A specific form of cognitive rigidity following excitotoxic lesions of the basal forebrain in marmosets.

The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain were studied on performance of a series of visual discrimination tests that examined a range of cognitive functions in the marmoset. These included the ability to attend to the various dimensional properties of stimuli and to use just one of these properties in order to solve a discrimination (intra-dimensional shift); to switch attention from one dimension to another (extra-dimensional shift); to learn the reinforcement value of specific exemplars within a dimension (new learning); and to relearn their reinforcement value following reversal of the reward contingencies (serial reversals). Lesions of the basal forebrain did not impair the ability either to attend selectively to the dimensional properties of the stimuli or to switch attention from one dimension to the other. However, the lesion did affect various aspects of associative learning including a transient impairment of new learning and a marked disruption of serial reversal learning. The reversal deficit could be characterised as a tendency to perseverate on the previously correct stimulus and as a failure to to show the formation of a reversal learning set. In addition, the lesion prevented disruption of performance of a well-learned discrimination when novel exemplars from the irrelevant dimension were introduced (probe test). It is suggested that the functional effects of the basal forebrain lesion reflect impaired learning of stimulus-reward associations and behavioural rigidity. The finding, however, that there was no effect of the lesion on attentional set-shifting suggests that any loss of inhibitory control was specific to the level of stimulus-response or stimulus-reward associations, inhibitory control at the level of attentional selection remaining intact. The similarity of the effects of damage to the basal forebrain to those seen following damage to the orbitofrontal cortex and the amygdala are discussed in the context of the close anatomical and functional relationships that exist among these three structures.     

Dissociable effects on spatial maze and passive avoidance acquisition and retention following AMPA- and ibotenic acid-induced excitotoxic lesions of the basal forebrain in rats: differential dependence on cholinergic neuronal loss

Excitotoxic lesions of the basal forebrain were made by infusing either alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or ibotenic acid. Acquisition and performance of spatial learning in the Morris water maze, over a ten day, two trials per day, training regimen were unaffected by the AMPA-induced lesions which reduced cortical choline acetyltransferase activity by 70%. However, acquisition was significantly impaired in rats with ibotenic acid-induced lesions that reduced cortical choline acetyltransferase by 50%. Additionally, ibotenic acid-lesioned rats swam further than either sham or AMPA-lesioned rats, in the "training" quadrant during a probe trial, in which the escape platform was removed, suggesting a perseverative search strategy. Lesions induced with AMPA, but not ibotenate, significantly impaired the acquisition of "step-through" passive avoidance. Both AMPA- and ibotenate-induced lesions significantly impaired the 96 h retention of passive avoidance, but the effect of AMPA was greater on latency measures. Histological analysis revealed that AMPA infusions destroyed more choline acetyltransferase-immunoreactive neurons than did ibotenate infusions but, unlike ibotenate, spared the overlying dorsal pallidum and also parvocellular, non-choline acetyltransferase-immunoreactive neurons in the ventral pallidal/substantia innominata region of the basal forebrain. The impairment in acquisition of the water maze following ibotenate-induced basal forebrain lesions therefore appears unrelated to damage to cholinergic neurons of the nucleus basalis of Meynert and to depend instead on damage to pallidal and other neurons in this area. The AMPA- and perhaps also the ibotenate-induced impairment in the retention of passive avoidance appears to be more directly related to destruction of cholinergic neurons of the nucleus basalis. These data are discussed in the context of cortical cholinergic involvement in mnemonic processes.     

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)     

Non-spatial acquisition and retention deficits following small excitotoxic lesions within the hippocampus in monkeys.

Marmoset monkeys with excitotoxic lesions confined to cornu ammonis subfields 1-3, subiculum and pre-subiculum, but sparing the entorhinal cortex, were impaired on retention and learning of conditional object-choice discriminations. For each of these discriminations, the monkeys were required to choose one of two objects depending on which of two patterned backgrounds was used on each trial. Two styles of order of trial presentation were used: 'random' presentation which maximised the degree of interference between trials, and 'runs' presentation which was intended to encourage the monkeys to learn each component of the discrimination separately. Before surgery monkeys found the discriminations more difficult to learn when the trials were presented in the 'runs' style than when presented in the 'random' style suggesting that the task is best learnt by applying a conditional rule. After surgery a significant 'group x style' interaction indicated that the 'runs' style was especially difficult for the lesioned monkeys.From these results we suggest that the hippocampus is involved in learning about and remembering non-spatial, conditional relations between objects.     

