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H Hodges

Publications and source records attributed to H Hodges.

At least 19 recordsLinked to original sources
PubMed2005

Transplantation of cultured astrocytes attenuates degenerative changes in rats with kainic acid-induced brain damage.

Viability of astrocyte grafts introduced into CA1 pyramidal layer of the left dorsal hippocampus after injection of kainic acid into this brain region and the effects of these grafts on the hippocampus and amygdala were studied on Wistar rats. In rats with astrocyte grafts the degree of destruction in fields CA1-CA2 of the dorsal and ventral hippocampus, fields CA3-CA4 of the ventral hippocampus, and central and basolateral amygdala was lower compared to animals with kainic acid-induced hippocampal damage and control rats; destructions in the dentate fascia were absent. Our results suggest that astrocyte grafts stimulate neurogenesis in the mature brain of recipient rats with kainic acid-induced brain damage.

Amygdala↗
PubMed2003

Transplantation of neural stem cells modulates apolipoprotein E expression in a rat model of stroke.

The expression of apolipoprotein E (apoE) after ischemic brain damage has been associated with plasticity involved in promoting functional recovery. We therefore examined the expression and distribution of apoE in rats that received intraparenchymal grafts of the conditionally immortal stem cell line MHP36 either ipsilateral or contralateral to the lesion or intraventricular grafts 4 months after transplantation. ApoE immunoreactivity was highly expressed in the striatum, somatosensory cortex, and thalamus of the lesioned hemisphere in all rats subjected to middle cerebral artery occlusion. Only in rats with intraparenchymal grafts, apoE was significantly upregulated in the contralateral hemisphere, whereas levels and distribution in rats with intraventricular grafts resembled those of ischemic controls. In ischemic rats, apoE was seen in both astrocytes and neurons on the lesioned side, and in grafted rats, apoE was present in host and transplanted neurons and astrocytes. Previously we have shown that intraparenchymal grafts reduced sensorimotor asymmetry, whereas intraventricular grafts improved cognitive dysfunction, with transplanted cells being widely distributed in cortex, striatum, and corpus callosum on both sides of the brain in all grafted groups. Thus, stem cells grafted in the parenchyma are not only capable of limited expression of apoE in the host brain but also trigger a robust increase on the side contralateral to stroke damage where this does not normally occur. Findings that parenchymal, but not ventricular, grafts facilitated sensorimotor recovery suggests that apoE might contribute to plastic changes in relevant pathways, possibly on both sides of the brain. In contrast, no evidence was found for an association between apoE and recovery of cognitive function in rats with intraventricular grafts.

Animals↗
PubMed2001

Behavioural, histological and immunocytochemical consequences following 192 IgG-saporin immunolesions of the basal forebrain cholinergic system.

Use of the selective immunotoxin; 192 IgG-saporin, is helping to elucidate the role of the cholinergic system in cognition by overcoming the problems of interpretation associated with the use of non-specific lesioning agents. In separate studies, we have compared the long- and short-term effects of single site and combined saporin lesions of the nucleus basalis magnocellularis and medial septal area, on spatial learning and memory in radial arm and water maze tasks. At 11 months, only rats with combined lesions showed deficits in both radial and water maze tasks, although terminal cholinergic deafferentation was substantial and extensive tissue loss was seen at the injection sites in both single and combined lesions. However, the extensive tissue loss with long-term lesions suggested that behavioural deficits were not solely attributable to cholinergic deafferentation. In contrast, when rats with combined lesions were tested 5 months after lesioning, no deficits were apparent, although there was almost complete loss of choline acetyltransferase- and nerve growth factor receptor-immunoreactivity in the basal forebrain with no tissue damage at the injection sites. This study supports existing literature that selective loss of cholinergic neurons in the basal forebrain does not produce behavioural impairments in standard tasks of learning and memory, but deficits are apparent when damage is non-selective as occurs late after lesioning, confounding interpretation of behavioural data. It further highlights potential problems with this immunotoxin in long-term studies.

