional associative learning in rats. They may also shed light on the involvement of cholinergic projections to the hippocampus in modulating and remodeling hippocampal spatial representations.

Animals↗

Study of CA1 place cell activity and exploratory behavior following spatial and nonspatial changes in the environment.

Changes in the spatial arrangement or identity of objects inside a familiar environment induce reexploration. The present study looks at modifications of place cell activity during such renewed exploration. Hungry rats foraged for food in a cylinder with a salient cue card attached to the wall and with two distinct objects at fixed positions on the floor relative to each other and to the cue card. Once a set of CA1 place cells was recorded in this standard configuration, additional sessions were done after two kinds of manipulation. In the first, the two objects were rotated as a rigid set 90 degrees counterclockwise around the cylinder center while leaving the cue card in place; this was considered a spatial change. The effects of rotating the objects were different for fields near the objects (near fields) and fields far from the objects (far fields). Object rotation altered most near fields in complex ways, including remapping and cessation of firing. Near fields that remained intact after object rotation underwent unpredictable rotations that frequently departed considerably from the expected value of 90 degrees CCW. In contrast, the only change induced in far fields was a reduction of discharge rate on day 1, but not day 2, exposures of the rat to the rotated objects. The effects on both near and far fields were reversed when the objects were returned to their standard position. In the second manipulation, substitution of one of the two familiar objects with a novel object, a nonspatial change, had no detectable effect on place cell activity, regardless of field location. The sensitivity of hippocampal place cells to spatial changes but not to nonspatial changes is in agreement with earlier results showing that hippocampal lesions abolish reexploration after spatial but not after nonspatial object manipulations. The fact that reexploration is accompanied by place cell changes after spatial but not nonspatial changes reinforces the role that the hippocampus is believed to play in navigational computing and is perfectly compatible with the idea that another brain structure, likely perirhinal cortex, is responsible for object recognition.

Action Potentials↗

Preserved configural learning and spatial learning impairment in rats with hippocampal damage.

This study was undertaken to compare the effect of hippocampal neurotoxic lesions in rats on two behavioral tasks, one a test of spatial learning, and the other an operant discrimination task that is acquired by forming nonspatial configural associations. Lesions of the hippocampus were made with microinjections of ibotenic acid. After postoperative recovery, rats were trained initially to locate a camouflaged escape platform in a water maze using distal spatial cues. Rats also were trained in the maze apparatus with a visible escape platform under conditions in which spatial information was made irrelevant to performance, i.e., cue learning. In an operant task, the same rats were then trained on a discrimination that included simultaneous feature positive and feature negative components (trial types XA+, A-, XB-, B+). After completion of this nonspatial configural learning task, rats received additional training in the water maze using a new platform location for spatial learning. To the extent that proficient performance in both the maze and operant tasks depends on a common function of the hippocampus, i.e., configural learning, the expectation was that hippocampal lesions would prove equally detrimental to performance in both tasks. Contrary to this expectation, lesioned rats were severely impaired in spatial learning but readily acquired the operant discrimination, even exhibiting some evidence of enhanced performance on this nonspatial configural learning task. Performance of the lesioned rats during cue training in the water maze was also enhanced relative to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

Amygdala kindling-induced seizures selectively impair spatial memory. 2. Effects on hippocampal neuronal and glial muscarinic acetylcholine receptor.

The muscarinic acetylcholine receptor is linked via hydrolysis of phosphoinositides to the protein kinase C pathway. In a preceding paper (Beldhuis, H. J. A., H. G. J. Everts, E. A. Vander Zee, P. G. M. Luiten, and B. Bohus (1992) Amygdala kindling-induced seizures selectively impair spatial memory. 1. Behavioral characteristics and effects on hippocampal neuronal protein kinase C isoforms. Hippocampus 2:397-410), the role of different isoforms of protein kinase C in neurobiological processes associated with plasticity was studied using both a spatial learning paradigm and amygdala kindling in the rat. This study extended the findings on protein kinase C activity to the level of the muscarinic acetylcholine receptor. Rats were trained in a spatial learning paradigm and kindled simultaneously in the amygdala to develop generalized motor convulsions. Control rats were trained only in the spatial learning paradigm to acquire stable working and reference memory performance. Alteration in the expression of the muscarinic acetylcholine receptor was investigated using a monoclonal antibody to muscarinic acetylcholine receptor proteins. Trained control rats that were exposed repeatedly to the spatial learning paradigm showed an increase in immunoreactivity for the muscarinic acetylcholine receptor located in the same hippocampal regions in which the protein kinase C activity was increased. In fully kindled rats, however, this increase located in principal neurons was absent, whereas expression of muscarinic acetylcholine receptor proteins was increased in hippocampal astrocytes. Moreover, fully kindled rats showed an impairment in reference memory performance as compared to trained control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗

Spatial selectivity of unit activity in the hippocampal granular layer.

