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.     

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.     

Pilocarpine and physostigmine attenuate spatial memory impairments produced by lesions of the nucleus basalis magnocellularis

The effects of bilateral ibotenic acid-induced lesions of the nucleus basalis magnocellularis (nBM) on the acquisition and retention of several spatial memory tasks were studied in the rat. Maintenance of spatial memory in a food search task was impaired following nBM lesions. Acquisition of spontaneous alternation and reinforced alternation in a T-maze was also significantly impaired in animals with these lesions. In contrast, the animals with nBM lesions were not impaired in the acquisition of a position habit in a T-maze. In several of the tasks there was evidence of some learning in the lesion animals after substantial training, although they were significantly deficient when compared with the controls. Administration of the cholinergic agonists physostigmine sulfate or pilocarpine nitrate prior to behavioral testing resulted in a rapid and significant improvement in the performance of the lesion animals. The ibotenate-induced lesions significantly reduced the activity of choline acetyltransferase (CAT) in the anterior and the posterior neocortex. Hippocampal CAT activity was not changed. The results indicate that the cholinergic projections originating in the nBM are involved in the learning and memory of spatial tasks.     

Behavioural, biochemical and histochemical effects of different neurotoxic amino acids injected into nucleus basalis magnocellularis of rats

Lesions of the nucleus basalis magnocellularis in rats have been used to investigate functions of the extrinsic cortical cholinergic system which originates from these neurons. These lesions also produce extensive non-specific subcortical damage and associated regulatory and neurological impairments, causing doubt about the specificity of consequent functional impairments. Here, nucleus basalis magnocellularis lesions made with four different neurotoxic amino acids (kainic acid, ibotenic acid, N-methyl-D-aspartate, and quisqualic acid) have been compared. Quisqualic acid produced less subcortical damage and lesser neurological and regulatory impairments than the other toxins at doses that produced comparable cholinergic deafferentation of the neocortex, as assessed both histologically and biochemically. This suggests that these impairments are non-specific rather than specific consequences of cholinergic cell loss. The effects on learning a spatial navigation task were more ambiguous, suggesting the involvement of both cholinergic and non-cholinergic systems. Impairment of a passive shock avoidance task was as great following quisqualic acid as the other neurotoxins, which may suggest a more direct relationship specifically with the decline in cortical cholinergic activity. It is concluded that in the absence of availability of a specific cholinergic neurotoxin, quisqualic acid produces less non-specific neuroanatomical and neurological side effects than the more widely used toxins N-methyl-D-aspartate, kainic acid or ibotenic acid.     

Differential activation and survival of basal forebrain neurons following infusions of excitatory amino acids: studies with the immediate early gene c-fos

These experiments investigated, by studying patterns of c-fos expression, the distribution of neurons activated or destroyed by the infusion into the basal forebrain of various excitatory amino acids at toxic and subtoxic doses. The results of experiment 1 showed that N-methyl-d-aspartic acid (NMDA), quisqualic acid and amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) differentially increased the expression of c-fos in magnocellular cholinergic nucleus basalis, dorsal and ventral pallidal neurons. AMPA was the most, and NMDA the least, effective in inducing FOS in nucleus basalis magnocellularis (nbM) neurons, with quisqualic acid having an intermediate effect, whereas the reverse was true in terms of the induction of FOS in pallidal neurons. In experiment 2, it was demonstrated that, in animals with ibotenic acid-induced lesions of the basal forebrain that were targetted on the nbM, virtually no pallidal neurons could be visualized that expressed FOS following AMPA-induced excitation of the dorsal and ventral striatum. By contrast, in animals with AMPA-induced lesions of the nbM, excitation of the striatum was followed by the expression of FOS in many dorsal and ventral pallidal neurons. Thus, infusions of AMPA into the basal forebrain appears preferentially to activate or destroy, depending on the concentration infused, cholinergic nbM neurons, whereas ibotenic acid or NMDA preferentially destroys or activates neurons of the dorsal and ventral pallidum. These results provide novel and complementary information regarding the organization of the basal forebrain and allow a clearer understanding of the different behavioural consequences of NMDA agonist-induced and non-NMDA agonist-induced excitotoxic lesions of this area.     

Serotonergic input to cholinergic neurons in the substantia innominata and nucleus basalis magnocellularis in the rat.

