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J Sinden

Publications and source records attributed to J Sinden.

16 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↗
PubMed2001

Regulation of glial differentiation of MHP36 neural multipotent cell line.

MHP36 is a nestin bFGF-dependent cell line isolated from embryonic hippocampus using a thermolabile form of SV40 T antigen. When grafted in ischemic hippocampus MHP36 cells differentiate and alleviate the cognitive deficit associated with the lesion. We report here in vitro features of MHP36 cells. First, we found that T Ag expression was not necessary for MHP36 growth as cells cultured at the nonpermissive temperature carry on proliferating at a normal rate, Second, we observed that part of MHP36 cells spontaneously differentiate into astrocytes when bFGF is removed at39 degrees C. This differentiation was increased 4-fold by leukemia inhibitory factor. Third, we found that the majority of cells spontaneously expressed oligodendrocytic markers (CNPase, A2B5, GalC) when cultured at low density.

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↗
PubMed1994

Immunoidentification of cellular brain proteins associated with cognitive recovery in brain transplants.

In adult, lesion-impaired rat brain receiving embryonic day 15 (E15) fetal transplants, the level of expression of glial fibrillary acidic protein (GFAP) correlates positively with choline acetyltransferase (ChAT) levels and also with measurements of successful behavioural recovery. These results suggest that glial cells may play a pivotal role in the cognitive success of so-called cholinergic-rich transplants. The objective of this study was to investigate the association between GFAP- and ChAT-staining antigens in or around cholinergic-rich fetal grafts transplanted in adult cortex. An immunohistochemical fluorescent double-labelling technique was used to simultaneously identify GFAP- and ChAT-staining cells to assess whether there was a different type or distribution of cells present in these successful transplants. On brain sections of transplant area, GFAP-staining glial cells did not co-label with ChAT-staining cells. The transplant area, therefore, did not reveal a different type of cell from those seen in comparable normal cortical brain but rather a greater concentration of both GFAP- and ChAT-positive staining cells.

Animals↗
PubMed1991

The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats.

Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.

Acetylcholine↗
PubMed1991

Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system--I. Amelioration of cognitive deficits by transplants into cortex and hippocampus but not into basal forebrain.

After ibotenate (10.0 mg/ml) 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 stable impairment in reference and working memory in both spatial (place) and associative (cue) radial maze tasks. Cell suspension transplants of cholinergic-rich fetal basal forebrain tissue dissected at embryonic day 15 substantially improved all aspects of radial maze performance to a comparable degree whether sited in cortex, hippocampus, or both regions of the host brain. No additive effects were obtained with grafts in both terminal regions, but total graft volume, assessed stereologically, showed a significant negative correlation with error scores. Rats with behaviourally effective grafts, like controls, were disrupted in the place task when tested in dim light which obscured extra-maze spatial cues. Lesioned rats were not affected by change in lighting. Grafts of cholinergic-poor fetal hippocampal tissue did not improve radial maze performance; neither did grafts of cholinergic-rich tissue placed within the host basal forebrain lesion sites. In rats with cholinergic-rich terminal grafts, cortical and hippocampal choline acetyltransferase activity was restored to control level, commensurate with site of transplant, whereas it was significantly reduced in lesioned animals and those with functionally ineffective grafts. The indiscriminate error pattern and insensitivity to changes in lighting shown by lesioned rats suggested that lesioning primarily disrupted attention rather than short- or long-term spatial or associative memory processes. Since rats with cholinergic-rich grafts showed both reduced errors and recovery of stimulus control, the data indicated that grafts affected information processing, rather than changes in motor or motivational processes. Changes in choline acetyltransferase activity and the behavioural efficacy of cholinergic-rich grafts are consistent with the involvement of acetylcholine in the behavioural deficits and recovery displayed by lesioned and grafted groups, but do not rule out contributions from other factors. The equipotency of grafts within each terminal region suggests also that there may be a considerable degree of functional cooperation between the two branches of the forebrain cholinergic projection system. Functional recovery may involve local, nonspecific synaptic or paracrine mechanisms within the target regions, since grafts were efficacious only when placed in the terminal areas, but not when sited homotopically in the basal forebrain, indicating that they did not achieve any functionally significant structural repair to the host brain at that site.

Acetylcholine↗
PubMed1991

Effects of cholinergic-rich neural grafts on radial maze performance of rats after excitotoxic lesions of the forebrain cholinergic projection system--II. Cholinergic drugs as probes to investigate lesion-induced deficits and transplant-induced functional recovery.