Acetylcholinesterase↗
PubMed2001

Resolution of stroke deficits following contralateral grafts of conditionally immortal neuroepithelial stem cells.

BACKGROUND AND PURPOSE: Grafts of MHP36 cells have previously been shown to reduce dysfunction after global ischemia in rats. To test their efficacy after focal ischemia, MHP36 cells were grafted 2 to 3 weeks after transient intraluminal middle cerebral artery occlusion (tMCAO) in rats. METHODS: MHP36 cells were implanted into the hemisphere contralateral to the lesion, with 8 deposits of 3 microL of cell suspension (25 000 cells per microliter). Sham grafted rats received equivalent volumes of vehicle. Three groups, sham-operated controls (n=11), MCAO+sham grafts (n=10), and MCAO+MHP36 grafts (n=11), were compared in 3 behavioral tests. RESULTS: In the bilateral asymmetry test, MCAO+MHP36 grafted rats exhibited neglect before grafting but subsequently showed no significant dysfunction, whereas MCAO+sham grafted rats showed stable sensorimotor deficits over 18 weeks relative to controls. MCAO+sham grafted rats demonstrated spontaneous motor asymmetry and increased rotational bias after injection of dopamine agonists. MCAO+MHP36 and control groups exhibited no bias in either spontaneous or drug-induced rotation. In contrast to motor recovery, MCAO+MHP36 grafted rats showed no improvement relative to MCAO+sham grafted rats in spatial learning and memory in the water maze. MCAO produced large striatal and cortical cavitations in both occluded groups. Lesion volume was significantly reduced (P<0.05) in the MCAO+MHP36 grafted group. The majority of MHP36 cells were identified within the intact grafted hemisphere. However, MHP36 cells were also seen in the cortex, striatum, and corpus callosum of the lesioned hemisphere. CONCLUSIONS: MHP36 cells may improve functional outcome after MCAO by assisting spontaneous reorganization in both the damaged and intact hemispheres.

Amphetamine↗
PubMed2001

Modification of radiation myelopathy by the transplantation of neural stem cells in the rat.

In a novel approach, neural stem cells were transplanted to ameliorate radiation-induced myelopathy in the spinal cords of rats. A 12-mm section of the cervical spinal cord (T2-C2) of 5-week-old female Sprague-Dawley rats was locally irradiated with a single dose of 22 Gy of (60)Co gamma rays. This dose is known to produce myelopathy in all animals within 6 months of irradiation. After irradiation, the animals were subdivided into three groups, and at 90 days after irradiation, neural stem cells or saline (for controls) were injected into the spinal cord, intramedullary, at two sites positioned 6 mm apart on either side of the center of the irradiated length of spinal cord. The injection volume was 2 microl. Group I received a suspension of MHP36 cells, Group II MHP15 cells, and Group III (controls) two injections of 2 microl saline. All rats received 10 mg/kg cyclosporin (10 mg/ml) daily i.p. to produce immunosuppression. All animals that received saline (Group III) developed paralysis within 167 days of irradiation. The paralysis-free survival rates of rats that received transplanted MHP36 and MHP15 cells (Groups I and II) were 36.4% and 32% at 183 days, respectively. It was concluded that transplantation of neural stem cells 90 days after irradiation significantly (P = 0.03) ameliorated the expression of radiation-induced myelopathy in the spinal cords of rats.

Animals↗
PubMed2000

Neurological sequelae and long-term behavioural assessment of rats with transient middle cerebral artery occlusion.

