Neural transplantation and recovery of function: animal studies.
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Animals↗
Biomedical subjects
H Hodges
Publications and source records attributed to H Hodges.
Comparison of radial maze performance of rats after ibotenate and quisqualate lesions of the forebrain cholinergic projection system: effects of pharmacological challenge and changes in training regime.
Rats with ibotenic or quisqualic acid lesions to cholinergic projections showed similar significant increases in both short-term working and long-term reference memory errors in radial maze spatial (place) and nonspatial (cue) tasks, throughout a period of 10 weeks after lesioning. All types of error were dose-relatedly reduced to a similar extent in lesioned rats after treatment with nicotine and the beta-carboline ZK93426. Performance of controls was not affected by nicotine, but errors were increased with the higher doses of ZK93426. In contrast, amphetamine increased errors in both control and lesioned rats. With extensive training, lesioned rats improved to control level, but were more disrupted than controls by a break in testing, which reinstated high error rates to an equivalent extent in lesioned groups. Choline acetyltransferase (ChAT) activity showed a comparable degree of depletion in quisqualate and ibotenate lesioned groups to around 60% of control level in cortex and 75% in hippocampus. These results indicate that at volumes and concentrations that produced an equivalent degree of ChAT depletion, detrimental effects of ibotenate and quisqualate lesions on radial maze performance were very similar. The time course of improvement with over-training and impairment after a break in training were also comparable with both lesioning agents. Reduced errors following compounds acting directly (nicotine) or possibly indirectly (ZK 93426) to enhance cholinergic function, but not after amphetamine, suggested that damage to cholinergic neurons contributed to the behavioural deficits induced by both ibotenic and quisqualic acid.
Journal Article↗
Neural transplantation: problems and prospects for therapeutic application.
Successful demonstrations of behavioural recovery in a variety of lesion and mutant animal models have encouraged the application of neural transplantation to the alleviation of neurodegenerative disease. Apart from the continuing shortage of foetal tissue, the major problems to be resolved for successful application of neural transplantation to humans are: first, immune rejection of allograft tissue and its pathological consequences to both graft and host tissue; and second, the establishment of normal and extensive graft-host connectivity. Recent developments in transplant research are beginning successfully to apply a number of strategies to resolve these problems.
Animals↗
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↗
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↗
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↗
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↗
Low dose tetrahydroaminoacridine (THA) improves cognitive function but does not affect brain acetylcholine in rats.
Eight days of treatment with two low doses of tetrahydroaminoacridine (THA), given once daily, substantially improved radial maze performance in two groups of rats which showed persistent deficits either after ibotenic acid lesions at the source of forebrain cholinergic projections, or after 28 weeks treatment with alcohol (20% v/v) in drinking water. However, in immature, aged or aged and alcohol-treated rats, acetylcholine content was not significantly affected in any of the brain areas measured, even though the treatment regime had proved behaviourally effective. Inhibition of brain acetylcholinesterase activity was only marginally increased by this treatment regime. Thus, if THA influences behaviour by enhancing cholinergic transmission, its effects do not appear to be related to its activity as a cholinesterase inhibitor, and alternative mechanisms of action should be investigated.
Acetylcholine↗
Lever pressing for food reward and changes in dopamine turnover and uric acid in rat caudate and nucleus accumbens studied chronically by in vivo voltammetry.
The neurotransmitter dopamine (DA) is widely held to be involved in the maintenance of positively reinforced behaviour, on the basis of self-stimulation experiments and of the effects of drugs which alter DA transmission on self-stimulation, and on behaviours controlled by natural reinforcers. We have used the technique of linear sweep voltammetry at chronically implanted carbon paste electrodes to demonstrate that 30-min sessions of responding on a variable interval schedule for food pellet reward increases first uric acid and then homovanillic acid (HVA, the DA metabolite) in rat caudate. Ascorbic acid levels are reduced, but at later times. We have now established that very similar responses in magnitude and timing are seen in the nucleus accumbens. Furthermore, in individual animals, the response rates, the increases in dopamine turnover, and the changes in uric acid and ascorbic acid remain stable when studied periodically over a 3 month period. Our previous results are broadly consistent with those obtained by others using indirect single-point methods (ex vivo neurochemistry) or in vivo dialysis. However, our present extended observations made possible by the use of paste electrodes (rather than fibre electrodes or dialysis probes) open the possibilities of studying the evolution of neurochemical responses during learning, and the covariation of neurochemical and behavioural effects of drugs within individual animals.