The effects of two doses of muscarinic (arecoline and scopolamine) and nicotinic (nicotine and mecamylamine) cholinergic receptor agonists and antagonists on the radial maze errors of rats, performing poorly after ibotenate lesions to the nucleus basalis and medial septal brain regions, were assessed before and after transplantation of cholinergic-rich and -poor fetal grafts, using tasks which measured short- (working) and long-term (reference) spatial and associative memory. Lesioned rats showed improvement with the agonists, and impairment with the antagonists, at low doses which did not affect the performance of controls; these effects were more marked for working than reference memory, especially in the spatial task. The peripherally acting antagonists N-methylscopolamine and hexamethonium did not affect the performance of control or lesioned rats. Effects of the cholinergic probes were re-examined 16 weeks after grafting, in groups with cholinergic-rich grafts to cortex and/or hippocampus which showed functional recovery, and groups with cholinergic-rich grafts to basal forebrain, or cholinergic-poor grafts to basal forebrain, cortex, and hippocampus, which showed no improvement. All lesioned rats, regardless of site, type, or efficacy of transplant, continued to show marked impairment with the antagonists. Poorly performing grafted animals also showed improvement with the agonists. In rats with behaviourally effective cholinergic-rich grafts, arecoline had no effect, but nicotine substantially increased working and reference memory errors, particularly spatial working memory errors. Rats with grafts in both cortex and hippocampus showed the largest increases in errors after nicotine. These results show that lesioned rats were more sensitive to the bi-directional effects of cholinergic receptor ligands than controls, consistent with a role for acetylcholine in the lesion-induced deficits. The predominant effect of drugs on working memory may also be consistent with disruption of acquisition rather than of storage or retrieval processes in memory, and may be related to impairment of attention. The results further show that, despite behavioural recovery, supersensitive responses to cholinergic drugs were not normalized in rats with cholinergic-rich grafts, and that an additive interaction between graft and host may have occurred in response to nicotine.

Acetylcholine↗
PubMed1991

Specific brain protein changes correlated with behaviourally effective brain transplants.

The objective of this study was to identify cellular proteins that are associated with foetal brain transplants effective in reinstating memory function in adult rats with brain lesions. Quantitative memory deficits can be created in rats by lesioning the cholinergic projection system, using ibotenic acid. Previous work suggested that injection of cell suspensions prepared from presumptive cholinergic cells of foetal basal forebrain into adult brain, after such lesions, are most effective in restoring cognitive function. It was not clear, however, whether it was the cholinergic nature of the transplants that was critical for their success or whether other factors were involved. In this study, the proteins present in transplanted tissues and control brains were analysed by two-dimensional polyacrylamide gel electrophoresis to identify markers for the cells that were specifically correlated with restoration of cognitive function. On each gel, the relative optical densities of the same 33 selected proteins were measured on an interactive computerised image analyser. The amount of each protein was compared between treatment groups and correlated with four behavioural measurements. Seven of the proteins analysed had levels of expression that were either related to transplantation or correlated with behavioural performance. The proteins of interest were divided into the following three groups: (1) transplant-related proteins, (2) cholinergic transplant-specific proteins, and (3) behaviour-related proteins. Notable among the proteins of interest was one of the cholinergic transplant-specific proteins that was positively correlated with three of the four behavioural measurements and was also the only protein among those analysed that was significantly correlated with choline acetyltransferase (ChAT) levels. This has been identified, by immunoblotting, as glial fibrillary acidic protein, an astrocytic cell marker. These results suggest, therefore, that at least two cell types, astrocytes and ChAT(+)-staining cells, play an important role in the successful recovery of cognitive function. This study also identified possible protein markers for cognitive performance. The level of expression of two of the proteins analysed was not affected by lesioning or transplantation, but was significantly correlated with behaviour. One of these proteins, whose amounts correlated negatively with behavioural measurements, has been identified as neurone-specific enolase, a brain-specific neuronal cell marker.

Animals↗
PubMed1990

Effects of GABAergic drugs, fornicotomy, hippocampectomy and septal lesions on the extinction of a discrete-trial fixed ratio 5 lever-press response.