Attentional functions of the forebrain cholinergic systems: effects of intraventricular hemicholinium,physostigmine, basal forebrain lesions and intracortical grafts on a multiple-choice serial reaction time task

Summary Degeneration of the cholinergic magnocellular neurons in the basal forebrain and their cortical projections is a major feature of the neuropathology of Alzheimer's disease. In the present study, two experiments examined the disruptive effects on visual attentional performance of two different manipulations that reduce central cholinergic function. In Expt. I, pharmacological manipulation of the cholinergic system was investigated using icv administration of hemicholinium (HC-3), a 9high affinity choline uptake blocker, administered either alone or in conjunction with the anticholinesterase, physostigmine. The results revealed impairments in the ability of the rats to localize brief visual targets in a serial reaction time task, as shown in particular by a reduction in choice accuracy and lengthening of the latency to respond correctly to the visual stimulus. Cholinergic specificity was supported by the reversal of these behavioural impairments by pre-treatment with the anticholinesterase, physostigmine. In Expt. II, quisqualateinduced lesions of the basal forebrain produced behavioural deficits at 3 weeks post-lesion surgery similar to those observed following icv infusion of HC-3. In an attempt to restore the extrinsic cortical cholinergic innervation by reinnervation of the deafferented cortex, embryonic basal forebrain cholinergic cells were transplanted into the cortex of lesioned animals. After three months recovery, impairments in performance on the baseline schedule of the task were no longer apparent in lesioned animals. However, behavioural deficits, observed predominantly as a lengthening of correct response latency, could be reinstated in the lesioned animals by interpolation of distracting bursts of white noise during each trial, and this deficit was ameliorated by the cholinergic grafts. Furthermore, a non-specific effect of both cholinergic and non-cholinergic grafts in controlling the increase in perseverative time-out responses which occurred as a result of the basal forebrain lesion was consistently observed. These results suggest that cholinergic dysfunction can produce deficits in visual attention which can be ameliorated by cholinergic treatments such as physostigmine or cholinergic-rich cortical grafts. These data provide support for a role for the basal forebrain-neocortical cholinergic projection in attentional function.     

The effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on the acquisition and retention of a conditional visual discrimination: implications for cholinergic hypotheses of learning and memory

The effects of ibotenic acid-induced lesions of the ventral pallidum/substantia innominata region, the dorsal pallidum or both on the acquisition and retention of a conditional visual discrimination have been studied in the rat. Lesions of the ventral pallidum and large lesions of the dorsal and ventral pallidum severely impaired both the acquisition and retention of the conditional discrimination. Dorsal pallidal lesions had similar, but less marked effects. The same lesions also impaired the retention of a passive avoidance task, but had no effect on a conditioned taste aversion. Neurobiological investigations revealed that the lesions destroyed cholinergic neurons in the magnocellular nucleus basalis and caused reductions in cortical choline acetyltransferase activity of about 30-40%. Tract-tracing experiments indicated that the lesions destroyed, in particular, cholinergic neurons projecting to the frontal dorsolateral cortex and also those projecting to more posterior cortex, but not the occipital lobes. Contingency analysis of the behavioural, neurochemical and neuroanatomical data indicated that those animals with the largest decreases in choline acetyltransferase activity, or the largest areas of neuronal loss in the ventral and dorsal globus pallidus, were most impaired in the retention of the conditional discrimination. The results do not, therefore, indicate a simple relationship between cholinergic neuronal loss and the retention of response rules essential for performance of the task ("reference memory"). The relevance of the results to cholinergic hypotheses of learning and memory is discussed.     

Environmental enrichment mitigates the effects of basal forebrain lesions on cognitive flexibility

The aim of the present study was to investigate whether basal forebrain lesions were able to impair a task requiring cognitive flexibility abilities and analyzing the effect of the rearing in an enriched environment on such form of flexibility in rats with or without basal forebrain cholinergic lesions. In adult rats reared in enriched or standard conditions of the cholinergic projection to the neocortex damage was inflicted by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance was compared with those of intact animals reared in analogous conditions in a four-choice serial learning task which taps flexibility in adapting to changing response rules. The results underlined the crucial role of the basal forebrain in mediating cognitive flexibility behaviors and revealed that the increase in social interactions, cognitive stimulation and physical activity of the rearing in enriched environment attenuated impairments caused by the cholinergic lesion. These findings demonstrate that rearing in an enriched environment can improve the ability to cope with brain damage suffered in adulthood.     