Animal models of stroke, notably transient middle cerebral artery occlusion (MCAo), are used to assess the efficacy of pharmacological and transplant treatments. Long-term studies (>1 month) of the functional effects of treatments in animal models are required to predict treatments likely to improve dysfunctions associated with stroke damage. These pre-clinical studies require (1) optimum post-operative care to ensure long-term survival, (2) methods for assignment of rats to groups with equivalent impairments to reduce variability and enhance detection of treatment effects, and (3) behavioural tests that detect long-term stable deficits. For long-term functional assessment, a battery of behavioural tests sensitive to a range of deficits observed after MCAo was developed. The bilateral asymmetry test evaluated the time course of sensory neglect. Deficits of motor integration were examined in the footfault test, and motor bias was assessed by pharmacological stimulation of rotation. The water maze was used to detect long-term deficits in spatial information processing. Long-term differences between control and MCAo animals in this battery of tests indicate that the protocol provides an efficient assessment suitable for evaluating treatment outcomes in pre-clinical studies of stroke, and that the post-operative care procedure and method of assignment to groups were effective.

Animals↗
PubMed2000

Conditional discrimination learning in rats with global ischaemic brain damage.

Hippocampal cell loss was induced by the four-vessel occlusion (4VO) method, a model of global ischaemia. Global ischaemia for 15 min induced a selective damage to the CA1 subfield. Occlusion for 25 min produced a larger cell loss within the CA1 and more variably the CA2, CA3, the striatum and cortex. Ischaemic and sham control groups were assessed on two conditional discrimination tasks (presenting the conditional cues either in the choice arms or the start arm) and two spatial tasks (water maze and a simple spatial discrimination task). No significant effects were found on either of the spatial tasks (apart from the speed measure on the water maze). However, on the conditional discrimination task with the cues in the choice arms, animals with 25 min ischaemia learned the task significantly more slowly than the 15 min ischaemic and control groups. Results for the task with cues presented in the start arm differed according to choice of criterion for learning. With a standard criterion of 90% accuracy on one session controls were significantly superior to both ischaemic groups. However, in this task rats with 15 min occlusion showed the greatest impairment, and were significantly worse than both the controls and the 25 min occlusion group. These results suggest that hippocampal ischaemic damage disrupts the learning of conditional discrimination but not simple spatial tasks. No clear relationship between the extent of hippocampal cell loss and behavioural impairment was evident. These results highlight the critical importance of procedural factors in the assessment of cognitive impairment.

Animals↗
PubMed2000

Functional repair with neural stem cells.

Approval to commence phase I/II clinical trials with neural stem cells requires proof of concept in well-accepted animal models of human neurological disease or injury. We initially showed that the conditionally immortal MHP36 line of hippocampal origin (derived from the H-2Kb-tsA58 transgenic mouse) was effective in repopulating CA1 neurons in models of global ischaemia and repairing cognitive function, and have now shown that this line is multifunctional. MHP36 cells are effective in restoring spatial memory deficits in rats after excitotoxic lesions of the cholinergic projections to cortex and hippocampus and in rats showing cognitive impairments due to normal ageing. Moreover, grafts of MHP36 cells are effective in reversing sensory and motor deficits and reducing lesion volume as a consequence of occlusion of the middle cerebral artery, the major cause of stroke. In contrast, MHP36 cell grafts were unable to repair motor asymmetries in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine system, the prototype rodent model of Parkinson's disease. These data show that conditionally immortal neuroepithelial stem cells are multifunctional, being able to repair diverse types of brain damage. However, there are limitations to this multifunctionality, suggesting that lines from different regions of the developing brain will be required to treat different brain diseases. ReNeuron is currently developing human neuroepithelial stem cell lines from different brain regions and with similar reparative properties to our murine lines.

Animals↗
PubMed2000

Functional reconstruction of the hippocampus: fetal versus conditionally immortal neuroepithelial stem cell grafts.