The effects of certain GABA-modulating drugs, fornicotomy, hippocampectomy and various septal lesions were analysed in a discrete-trial fixed ratio 5 (FR5) bar-press paradigm. Chlordiazepoxide, fornicotomy, hippocampectomy, electrolytic lateral septal lesions and ibotenic acid medial septal lesions facilitate extinction of the FR5 response. Some of these treatments (chlordiazepoxide, hippocampectomy, electrolytic lateral septal lesions) have previously been found to increase resistance to extinction of alley-running after continuously reinforced (CRF) acquisition training. The treatments which facilitated extinction in the discrete-trial FR5 paradigm have been found to reduce or abolish the partial reinforcement extinction effect in the alley. These results indicate that the discrete-trial FR5 paradigm is not analogous to a runway CRF schedule, but may be analogous to a runway partial reinforcement schedule.

Animals↗
PubMed1989

Early rearing environment and dorsal hippocampal ibotenic acid lesions: long-term influences on spatial learning and alternation in the rat.

Behavioural responses in a set of spatial and cue tasks were assessed in adult rats that had been given ibotenic acid lesions of the dorsal hippocampus at weaning. The lesions or sham operations were immediately followed by one month of differential rearing, either in enriched, social or isolated housing environments. The differential rearing was followed by standard (social) housing conditions until behavioural testing began at 4 months of age. Compared to sham-operated rats, the rats with early cytotoxic lesions showed substantial impairments on learning and efficient strategy formation in radial arm maze, retention of a spatial location, but not of a cue-marked location, in a + maze and spontaneous alternation. Differential rearing had some long-term effects depending on the task. Sham-operated rats which had been housed in isolation used a pattern of strategies in the radial arm maze that resembled the pattern used by rats with lesions. Early enrichment, on the other hand, alleviated lesion deficits only in a spontaneous alternation task in a T-maze where the variety and salience of proximal cues were maximised. Enrichment increased lesion deficits in the radial maze task, where distal cues only could guide performance. The results suggest that the hippocampus may play an important role in the use of contextual information and that behavioural recovery after early hippocampal damage--limited to situations in which featural information is highly salient--may be permanently induced by rearing in environments, as in enriched ones, where rats can attend to and manipulate environmental cues.

Animals↗
PubMed1989

Ibotenate-induced total septal lesions reduce resistance to extinction but spare the partial reinforcement extinction effect in the rat.

Rats were given sham operations, vehicle injections, or injections of the axon-sparing excitotoxin ibotenic acid into the septum. In Experiment 1, behavioural testing commenced 16 days after the operation; in Experiment 2 behavioural testing commenced following testing on another task, 31 days after the operation. The rats were trained to run in an alley for food reward given on every trial (Continuous Reinforcement, CR) or on a random fifty percent of trials (Partial Reinforcement, PR) and then the running response was extinguished. All the experimental groups showed the normal partial reinforcement extinction effect (PREE) in that PR-trained animals were significantly more resistant to extinction than CR-trained animals. However the rats with ibotenic acid lesions also showed a significant decrease in resistance to extinction regardless of training condition. The same pattern of results was seen at each of the two post-operative testing times. The results were thus readily replicable, and entirely unlike previous reports of the behavioural effects on this task of conventional septal lesions of equivalent size. In Experiment 3, neurochemical analysis of the hippocampus in rats with ibotenic acid-induced lesions demonstrated that choline acetyl-transferase levels were reduced to the same extent as in rats with comparable conventional lesions.

Animals↗
PubMed1989

Cholinergic system and memory in the rat: effects of chronic ethanol, embryonic basal forebrain brain transplants and excitotoxic lesions of cholinergic basal forebrain projection system.

Oral administration of ethanol (20% v/v) to male Sprague-Dawley rats for different periods of time up to 28 weeks resulted in profound reductions of acetylcholine content, in vitro synthesis and release of acetylcholine, choline uptake, activities of choline acetyltransferase, acetylcholinesterase and pyruvate decarboxylase, content of noradrenaline, serotonin and, to a lesser extent, dopamine throughout the brain. Changes were fully and partially reversible by a 4 weeks' ethanol-free period following a treatment of 8 and 18 weeks, respectively. They remained persistent, however, after 28 weeks of treatment. Performance in an eight arm-radial maze revealed a severe impairment in both spatial and non-spatial reference and working memory. A similar pattern of memory impairment was obtained after ibotenate lesion of the cholinergic basal forebrain projection system. In order to test whether this memory impairment depends on cholinergic deafferentation of the cortex, cholinergic-rich fetal basal forebrain cell suspensions were transplanted into cortex, hippocampus or both these sites in ethanol treated rats. Cholinergic-rich transplants, but not cholinergic-poor transplants, were effective in ameliorating impaired memory function and measures of cholinergic activity in the basal forebrain projection system. The behavioural efficacy of the basal forebrain grafts was well correlated with measures of both transplant volume and the degree to which they restored acetylcholine content at the transplant site; these transplants had no effect, however, on brain monoamine levels. The effects of the cholinergic-rich transplants into cortical and hippocampal sites were additive in their amelioration of performance in the radial maze. Similarly, ibotenate lesions of the sites of origin of the cholinergic projections to neocortex (in the region of the nucleus basalis magnocellularis) and hippocampus (the medial septal areas and nucleus of the diagonal band), respectively, were additive in their deleterious effects on maze performance. There were no qualitative differences in the susceptibility of the four different types of memory performance measured (spatial and non-spatial reference and working memory) to the effects of ethanol, ibotenate lesions of the cholinergic projection system, or cholinergic-rich brain tissue transplants. Thus, overall, the results indicate that the forebrain cholinergic system acts as a whole, without major functional differences between the projections originating in the medial septal area/diagonal band complex and the basal nucleus, and that it discharges a very general function in cognitive processes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