Brain temperature alterations and the retention of visual pattern discriminations in pigeons

Pigeons were taught visual discriminations. Immediately after they had reached criterion their forebrain was either left untreated or heated (by ≈1°C) or cooled (by≈2°C) for 30 min, with water flowing through a chronically implanted cannula system. The effects of the treatments on retention were assessed in retraining sessions. Both brain temperature alterations led to slight saving scores and marked, significant response latency advantages, compared with the control treatment.     

Effects of subcortical lesions on visual intensity discriminations in rats

The role of several subcortical structures in visual intensity discrimination was examined by comparing the effects of localized lesions on a variety of intensity discriminations. In Experiment 1 light avoidance was unimpaired after lesions of the ventral lateral geniculate nucleus (LGNv), nucleus lateralis posterior (TLP), nucleus posterior of Gurdjian (NPG), dorsal pretectum (PTd), and ventral pretectum (PTv). The LGNv, TLP, NPG and PTv, but not the PTd, groups were impaired on a simultaneous black versus white (BW) discrimination in Experiment 2. None of these groups was impaired on a horizontal versus vertical discrimination (HV). The TLP group showed a transient impairment on a successive light versus dark discrimination, not present with the LGNv and NPG groups (Experiment 3). In Experiment 4 all three groups were impaired on a successive BW discrimination. In Experiment 5 rats with LGNv lesions but not with TLP lesions had elevated relative brightness thresholds. Both groups had normal absolute thresholds. The results are related to the possibility that information about intensity and pattern is coded in separate visual pathways.     

Behavioral effects of basal forebrain cholinergic lesions in young adult and aging rats

The interactive effects of age and cholinergic damage were assessed behaviorally in young and middle-aged rats. Rats were lesioned at either 3 or 17 months of age by injection of 192 IgG-saporin immunotoxin into the medial septum and the nucleus basalis magnocellularis, and they were then tested on a range of behavioral tasks: a nonmatching-to-position task in a T-maze, an object-recognition task, an object-location task, and an open-field activity test. Depending on the task used, only an age or a lesion effect was observed, but there was no Age X Lesion interaction. Middle-aged and young rats responded to the cholinergic lesions in the same manner. These results show that in the middle-aged rats in which cholinergic transmission was affected, additional injury to the system was not always accompanied by major cognitive dysfunctions.     

Benzodiazepines impair the acquisition and reversal of olfactory go/no-go discriminations in rats

The present study assessed whether benzodiazepines impair the acquisition, performance, and reversal of olfactory and auditory go/no-go discriminations in rats. Experiment 1 showed that midazolam (0.5-2 mg/kg sc) did not affect the performance of a well-learned two-odor olfactory discrimination and moderately facilitated performance of a go/no-go auditory discrimination. Experiment 2 found that midazolam (1 mg/kg) increased the number of errors made in the acquisition of a novel go/no-go olfactory discrimination task and in the reversal of a previously well-learned olfactory discrimination. However, midazolam did not affect the acquisition and reversal of an equivalent auditory discrimination task. Experiment 3 showed that diazepam (1 mg/kg) also impaired the acquisition and reversal of a novel olfactory discrimination task. Taken together, these results indicate that benzodiazepines cause a selective impairment of olfactory discrimination learning. This may reflect an effect of benzodiazepines in the glomerular circuitry of the olfactory bulb and at downstream olfactory processing sites such as the piriform cortex and orbitofrontal cortex.     

Plaque-like lesions in the basal forebrain in Alzheimer's disease

Silver staining (Bodian procedure) in the nucleus of the sublenticular substantia innominata (SI), also referred to as the nucleus basalis of Meynert, was evaluated in autopsy material from patients with Alzheimer's disease or senile dementia of the Alzheimer type (age at death: mean 69 years, range 63 to 81 years; time between onset of symptoms and death: mean 5.6 years, range 2.5 to 11.0 years). Although a decrease in the number of neurons and an increase in gliosis were observed in the SI in the Alzheimer dementia cases, classic senile plaques, as well as neurofibrillary tangles and granulovacuolar degeneration, were, with rare exception, not present in the basal forebrain. Small plaque-like lesions, 30-50 micron in diameter, were found scattered throughout the SI, however. These pathologic entities, like traditional senile plaques, demonstrated increased argentophilia compared to background, neuritic elements, and an increase in the number of glial cells. The magnitude of silver staining in the plaque-like lesions in the SI, however, was generally less than that associated with plaques in the cortex, hippocampus and amygdala. Although their significance is not known, plaque-like structures in the SI could represent the final degenerative phases of basal forebrain neurons and/or of fibers afferent to them. Their precise relationship to classic senile plaques remains to be elucidated.     