Animals↗
Cholinergic-rich transplants alleviate cognitive deficits in lesioned rats, but exacerbate response to cholinergic drugs.
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Animals↗
Lever pressing for food reward and in vivo voltammetry: evidence for increases in extracellular homovanillic acid, the dopamine metabolite, and uric acid in the rat caudate nucleus.
Linear sweep voltammetry at chronically implanted carbon paste electrodes was used to study extracellular levels of homovanillic acid, a metabolite of dopamine, in the caudate nucleus of freely moving rats. Local infusion of homovanillic acid close to the electrode confirmed that peak 3, at about 550 mV, could be used for this purpose. Thirty minutes of lever pressing for food reward was followed by an increase in homovanillic acid, maximal about 30 min later (+42%). An earlier and larger (+51%) increase in peak 2 (350-400 mV) was seen, highly correlated (r = 0.98) with the rate of lever pressing across individuals. A smaller decrease (-23%) in peak 1 (200 mV; ascorbic acid) was seen 75 min after the behavioural session. Administration of allopurinol, an inhibitor of uric acid production, selectively abolished peak 2. Allopurinol prior to lever pressing reduced the increase in peak 2 very substantially (by 77%), confirming that this too was mainly due to uric acid. These results indicate that linear sweep voltammetry can be used to study the time course of changes in dopamine metabolism, and in other neurochemicals, in individual freely moving rats in relation to behaviour under experimental control. More specifically, they demonstrate directly that rewarded lever pressing increases dopamine metabolism in the caudate, which had previously only been inferred from indirect approaches. The level of uric acid is also increased, and it is suggested that this may serve as an index of metabolic activity.
Allopurinol↗
Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination.
Interactions between the benzodiazepines (BZs) chlordiazepoxide (CDP) and midazolam (MDZ), the BZ antagonist R0 15-1788, the inverse BZ receptor agonists CGS 8216 and FG 7142, gamma-aminobutyrate (GABA), serotonin (5-HT), the 5-HT2 antagonist methysergide and the putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were investigated using peripheral and intra-amygdaloid treatments. A multiple schedule consisting of rewarded, nonrewarded (Time out: TO) and conflict periods was used to compare in parallel effects on successive discrimination between rewarded and nonrewarded periods and punished responding. The three components were presented in both a fixed order (Experiment 1) and a random order (Experiments 2 and 3). Intra-amygdaloid treatments with GABA and the BZs selectively increased rates of punished responding. CDP given systemically, on the other hand, increased both TO and conflict rates, suggesting an additional impairment of discrimination, which was more marked in the random than the fixed order condition. R0 15-1788, CGS 8216 and FG 7142 given by both routes counteracted the anti-conflict effects of CDP given centrally or systemically. However increases in TO rates induced by IP CDP were antagonized only by IP treatments with these compounds. The two inverse agonists, but not R0 15-1788, also counteracted increases in punished responding which were found after intra-amygdaloid GABA infusions. In Experiments 2 and 3 where baseline rates of pressing in Conflict periods were sufficiently high to detect decreases, CGS 8216 and FG 7142 reduced responding below control level, suggesting a specific anxiogenic activity. Evidence for effects of R0 15-1788 by itself was inconclusive. 5-HT injected into the amygdala also reduced punished responding below control level, whereas methysergide increased it with both central and peripheral treatment. Effects of 8-OH-DPAT varied according to route of administration. With IP treatment Conflict rates were increased, but after amygdaloid infusion both TO and Conflict rates were marginally reduced below control level, with a more consistent depression of punished responding. These results provide evidence that effects of BZs on punished responding are mediated by a GABAergic system which includes the lateral/basolateral amygdala, but which does not participate in BZ-induced disruption of discrimination. They also indicate that the antagonistic effects of CGS 8216 and FG 7142 involve a decrease in GABA transmission, and that these compounds may also be anxiogenic.(ABSTRACT TRUNCATED AT 400 WORDS)
Amygdala↗
Are the effects of benzodiazepines on discrimination and punishment dissociable?