Cholinergic-rich brain transplants reverse alcohol-induced memory deficits.

Alcohol-induced memory impairment in man has been attributed to deficiencies in subcortical noradrenergic and cholinergic systems, as well as to damage in midbrain structures. Korsakoff's psychosis, a disease in which alcohol poisoning causes apparently irreversible memory defects, is characterized by lesions in cholinergic and noradrenergic nuclei and by a decrease in the activity of choline acetyltransferase (ChAT) and the content of noradrenaline (NA) in forebrain areas such as cerebral cortex and hippocampus, innervated by these nuclei. Prolonged intake of ethanol in rodents similarly produces signs of noradrenergic and cholinergic deafferentation in the cortex and hippocampus, as well as persistent memory deficits. To test whether alcohol-induced memory impairments depend on cholinergic deafferentation, we transplanted cholinergic-rich fetal basal forebrain cell suspensions into the cortex and hippocampus of alcohol-treated rats. The substantial and persistent memory losses produced in our rats by ethanol intake were associated with an impairment of cholinergic function, and were reversed by cholinergic-rich transplants into cortex and hippocampus.

Acetylcholine↗
PubMed1988

Ibotenic acid induced demyelination in the central nervous system: a consequence of a local inflammatory response.

We examined the effects of injections of ibotenic acid into the medial septum (MS), dorsal lateral geniculate nucleus (dLGN), caudate-putamen (CP) or fornix-fimbria (FF) on fibres close to the injection site. Injections into the MS and dLGN resulted in demyelination. The area of demyelination correlated with the area of maximal gliosis. The major cell type in the area of gliosis were cells of haemopoietic origin, as revealed by using monoclonal antibodies (Mabs). Demyelination was not observed in the CP or FF. Axonal transport in fibres en passage through the dLGN lesion was also disrupted following injections of horseradish peroxidase (HRP) into the eye contralateral to the lesion. These results show that when ibotenic acid induces cell death it can secondarily damage myelin sheaths and disrupt axonal transport in areas containing diffuse fibre systems. We suggest that this is due to a non-specific effect of the inflammatory response.

Animals↗
PubMed1988

Effects of RO 15-1788 on a running response rewarded on continuous or partial reinforcement schedules.

Two experiments were run in which rats were rewarded with food for running in a straight alley at one trial a day, followed by extinction of the running response. During acquisition of the response, reward was delivered either on a continuous reinforcement (CRF) or on a quasirandom 50% partial reinforcement (PRF) schedule. The groups given PRF were more resistant to extinction than those given CRF, the well-known partial reinforcement extinction effect. In Experiment 1 different groups of rats were injected during acquisition only with 1, 5 or 10 mg/kg of the benzodiazepine antagonist, RO 15-1788, or with placebo. In Experiment 2, 5 mg/kg RO 15-1788 or placebo were administered in a full cross-over design during acquisition, extinction or both. At the end of Experiment 2 only [3H]-flunitrazepam binding was measured in either the presence or absence of added gamma-aminobutyrate (GABA) in homogenates of hippocampi dissected from the animals that had received behavioural training. The drug affected running speeds during both acquisition and extinction in different ways depending upon the schedule of reinforcement (CRF or PRF) and also gave rise to enhanced GABA stimulation of [3H]-flunitrazepam binding. The results are discussed in relation to the hypothesis that the neurochemical pathways by which reinforcement schedules modify behaviour include a step influenced by benzodiazepine receptors.

Animals↗