Late fetal CA1 hippocampal grafts and stem cell grafts from the conditionally immortal MHP36 clonal line derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium both improved spatial deficits in rats with ischaemic CA1 damage induced by four-vessel occlusion (4VO). However, the distribution of fetal and MHP36 grafts differed. Fetal cells lodged in clumps around the implant sites and along the corpus callosum, whilst MHP36 grafts infiltrated the area of CA1 ischaemic damage, achieving apparent architectural reconstruction of the hippocampus. The migration of MHP36 cells is damage-dependent. Few cells were found in intact brain; after 15 min of 4VO cells repopulated only the discrete area of CA1 cell loss, whereas with more extensive damage after 30 min occlusion cells migrated to all hippocampal fields and to cortex. A higher proportion of grafted MHP36 cells differentiated into neurons in the host CA1 field than grafts of striatal or cortical expanded cell populations. Cortical population grafts were as effective as MHP36 grafts in improving water maze learning, whereas striatal or ventral mesencephalic cells were ineffective, indicating a degree of stem cell specificity. The efficacy of MHP36 cells extends to primates. In marmosets with profound impairments in conditional discrimination tasks after lesions of the CA1 field, MHP36 cells improved performance as effectively as fetal grafts and migrated evenly through the CA1 field, in contrast to clustered fetal cells. These findings suggest that MHP36 stem cell grafts are as effective as fetal grafts in functional repair of hippocampal damage, and that their preference for areas of cell loss and adoption of appropriate morphologies is consistent with a point-to-point repair mechanism.

Animals↗
PubMed2000

Conditionally immortal neuroepithelial stem cell grafts reverse age-associated memory impairments in rats.

In order to investigate the effects of stem cell grafts on water maze deficits in aged (22-month-old) rats, three groups of aged rats, assigned by pre-training latency scores to unimpaired, impaired control and impaired grafted groups, were compared with young (five-month-old) controls, six to eight weeks after implantation of cells from the conditionally immortal Maudsley hippocampal stem cell line, clone 36 (MHP36 stem cell line), in the cortex, striatum and hippocampus. Grafted rats were substantially superior to their matched impaired aged controls, and learned to find the platform as rapidly as unimpaired aged rats, although young controls were more efficient than all aged groups in several measures of spatial search during training. On the probe trial, however, aged rats with grafts showed significantly better recall of the precise position of the platform than any other group, including young controls, possibly indicating some perseveration. A further comparison found that groups of unimpaired and moderately impaired aged rats showed far less improvement from water maze pre-training to acquisition phases than young controls, indicative of progressive deficits over time. Histological investigation showed that beta-galactosidase-positive MHP36 cells migrated widely from the implantation sites to infiltrate the striatal matrix, all hippocampal fields and areas of the cortex. Grafted cells showed both astrocytic and neuronal morphologies, with cells of pyramidal and granular appearance in appropriate hippocampal strata.Taken together, these results indicate that neuroepithelial stem cell grafts extensively colonize the aged rat brain and substantially reverse progressive cognitive decline associated with ageing.

Aging↗
PubMed2000

A temporal MRI assessment of neuropathology after transient middle cerebral artery occlusion in the rat: correlations with behavior.

The purpose of this study was to evaluate the temporal and spatial pathological alterations within ischemic tissue using serial magnetic resonance imaging (MRI) and to determine the extent and duration of functional impairment using objective behavioral tests after transient middle cerebral artery occlusion (tMCAO) in the rat. MRI signatures derived from specific anatomical regions of interest (ROI) were then appropriately correlated to the behavioral measures over the time course of the study (up to 28 days post-tMCAO). Sprague-Dawley rats (n = 12) were initially trained on the following behavioral tasks before surgery: bilateral sticky label test (for contralateral neglect); beam walking (for hindlimb coordination); staircase test (for skilled forelimb paw-reaching). Rats were then randomly assigned to receive either tMCAO (90 minutes, n = 6), by means of the intraluminal thread technique, or sham-control surgery (n = 6). Proton density, T2- and T2-diffusion-weighted MR images were acquired at 1, 7, 14, and 28 days post-tMCAO that were then smoothed into respective proton density, T2 relaxation, and apparent diffusion coefficient (ADC) maps. Apparent percent total lesion volume was assessed using T2W imaging. MR signatures were evaluated using the tissue maps by defining ROI for MCAO and sham-control groups, which corresponded to the caudate-putamen, forelimb, hindlimb, and lower parietal cortices both ipsilateral and contralateral to the occlusion site. Behavioral tests were undertaken daily from 1 to 28 days post-tMCAO. Results demonstrate that apparent percent lesion volume reduced from 1 to 7 days (P < 0.05) but then remained constant up to 28 days for the MCAO group. Pathological changes in the temporal profile of T2 and ADC tissue signatures were significantly altered in specific ROI across the time course of the study (P < 0.05 to <0.001), reflecting the progression of edema to necrosis and cavitation. Both T2 and ADC measures of ischemic pathology correlated with parameters defined by each of the functional tests (r > or =0.5, P < 0.05) across the time course. The staircase test revealed bilateral impairments for the MCAO group (P <0.001), which were best predicted by damage to the ipsilateral lower parietal cortex by means of hierarchical multiple regression analyses (R2 changes > or =0.21, P < or =0.03). Behavioral recovery was apparent on the beam walking test at 14 to 28 days post-MCAO, which was mirrored by MRI signatures within the hindlimb cortex returning to sham-control levels. This long-term study is the first of its kind in tracing the dynamic pathologic and functional consequences of tMCAO in the rat. Both serial MRI and objective behavioral assessment provide highly suitable outcome measures that can be effectively used to evaluate promising new antiischemic agents targeted for the clinic.