The development of basal forebrain projections to the rat visual cortex

Summary The development of the basal forebrain projections to the visual cortex of the rat were studied using retrograde tracer techniques. Injections of wheat germ agglutinin-horseradish peroxidase placed in the visual cortex of newborn animals resulted in labelling of neurons throughout the basal forebrain nuclei. Although at this time the overall distribution of retrogradely labelled cells within the basal forebrain appeared similar to that seen in the adult, cells were smaller and weakly stained. It was only at the end of the second postnatal week that the somata of stained neurons showed sizes and staining intensity comparable to the adult. This precedes or coincides with the reported significant increases in cortical and basal forebrain ChAT activity and the first detection of ChAT-labelled fibres in this cortical area. These data suggest an important developmental point around the end of the second postnatal week that may correspond to the time when a significant number of cholinergic axons first appear within the visual cortex. They also suggest that the cholinergic projections to the visual cortex develop late in comparison with the thalamic and other subcortical afferents in this cortical area.     

Consequences of serial cortical, hippocampal, and thalamic lesions and of different lengths of overtraining on the acquisition and retention of learning tasks

The ability of the rat brain to acquire or to retain specific learning tasks was tested under conditions of multiple lesions and widely different amounts of practice. Lesion targets were (a) the medial prefrontal and cingulate cortex, (b) the anterior and mediodorsal thalamus, and (c) the dorsal and ventral hippocampus. Rats were divided into seven groups. The first group received lesions of all three structural complexes prior to training in a delayed alternation and an active avoidance task. Groups 2-4 received lesions in different combinations of two of the three structural complexes prior to task acquisition. Group 5 first learned both tasks and then received the medial cortical lesion; thereafter it was retrained to criterion. Then, the thalamic lesion was made, and relearning was tested a second time. Finally, the hippocampal region was damaged, and a last relearning test was given. Groups 6 and 7 also first acquired both tasks; however, after that, they received 240 (Group 6) or 1,280 (Group 7) trials of overtraining. Following this, all three structural complexes were given lesions serially before relearning of the two tasks was tested. Nine of the ten animals of Group 1 failed to acquire the alternation task, but all learned the avoidance task. In Groups 2-4, all rats acquired both tasks. Postoperatively, rats of Group 5 were inferior to those of Group 6 in both tasks, and rats of Group 7 were the most successful animals of the last three groups. These results question the assumption that serial lesions with intermittent training between lesions have beneficial effects, and they also stress the importance of task practice, that is, of behavioral experience. It is argued that prolonged training will lead to a widely distributed storage of information within the brain. The process of wide diffusion of information will, however, be disturbed (or at least retarded) by lesions made shortly after task acquisition or task reacquisition (as was the case for animals of Group 5).     

Excitotoxic lesions of rat basal forebrain: differential effects on choline acetyltransferase in the cortex and amygdala.

Previous studies have shown that basal forebrain lesions using different excitotoxins produce similar decreases in cortical choline acetyltransferase, but differential effects on memory. However, basal forebrain cholinergic neurons send efferents to the amygdala and cortex. The present studies compared the effects of several excitotoxins on choline acetyltransferase levels in both of these structures. Lesions of the basal forebrain were made in rats by infusing different doses of either alpha-amine-3-hydroxy-5-methyl-4-isoxazole propionic acid, ibotenic acid, quisqualic acid, quinolinic acid or N-methyl-D-aspartic acid and measuring choline acetyltransferase seven days later. All of the excitotoxins exerted a differential response on cholinergic neurons of the basal forebrain projecting to the cortex or amygdala. Quinolinic acid was a more potent neurotoxin to cholinergic neurons innervating the amygdala than those projecting to the cortex. In contrast, quisqualic acid and alpha-amine-3-hydroxy-5-methyl-4-isoxazole were more potent neurotoxins to the cortical projection. alpha-Amine-3-hydroxy-5-methyl-4-isoxazole propionic acid was the most potent excitotoxin for destroying cholinergic neurons innervating either the cortex or amygdala. A parallel neurotoxic response was obtained in the cortex and amygdala following infusion of ibotenic acid or N-methyl-D-aspartic acid with little selectivity for choline acetyltransferase depletion in the cortex or amygdala. Histological analysis of the injection site revealed that acetylcholinesterase-positive neurons were destroyed by the excitotoxins in a dose-dependent manner. Excitotoxins (ibotenic acid, quinolinic acid, N-methyl-D-aspartic acid) that produce the greatest impairments in memory were found to produce the greatest depletion of choline acetyltransferase in the amygdala.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of cytotoxic entorhinal lesions and electrolytic medial septal lesions on the acquisition and retention of a spatial working memory task