Single neuron activity was recorded in the granular layer of the fascia dentata in freely moving rats, while the animals performed a spatial "working" memory task on an eight-arm maze. Using recording methods that facilitate detection of units with low discharge rates, it was found that the majority (88%) of cells in this layer have mean rates below 0.5 Hz, with a minimum of 0.01 Hz or less. The remaining recorded cells exhibited characteristics typical of the theta interneurons found throughout the hippocampus. Based on several criteria including relative proportion and the relation of their evoked discharges to the population spike elicited by perforant path stimulation, it was concluded that the low-rate cells correspond to granule cells. Granule cells exhibited clear spatially and directionally selective discharge that was at least as selective as that of a sample of CA3 pyramidal cells recorded under the same conditions. Granule cells had significantly smaller place fields than pyramidal cells, and tended to have more discontiguous subfields. There was no spatial correlation among simultaneously recorded adjacent granule cells. Granule cells also exhibited burst discharges reminiscent of complex spikes from pyramidal cells while the animals sat quietly; however, the spike duration of granule cells was significantly shorter than CA3 pyramidal cell spike durations. Under conditions of environmental stability, granule cell place fields were stable for at least several days. Following occasional maze rotations relative to the (somewhat impoverished) visual stimuli of the recording room, granule cell place fields were maintained relative to the distal spatial cues; however, frequent rotations of the maze sometimes resulted in a shift in the reference frame to the maze itself. These observations indicate that granule cells of the fascia dentata provide their CA3 targets with a high degree of spatial information, in the form of a sparsely coded, distributed representation.

Action Potentials↗

Spatial information content and reliability of hippocampal CA1 neurons: effects of visual input.

The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 "complex spike" (CS) cells were studied in young and old Fischer-344 rats during food-motivated performance of a randomized, forced-choice task on an eight-arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms. In the dark, a lower proportion of CS cells had "place fields," and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields. Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness. While the task was simple and errors rare, rats that made fewer errors (i.e., re-entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention.

Action Potentials↗

Alterations in the immunoreactivity for muscarinic acetylcholine receptors and colocalized PKC gamma in mouse hippocampus induced by spatial discrimination learning.