Animals↗
PubMed1999

Prospects for the clinical application of neural transplantation with the use of conditionally immortalized neuroepithelial stem cells.

Although neural transplantation has made a relatively successful transition from the animal laboratory to human neurosurgery for the treatment of Parkinson's disease, the use of human embryonic brain tissue as the source of transplants raises difficult ethical and practical problems. These are likely to impede the widespread use of this otherwise promising therapy across the range of types of brain damage to which the results of animal experiments suggest its potential applicability. Various alternative approaches are reviewed briefly, aimed at developing sources of tissue for transplantation that can be maintained in vitro until needed, so obviating the requirement for fresh embryonic tissue at each occasion of surgery. Particularly promising are conditionally immortalized neuroepithelial stem cell lines in which the immortalizing gene is downregulated upon transplantation into a host brain. We describe experiments from our laboratory with the use of cells of this kind, the multipotent MHP clonal cell lines, derived from the developing hippocampus of a transgenic mouse harbouring a temperature-sensitive oncogene. Implanted into the hippocampus of rats and marmosets with damage to the CA1 cell field, the MHP36 line gave rise to healthy surviving grafts and to essentially complete recovery of cognitive function. Postmortem study of the implanted rat brains indicated that MHP36 cells migrate to the region of damage, adopt both neuronal (pyramidal) and glial phenotypes in vivo, and reconstitute the normal laminated appearance of the CA1 cell field. We have previously shown that, when primary differentiated foetal tissue is used as the source of grafts in rats with CA1 damage, there is a stringent requirement for replacement with homotypic CA1 cells. We interpret our results as showing that the MHP36 cell line responds to putative signals associated with damage to the hippocampus and takes up a phenotype appropriate for the repair of this damage; they therefore open the way to the development of a novel strategy with widespread applicability to the treatment of the diseased or damaged human brain.

Animals↗
PubMed1999

Counteractive effects of a partial (sabcomeline) and a full (RS86) muscarinic receptor agonist on deficits in radial maze performance induced by S-AMPA lesions of the basal forebrain and medial septal area.