Studies have shown that benzodiazepines (BZs) both disrupt discrimination and increase resistance to punishment. Using a delayed response task, we provide evidence that effects of BZs on discrimination cannot be fully explained by deficits in either short or long term memory, or by intolerance for delay of reward. A schedule with rewarded, nonrewarded (Time out: TO) and conflict components was used to investigate effects in rats of compounds active at the BZ receptor on successive discrimination and punished responding in parallel. The GABA transaminase inhibitor ethanolamine-O-sulphate exerted additive effects with chlordiazepoxide (CDP) on punished but not TO responding. Both GABA and CDP injected into the amygdala selectively increased conflict rates, but with peripheral treatment CDP also increased TO rates. Two inverse BZ agonists, CGS 8216 and FG 7142 antagonzied the anti-conflict effects of GABA and CDP, given within the amygdala or peripherally, but the increase in TO rates induced by systemic CDP was counteracted only by peripheral treatments. These compounds also reduced rates of conflict responding below baseline, consistent with anxiogenic activity. Effects of the BZ antagonist Ro 15-1788 were broadly similar to those of the inverse agonists, except that it did not antagonise the anti-conflict action of intra-amygdaloid GABA, nor significantly reduce punished responding at the single dose used. We conclude from these results that the anti-conflict effects of BZs are mediated by a GABAergic amygdaloid mechanism, but that the same mechanism is not involved in BZ effects on discrimination.
Amygdala↗
Effects of chlordiazepoxide on cued radial maze performance in rats.
Effects of chlordiazepoxide (CDP) were examined on the performance of rats in an eight-arm radial maze with four cued and food-baited arms. Two conditions were used; random, with cue location varying over trials, and constant, with the same subset of arms consistently cued. In rats pre-trained to a 60-70% efficiency level (Rewarded entries/Total entries X 100), the effects of CDP (2.5, 5.0 and 10.0 mg/kg, IP) differed according to condition. Efficiency was substantially reduced in the random condition, and types of error were undifferentiated. In the constant cue condition the post-drug drop in efficiency was less marked, and errors were selectively those of re-entry into rewarded arms. In both conditions there was a high incidence of error clusters involving re-entries into both rewarded and non-rewarded arms in the random condition, and rewarded arms in the constant condition. The results suggested that CDP induced a general disruption of information processing rather than a specific impairment of working memory, together with some response perseveration which could occur in the presence or absence of discrimination failure.
Animals↗
Behavioural and pharmacological dissociation of chlordiazepoxide effects on discrimination and punished responding.
Effects of chlordiazepoxide (CDP) and ethanolamine-O-sulphate (EOS) alone and in combination were tested on the acquisition and performance of continuous reinforcement - time out (CR-TO) and variable interval reinforcement - time out (VI-TO) operant discriminations in rats. CDP disrupted acquisition of CR-TO discrimination; effects were short lived, and neither CR-TO performance nor its reversal were impaired. Acquisition of VI-TO discrimination was increasingly impaired, and performance disrupted in pre-trained animals. EOS alone was inactive, and with CDP exerted only slight interactive effects. When a conflict component was added to the VI-TO schedule, however, EOS showed substantial additive effects with CDP on punished responding. The results suggest that CDP-induced increases in non-rewarded (TO) responding were related to task difficulty, pointing to a discrimination impairment rather than an anxiolytic effect. In addition, the specificity of EOS potentiation may reflect a pharmacological dissociation between CDP effects on discrimination and on punished responding, and suggest that GABA is selectively involved in resistance to punishment.
Animals↗
Differential effects of dorsal raphe lesions and intraraphe GABA and benzodiazepines on conflict behavior in rats.