This study describes changes in the immunoreactivity for muscarinic acetylcholine receptors (mAChRs) in the hippocampus of mice in relation to spatial discrimination behavior, employing the monoclonal antibody M35 raised against purified bovine mAChR protein. Performance in a hole board in which the animals learned the pattern of 4 baited holes out of 16 holes served as the measure of spatial discrimination learning and memory. Twenty-six adult male house mice were used, divided into four groups. Three groups served as various controls: group N (naive; blank controls); group H (habituated; animals were introduced to the hole board with all holes baited for 5 consecutive days), and group P (pseudo-trained; the animals were admitted to the hole board for 13 consecutive days with all holes baited). The T group (trained) was subjected to the hole board for 5 consecutive habituation days with all holes baited (similar to the H and P groups), followed by 8 successive training days with only four holes baited in a fixed pattern. During the 8 training days, the T group gradually acquired a pattern to visit the baited holes, whereas the P group continued visiting holes in a random fashion. The mice were killed 24 h after the last behavioral session. All principal cells in teh cornu ammonis (CA) and dentate gyrus (DG) of the habituated animals revealed increased levels of mAChR immunoreactivity (mAChR-ir) over the naive mice. A minor increase in mAChR-ir was found in the apical dendrites of the CA1 pyramidal cells. Pseudotraining resulted in a CA1-CA2 region with a low level of mAChR-ir, resembling naive animals, whereas the trained mice showed a further increase in mAChR-ir in the CA1-CA2 pyramidal cell bodies and apical dendrites. Optical density measures of the mAChR-ir in the CA1 region revealed a significant (P < 0.05) increase in the pyramidal cell bodies of the H and T group over the N and P group, and a significant (P < 0.05) increase in the apical dendrites of the T group over all other groups. In contrast to the CA1-CA2 region, both pseudotrained and trained mice revealed high mAChR staining in the CA3-CA4 region and the DG. These results indicate that prolonged exposure to the hole board is sufficient for an enhanced mAChR-ir in the CA3-CA4 and DG, whereas the increase in CA1-CA2 pyramidal cells is a training-specific feature related to spatial orientation. Nonpyramidal neurons within the CA1-CA2 region with enhanced mAChR-ir in the pyramidal cells, however, revealed a decreased level of mAChR-ir. The opposing effect of pyramidal and nonpyramidal cells suggests a shift in the excitability of the hippocampal microcircuitry. Previously we demonstrated an increase and redistribution of hippocampal protein kinase C gamma-immunoreactivity (PKC gamma-ir) induced by hole board learning in mice (Van der Zee et al., 1992, J Neurosci 12:4808-4815). Immunofluorescence double-labeling experiments conducted in the present study in naive and trained animals revealed that the principal cells and DG interneurons co-express mAChRs and PKC gamma, and that the immunoreactivity for both markers increased in relation to spatial orientation within these neurons. The mAChR-positive nonpyramidal cells of the CA1-CA2 region were devoid of PKC gamma and revealed an opposite training-induced effect. These results suggest that the postsynaptic changes in mAChR- and PKC gamma-ir reflect functional alterations of the hippocampal formation induced by spatial learning.

Animals↗

The effects of a sedative antihistamine, d-chlorpheniramine, on visuomotor spatial discrimination and regional brain activity as measured by positron emission tomography (PET).

Although most people taking antihistamines have experienced sedation and impaired performance, the neural correlates of these sedative properties are not well understood in man. Brain imaging can be used to demonstrate how regional brain activities are altered during such sedative effects. The aim of this study was to visualize the brain mechanism of impaired visuomotor spatial cognition with orally administered d-chlorpheniramine, a first-generation sedative antihistamine, using H(2) (15)O and positron emission tomography (PET). Normal subjects were randomly assigned to two groups (chlorpheniramine and placebo) and performed a spatial discrimination task after the oral administration of 6 mg d-chlorpheniramine or a placebo. The administration of d-chlorpheniramine impaired visuomotor spatial discrimination and altered cortical and subcortical activity. Decreased and increased activities were observed in the right parietal cortex (BA 40) which is related to visuomotor spatial cognition and the posterior cingulate cortex which constitutes the attention system of the brain, respectively. In particular, the brain activities of BA 40 were negatively and positively correlated to those of bilateral caudate nuclei and the dorsolateral prefrontal cortex, respectively. These findings clearly suggest that the alteration in the cortical and subcortical activity contributes to impaired spatial cognition caused by treatment with d-chlorpheniramine.

Adult↗

Visuo-spatial working memory deficits in current and former users of MDMA ('ecstasy').

Verbal working memory and executive deficits have been observed in ecstasy users. The present study sought to establish whether these also extended to visuo-spatial working memory. Thirty-six current ecstasy users, 12 former users (abstinent for at least 6 months) and 31 individuals that had never used ecstasy were tested on a maintenance plus type visuo-spatial working memory task. The task required participants to recall a sequence of specially marked cells in a four-by-four matrix display while at the same time performing a concurrent visual judgement task. Both the current and former user groups registered impairments relative to nonusers. These remained significant following statistical controls for a range of potentially confounding variables including the use of various other drugs during the 3 months prior to testing. Users were unimpaired on a simple spatial span measure suggesting that the deficits observed reflected the executive aspects of the spatial working memory task. Also consistent with executive involvement, statistical controls for measures of verbal working memory performance (computation span) removed half of the ecstasy-related variance in spatial working memory. The possibility that the pattern of results obtained might reflect some general impairment in information processing efficiency is discussed.

Adult↗

Spatial clustering of endemic Burkitt's lymphoma in high-risk regions of Kenya.