After S-AMPA (8.0 mM) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting and relatively stable impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Treatment with four doses of the partial agonist at the M1 cholinergic muscarinic receptor, sabcomeline (formerly known as SB 202026: 0.01-0.156 mg/kg), substantially reduced working and reference memory errors in both tasks in lesioned rats, in a mainly dose-related manner. These effects were more consistent than those found with the direct muscarinic agonist RS86 (0.05-0.781 mg/kg). The performance of non-lesioned controls was largely unaffected by either treatment. These findings are consistent with previous evidence for cholinergic participation in the radial maze deficits induced by excitotoxic lesions to the forebrain cholinergic projection system. They show that with a relatively selective lesion, which respectively, reduced choline acetyltransferase activity to 36.5 and 22.5% of control level in frontal and dorsolateral cortex, and to 61.8 and 69.2% of control level in dorsal and ventral hippocampus, lesioned rats were responsive to pharmacological treatments aimed to enhance cholinergic function by full or partial agonist activity at M1 receptors. Findings that nicotine (0.1 mg/kg) also reduced radial maze errors in the lesioned animals supports the suggestion that lesion-induced deficits in radial maze performance were amenable to improvement by cholinergic receptor manipulation. However, given the potential adverse side effects of full receptor agonists, which nonselectively target cholinergic receptors throughout the organism, the functional efficacy of sabcomeline, which shows regional selectivity for the central M1 receptor subtypes, suggests that deleterious effects of cholinergic depletion on cognition can be counteracted without incurring the risk of unwanted side effects.

Animals↗
PubMed1999

Primary CA1 and conditionally immortal MHP36 cell grafts restore conditional discrimination learning and recall in marmosets after excitotoxic lesions of the hippocampal CA1 field.

Common marmosets (Callithrix jacchus, n = 18) were trained to discriminate between rewarded and non-rewarded objects (simple discriminations, SDs) and to make conditional discriminations (CDs) when presented sequentially with two different pairs of identical objects signifying reward either in the right or left food well of the Wisconsin General Test Apparatus. After bilateral N-methyl-D-aspartate (0.12 M) lesions through the cornu ammonis-1 (CA1) field (7 microl in five sites), marmosets showed profound impairment in recall of CDs but not SDs, and were assigned to lesion only, lesion plus CA1 grafts and lesion plus Maudsley hippocampal cell line, clone 36 (MHP36) grafts groups matched for lesion-induced impairment. Cell suspension grafts (4 microl, 15-25 000 cells/microl) of cells dissected from the CA1 region of foetal brain at embryonic day 94-96, or of conditionally immortalized MHP36 cells, derived from the H-2Kb-tsA58 transgenic mouse neuroepithelium and labelled with [3H]thymidine, were infused at the lesion sites. The lesion plus MHP36 grafts group was injected five times per week with cyclosporin A (10 mg/kg) throughout testing. Lesion, grafted and intact control marmosets (n = 4-5/group) were tested on recall of SDs and CDs learned before lesioning and on acquisition of four new CDs over a 6-month period. Lesioned animals were highly impaired in recall and acquisition of CD tasks, but recall of SDs was not significantly disrupted. Both grafted groups of marmosets showed improvement to control level in recall of CDs. They were significantly slower in learning the first new CD task, but mastered the remaining tasks as efficiently as controls and were substantially superior to the lesion-only group. Visualized by Nissl staining, foetal grafts formed clumps of pyramidal-like cells within the denervated CA1 field, or jutted into the lateral ventricles. MHP36 cells, identified by beta-galactosidase staining and autoradiography, showed neuronal and astrocytic morphology, and were distributed evenly throughout the CA1 region. The results indicate that MHP36 cell grafts are as functionally effective as foetal grafts and appear to integrate into the host brain in a structurally appropriate manner, showing the capacity to differentiate into both mature neurons and glia, and to develop morphologies appropriate to the site of migration. These findings, which parallel the facilitative effects of foetal and MHP36 grafts in rats with ischaemic CA1 damage, offer encouragement for the development of conditionally immortal neuroepithelial stem cell lines for grafting in conditions of severe amnesia and hippocampal damage following recovery from cardiac arrest or other global ischaemic episodes.

Animals↗
PubMed1998

Late behavioural and neuropathological effects of local brain irradiation in the rat.