Both reductions in brain serotonin activity and injections of benzodiazepine drugs increase punished responding in rats, but the evidence is conflicting on the role of serotonin pathways in the benzodiazepine effect. Therefore a series of studies were carried out using a Geller-Seifter procedure with three components, to examine drug effects on rewarded, nonrewarded, and punished responding. Using male hooded Lister rats and chronic indwelling cannulae, it was found that neither chlordiazepoxide (1.5 and 5.0 micrograms in 0.5 microliter), midazolam (1.0 and 10.0 micrograms in 0.5 microliter), nor GABA (100, 500, 1000, and 5000 ng in 0.5 microliter), exerted significant anticonflict activity when injected into the dorsal raphe. Lesions of the dorsal raphe produced by injections of 5,6-dihydroxytryptamine significantly increased punished responding, and there were significant correlations between lesion size, extent of forebrain serotonin depletion, and increases in punished responding. Peripheral injections of chlordiazepoxide (5.0 and 10.0 mg/kg) and midazolam (1.25, 2.5, and 5.0 mg/kg) significantly increased punished responding both before and after raphe lesions. The increase in lesioned animals was significantly greater than after drug or lesion alone and represented a powerful additive effect which was specific to punished responding. As intraraphe benzodiazepines did not exert significant anticonflict activity, and raphe lesions did not attenuate the anticonflict activity of peripheral benzodiazepines, it is concluded that increases in punished responding seen after serotonin depletion and after benzodiazepine drugs may be dissociable.
5,6-Dihydroxytryptamine↗
Conditionally immortalized, multipotential and multifunctional neural stem cell lines as an approach to clinical transplantation.
Experiments are described using rats with two kinds of brain damage and consequent cognitive deficit (in the Morris water maze, three-door runway, and radial maze): 1) ischemic damage to the CA1 hippocampal cell field after four-vessel occlusion (4VO), and 2) damage to the forebrain cholinergic projection system by local injection of excitotoxins to the nuclei of origin or prolonged ethanol administration. Cell suspension grafts derived from primary fetal brain tissue display a stringent requirement for homotypical cell replacement in the 4VO model: cells from the embryonic day (E)18-19 CA1 hippocampal subfield, but not from CA3 or dentate gyrus or from E16 basal forebrain (cholinergic rich) led to recovery of cognitive function. After damage to the cholinergic system, conversely, recovery of function was seen with cell suspension grafts from E16 basal forebrain or cholinergic-rich E14 ventral mesencephalon, but not with implants of hippocampal tissue. These two models therefore provided a test of multifunctionality for a clonal line of conditionally immortalized neural stem cells, MHP36, derived from the E14 "immortomouse" hippocampal anlage. Implanted above the damaged CA1 cell field in 4VO-treated adult rats, these cells (multipotential in vitro) migrated to the damaged area, reconstituted the gross morphology of the CA1 pyramidal layer, took up both neuronal and glial phenotypes, and gave rise to cognitive recovery. Similar recovery of function and restoration of species-typical morphology was observed when MHP36 cells were implanted into marmosets with excitotoxic CAI damage. MHP36 implants led to recovery of cognitive function also in two experiments with rats with excitotoxic damage to the cholinergic system damage, either unilaterally in the nucleus basalis or bilaterally in both the nucleus basalis and the medial septal area. Thus, MHP36 cells are both multipotent (able to take up multiple cellular phenotypes) and multifunctional (able to repair diverse types of brain damage).
Animals↗
Effect of vibrissae removal on search accuracy in the water maze.
In two experiments the vibrissae were clipped on either the left, the right or both sides, and the rats were trained to find a submerged platform in the Morris water maze. In both experiments, animals without vibrissae on both sides or on the left consistently spent significantly more time in the 'counter' area twice the platform diameter in size, surrounding the submerged platform, than intact controls. Counter preference was not as consistent across experiments in rats with right vibrissae removed. These results suggest that the vibrissae are required for proprioceptive location of the platform itself, but not for proximal search accuracy. Since ischaemic damage to hippocampal CA1 pyramidal cells has also been reported to prolong counter search during training, the results support the suggestion that impaired hippocampal processing of proprioceptive information from the vibrissae may contribute to the increased latency to find the platform shown by ischaemic rats.
Animals↗