Endemic Burkitt's lymphoma (eBL), the most common childhood cancer in sub-Saharan Africa, occurs at a high incidence in western Kenya, a region that also experiences holoendemic malaria. Holoendemic malaria has been identified as a co-factor in the etiology of this cancer. We hypothesized that eBL may cluster spatially within this region. Medical records for all eBL cases diagnosed from 1999 through 2004 at Nyanza Provincial General Hospital were reviewed for case residential information to examine this hypothesis. Two cluster detection methods, Anselin's Local Moran test for spatial autocorrelation and a spatial scan test statistic, were applied to this residential data to determine whether statistically significant high- and low-risk areas were present in the Province. During the 6-year study period, 272 children were diagnosed with eBL, with an average annual incidence of 2.15 cases per 100,000 children. Using Empirical Bayes smoothed rates, the Local Moran test identified 1 large multi-centered area of low eBL risk (p-values < 0.01) and 2 significant multi-centered clusters of high eBL risk (p-values < 0.001). The spatial scan detected 3 small independent low-risk areas (p-values < 0.02) and 2 high-risk clusters (p-values = 0.001), both similar in location to those identified from the Local Moran analysis. Significant spatial clustering of elevated eBL risk in high-malaria transmission regions and of reduced incidence where malaria is infrequent suggests that malaria plays a role in the complex eBL etiology, but that additional factors are also likely involved.

Adolescent↗

Critical role of spatial resolution in dynamic contrast-enhanced breast MRI.

The spatial resolution of three-dimensional (3D) gradient-echo T1-weighted images, from 40 women with 25 malignant and 23 benign lesions, was purposely degraded to determine the role of spatial resolution in recording, analysis, and diagnosis of dynamic contrast-enhanced breast MRI. Images were recorded and analyzed at pixel resolution according to the 3TP method (Degani et al., Nat Med 1997;3:780-782). Reduction in spatial resolution degraded the appearance of foci with fast wash-in and fast washout dynamics. This resulted in an increase in false-negative diagnoses. The sensitivity for differentiating between malignant and benign lesions, using threshold criteria defined by the 3TP analysis, of 76% decreased to 60% and 24% for a 2- and 4-fold reduction in spatial resolution, respectively, without affecting significantly the high specificity (96-100%). In order to minimize false-negative diagnoses of contrast-enhanced breast MRI and maintain high specificity, it is essential to record and analyze the dynamic behavior at high spatial resolution. J. Magn. Reson. Imaging 2001;13:862-867.

Biopsy↗

Spatial normalization of diffusion tensor fields.

A method for the spatial normalization and reorientation of diffusion tensor (DT) fields is presented. Spatial normalization of tensor fields requires an appropriate reorientation of the tensor on each voxel, in addition to its relocation into the standardized space. This appropriate tensor reorientation is determined from the spatial normalization transformation and from an estimate of the underlying fiber direction. The latter is obtained by treating the principal eigenvectors of the tensor field around each voxel as random samples drawn from the probability distribution that represents the direction of the underlying fiber. This approach was applied to DT images from nine normal volunteers, and the results show a significant improvement in signal-to-noise ratio (SNR) after spatial normalization and averaging of tensor fields across individuals. The statistics of the spatially normalized tensor field, which represents the tensor characteristics of normal individuals, may be useful for quantitatively characterizing individual variations of white matter structures revealed by DT imaging (DTI) and deviations caused by pathology. Simulated experiments using this methodology are also described.

Algorithms↗

Three-dimensional spectral-spatial excitation.

A method of three-dimensional spectral-spatial excitation is presented which is selective simultaneously in two spatial dimensions and in the spectral or chemical shift dimension. This method can be used to create spectral passbands whose center frequency varies as a function of spatial location within an imaging plane. This variation of passband center frequency may be specified by an acquired main field (B0) map; the resulting excitations compensate for inhomogeneity of the B0 field. In vivo images are presented in which three-dimensional spectral-spatial excitation allows selective water-only imaging in the presence of large B0 inhomogeneity where conventional spectrally selective imaging falls. Phantom studies give a detailed profile of the performance of three-dimensional spectral-spatial pulses suitable for water-only or fat-saturation imaging. These pulses may also be useful for fat and water suppression in spectroscopic imaging. Performance constraints imposed by limited gradient slew rates are analyzed and quantified.

Humans↗