The aim of the present study was to determine, at the light microscopic level, whether the serotonergic fibers originating from the dorsal raphe nucleus (B7), median raphe nucleus (B8) and ventral tegmentum (B9) make putative synaptic contacts with cholinergic neurons of the nucleus basalis magnocellularis and substantia innominata. For this purpose, we utilized: (i) the anterograde transport of Phaseolus vulgaris leucoagglutinin combined with choline acetyltransferase immunohistochemistry; (ii) choline acetyltransferase/tryptophan hydroxylase double immunohistochemistry; and (iii) the FluoroGold retrograde tracer technique combined with tryptophan hydroxylase immunohistochemistry. Following iontophoretic injections of Phaseolus vulgaris leucoagglutinin in the dorsal raphe nucleus, labeling was observed primarily in the ventral aspects of the nucleus basalis magnocellularis and in the intermediate region of the substantia innominata. When Phaseolus vulgaris leucoagglutinin was combined with choline acetyltransferase immunohistochemistry, a close association between the Phaseolus vulgaris leucoagglutinin-positive fibers and cholinergic neurons was observed, even though the majority of the Phaseolus vulgaris leucoagglutinin-immunoreactive terminals seemed to establish contact with non-cholinergic elements. Following Phaseolus vulgaris leucoagglutinin injection in the median raphe nucleus, very few labeled fibers with no evident close contact with nucleus basalis magnocellularis and substantia innominata cholinergic neurons were observed. After tryptophan hydroxylase/choline acetyltransferase double immunohistochemistry, a plexus of serotonergic (tryptophan hydroxylase-positive) fibers in the vicinity of choline acetyltransferase-immunoreactive neurons of the substantia innominata and nucleus basalis magnocellularis was observed, and some serotonergic terminals have been shown to come into very close contact with the cholinergic cells. Most of the tryptophan hydroxylase-immunoreactive terminals seem to establish contacts with non-cholinergic cells. Following FluoroGold injection in the nucleus basalis magnocellularis and substantia innominata, the majority of retrogradely labeled neurons was observed mainly in the ventromedial cell group of the dorsal raphe nucleus. In this area, a minority of the FluoroGold-positive neurons was tryptophan hydroxylase immunoreactive. These findings show that serotonergic terminals, identified in very close association with the cholinergic neurons in the substantia innominata and nucleus basalis magnocellularis, derive primarily from the B7 serotonergic cell group of the dorsal raphe nucleus, and provide the neuroanatomical evidence for a direct functional interaction between these two neurotransmitter systems in the basal forebrain.     

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 excitotoxic lesions of the basal forebrain on the acquisition, retention and serial reversal of visual discriminations in marmosets

The effects of N-methyl-D-aspartate-induced lesions of the basal forebrain (which included the cholinergic cells of the nucleus basalis of Meynert) were studied on three aspects of visual discrimination; learning, retention and reversal performance, in the marmoset. Neurobiological investigations revealed that the lesion produced large reductions in choline acetyltransferase activity within anterior regions of cortex, particularly prefrontal. In Experiment 1 lesioned animals showed impaired retention, one week after surgery, of a visual discrimination learned immediately prior to surgery and subsequently showed impaired performance over a series of reversals. The reversal deficit could be characterized as a tendency to perseverate on the previously correct stimulus on the first reversal and as a failure to show serial reversal learning on subsequent reversals. Acquisition of a novel discrimination was not impaired five weeks after surgery. As time of testing may have been a confounding factor, in Experiment 2 the effects of the same lesion on new learning were examined immediately following surgery and the effects on retention a month later. The lesion was found to disrupt new learning but did not affect retention. From the two experiments it is clear that, whereas disruption of retention and new learning was relatively transient, the impairments in reversal performance were more long lasting. In addition, lesioned animals exhibited behavioural hyperactivity and elevations in consummatory and schedule-controlled licking. The disinhibitory and preservative effects observed following lesions of the basal forebrain in this study are similar to those following lesions of the orbitofrontal cortex while the disruption of serial reversal learning is commonly seen following damage to the amygdala. Therefore, these results are consistent with the hypothesis that the range of behavioural effects of the lesion result from damage to the cholinergic afferents to orbitofrontal cortex and to the amygdala, two structures intimately connected to one another.     