Rats with lesions either of medial septal nucleus (MSN) or the entorhinal cortex (ECx) were compared postoperatively with unoperated controls in a discrete-trial, delayed matching-to-position (DMTP) task, conducted on an elevated T-maze. A DMTP trial consisted of two consecutive visits to the maze: an information run and a choice run. The animals were first forced to visit a randomly selected choice arm in the information run. In the choice run, the correct response was to match the choice arm that had been visited on the information run, regardless of whether the information run itself had been rewarded or not. MSN animals failed to succeed in this task, performing at close to chance level throughout training. On the other hand, ECx rats consistently perform at a level comparable with that of unoperated controls; both groups attained more than 90% correct after 192 trials. Long-term retention testing was carried out after an intermission of 4 weeks, when the same task was re-administered to the ECx and unoperated control animals. ECx animals showed significantly less saving than controls in the retention test. In contrast, when the retention interval within a DMTP trial was increased by the imposition of a 20-s delay between the information and choice runs, the ECx group was not selectively affected by this manipulation. Received: 17 June 1997 / Accepted: 4 December 1997     

Retention and acquisition of fine temperature discriminations following somatosensory cortical lesions in the rat

Summary Rats with histologically confirmed bilateral lesions of one or both somatosensory cortical areas, occipital cortex, or sham operations were tested in a T-maze for retention of 29° vs. 39° C and 29° vs. 34° C temperature discriminations, and for acquisition of a 29° vs. 31° C habit. Statistical analyses failed to reveal group differences on the three postoperative discriminations. The suggestion that thermal habits are mediated by a diffuse and redundant forebrain afferent system is discussed. This investigation was supported by Biomedical Sciences Support Grant PR-07054 from the General Research Support Branch, Division of Research Resources, Bureau of Health Professions Education and Manpower Training, National Institutes of Health, by U.S.P.H.S. Grant 1-R03-MH17109-01 (MSM), and by N.S.F. Grant GB-12374 to the first author. A preliminary report has been presented at the annual meetings of the Psychonomics Society, St. Louis, November, 1969. The authors are indebted to John Morrison for his assistance on the project.     

Effects of hyperstriatal lesions on within-day serial reversal performance in pigeons

In Experiment 1, 12 pigeons performed each day for 17 days 3 serial reversals of a simultaneous color discrimination; 6 birds were then given hyperstriatal lesions, and 6 birds were sham operated. Analysis of the effects of lesions on postoperative reversal performance supported 2 hypotheses: first, that the hyperstriatum contains a mechanism involved in the generation of inhibition, and second, that minimal inhibition is generated (in intact birds) in the first of each day's reversals. Experiment 2 investigated the effects of hyperstriatal lesions on serial position reversal; results again supported the notion that the hyperstriatum is involved in response inhibition. Contrasts between the effects obtained in the 2 experiments suggested that inhibition plays a more central role in position, as opposed to color, reversals.     

Intracortical grafts of embryonic basal forebrain tissue restore low voltage fast activity in rats with basal forebrain lesions

Summary Unilateral injections of kainic acid into the basal forebrain in a series of rats resulted in an increase in large amplitude slow waves, a correlated burst-suppression pattern of multi-unit activity, and a decrease in acetylcholinesterase staining in the neocortex ipsilateral to the kainic acid injection. Subsequently, a cell suspension, prepared from rat embryonic basal forebrain tissue, was injected adjacent to the recording electrodes ipsilateral to the kainic acid injection. This produced a gradual recovery of low voltage fast activity (LVFA) and a correlated continuous discharge pattern of multi-unit activity in the neocortex ipsilateral to the kainic acid injection. LVFA recovered more slowly at neocortical recording sites that received an injection of a cell suspension of hippocampal primordial cells or no injection at all. Acetylcholinesterase-positive fibers from the basal forebrain tissue invaded host cortex; no comparable outrgrowths were demonstrable in the hippocampal primordium tissue grafts. Restoration of cholinergic electrocortical activation may play an important role in the improvements in behavioral performance produced by basal forebrain grafts in the cortex in animals with basal forebrain lesions.