The delayed consequences of radiation damage on learning and memory in rats were assessed over a period of 44 weeks, commencing 26 weeks after local irradiation of the brain with single doses of X-rays. Doses were set at levels known to produce vascular changes alone (20 Gy) or vascular changes followed by necrosis (25 Gy). Following T-maze training, 29 weeks after irradiation, irradiated and sham control groups performed equally well on the forced choice alternation task. When tested 35 weeks after irradiation, treated rats achieved a much lower percentage of correct choices than controls in T-maze alternation, with no difference between the two irradiated groups. At 38-40 weeks after irradiation, rats receiving both doses showed marked deficits in water maze place learning compared with age-matched controls; performance was more adversely affected by the higher dose. The extent of impairment was equivalent in the two groups of rats irradiated with 25 Gy, those trained or not previously trained in the T-maze, suggesting that water maze acquisition deficits were not influenced by prior experience in a different spatial task. In contrast to water maze acquisition, rats irradiated with 20 Gy showed no deficits in working memory assessed in the water maze 44 weeks after irradiation, whereas rats receiving 25 Gy showed substantial impairment. Rats receiving 25 Gy irradiation showed marked necrosis of the fimbria and degeneration of the corpus callosum, damage to the callosum occurring in animals examined histologically 46 weeks after irradiation, but in only a third of the animals examined at 41 weeks. However, there was no evidence of white matter necrosis in rats irradiated with 20 Gy, examined 46 weeks after irradiation. These findings demonstrated that local cranial irradiation with single doses of 20 and 25 Gy of X-rays produced delayed impairment of spatial learning and working memory in the rat. The extent of these deficits appears to be task- and dose-related, since rats treated with 25 Gy showed marked impairments in all measures, whereas rats treated with the lower dose showed less impairment in water maze learning and no deficits water maze working memory, despite significant disruption of working memory in the T-maze. The findings further suggest that although high dose irradiation-induced white matter necrosis is associated with substantial impairment, cognitive deficits may also be detected after a lower dose, not associated with the development of necrosis.

Animals↗
PubMed1997

Differential effects of global ischemia on delayed matching- and non-matching-to-position tasks in the water maze and Skinner box.

In order to assess effects of global ischemia in tasks of spatial learning and working memory, male Wistar rats were subjected to four vessel occlusion (4 VO) for periods of 5, 10, and 20 min and compared with sham-operated controls over four test phases, from 6 to 54 weeks after surgery. Rats were assessed on acquisition in the water maze, a task that is sensitive to ischemic impairments, before testing in Skinner box and water maze working memory tasks, which both require the short-term storage of information, but make different demands on spatial information processing. Phases 1 and 3 assessed spatial learning in a standard water maze procedure (12 and 10 training days, 2 trials/day with a 10-min intertrial interval: ITI). Phase 2 involved training and testing in delayed non-matching-to-position task in the Skinner box, with delays of 2-10 s between the information and choice stages. Phase 4 examined working memory in a water maze delayed matching-to-position task with 4 trials/day, an ITI of 30 s, and a novel platform position on each day. Ischemic rats showed duration-related impairments in water maze acquisition and working memory, but not in the less spatially demanding Skinner box task. Since water maze acquisition deficits were seen both before and after testing in the Skinner box the lack of effect cannot be attributed to time or to prior training. Ischemic deficits were more marked in Phase 3 than in Phase 1 of acquisition, suggesting that impairment may be progressive. Histological assessment showed that cell loss was largely confined to the hippocampal CA1 field and was linearly related to duration of occlusion. At the maximal level of loss (5.7 mm before the interaural line) the 20-min group showed 90% loss, the 10-min group 60% loss, and the 5-min group, which did not differ from controls, less than 10% loss. Only the 20-min group showed significant damage beyond the CA1 field, ranging from 30-40% loss in the CA3 field to 5% loss in one striatal area. No cortical damage was seen. The extent of CA1 cell loss correlated modestly with water maze acquisition (Phase 3) and working memory scores, but not with trials to criterion in the Skinner box task. There were significant correlations between different measures both within and between water maze tasks, but not Skinner box tasks, suggesting that the two types of procedure engaged different cognitive processes. The results indicate that the intrahippocampal damage induced by 4 VO impaired tasks which required processing of allocentric spatial information, but did not impair the storage of limited spatial information in working memory.

Animals↗