Basal forebrain lesions and memory: alterations in neurotensin, not acetylcholine, may cause amnesia

Behavioral impairments produced by lesions of the nucleus basalis magnocellularis (NBM) are usually attributed to the loss of cholinergic cells. A comparison between the effects of 2 different neurotoxins, ibotenic (IBO) and quisqualic (QUIS) acid, reveals that this interpretation is inconsistent with the data. Rats were given injections of either IBO or QUIS into the NBM and tested on an alternation task in a T-maze. At the start of behavioral testing, both IBO and QUIS rats had impaired choice accuracy. At the end of behavioral testing, however, IBO rats, but not QUIS rats, were more impaired than controls, and IBO rats were more impaired than QUIS rats. IBO decreased choline acetyltransferase (ChAT) activity and [3H] neurotensin binding in the neocortex. QUIS decreased ChAT activity but did not change [3H] neurotensin binding. The cholinergic system may not be the critical component responsible for behavioral impairments following NBM lesions.     

Dissociation of attention in learning and action: effects of lesions of the amygdala central nucleus, medial prefrontal cortex, and posterior parietal cortex

Many associative learning theories assert that the predictive accuracy of events affects the allocation of attention to them. More reliable predictors of future events are usually more likely to control action based on past learning, but less reliable predictors are often more likely to capture attention when new information is acquired. Previous studies showed that a circuit including the amygdala central nucleus (CEA) and the cholinergic substantia innominata/nucleus basalis magnocellularis (SI/nBM) is important for both sustained attention guiding action in a five-choice serial reaction time (5CSRT) task and for enhanced new learning about less predictive cues in a serial conditioning task. In this study, the authors found that lesions of the cholinergic afferents of the medial prefrontal cortex interfered with 5CSRT performance but not with surprise-induced enhancement of learning, whereas lesions of cholinergic afferents of posterior parietal cortex impaired the latter effects but did not affect 5CSRT performance. CEA lesions impaired performance in both tasks. These results are consistent with the view that CEA affects these distinct aspects of attention by influencing the activity of separate, specialized cortical regions via modulation of SI/nBM.     

Cortical serotonin receptor subtypes after lesion of ascending cholinergic neurones in rat

Serotonin (5-HT) S₁ and S₂ receptors were studied in rat cortex after lesion of the ascending cholinergic systems by injection of ibotenic acid into the nucleus basalis. The lesions produced a large (56%) decrease in choline acetyltransferase activity with no change in markers of γ-aminobutyric acid, dopamine and 5-HT containing neurones. Lesions of the ascending cholinergic neurones were accompanied by a loss of 5-HT S₁ receptor binding sites with no change in S₂ receptors. These results suggest that a proportion of S₁ receptors may be associated with cholinergic terminals.     

Apolipoprotein E-deficient mice are not more susceptible to the biochemical and memory deficits induced by nucleus basalis lesion

We investigated whether the nucleus basalis lesion induced by quisqualic acid was associated with a more severe impairment of spatial navigation in a water maze, a greater reduction in frontal choline acetyltransferase activity and decrease in the number of choline acetyltransferase-positive neurons in the nucleus basalis in apolipoprotein E-deficient mice than in control mice. We also studied the effect of ageing on water maze spatial navigation and cortical choline acetyltransferase activity in 16-month-old control and apolipoprotein E-deficient mice. We found that the lesion decreased choline acetyltransferase-positive neurons in the nucleus basalis and frontal choline acetyltransferase activity equally in control and apolipoprotein E-deficient mice. The nucleus basalis lesion had no effect on the initial acquisition in the water maze in control and apolipoprotein E-deficient mice after 25 or 106 days of recovery. However, the nucleus basalis lesion impaired the reversal learning in the water maze similarly in both strains after 25 days of recovery, but had no effect after 106 days of recovery. Finally, water maze spatial navigation and cortical choline acetyltransferase activity were similar in old control and apolipoprotein E-deficient mice.These results suggest that young and old apolipoprotein E-deficient mice do not have impairments in cholinergic activity or spatial navigation. Furthermore, apolipoprotein E deficiency does not increase the sensitivity to cholinergic and spatial navigation deficits induced by lesioning of the nucleus basalis with an excitatory amino acid and does not slow down the behavioral recovery.     

Disconnection of the amygdala central nucleus and the substantia innominata/nucleus basalis magnocellularis disrupts performance in a sustained attention task

The basal forebrain cholinergic system is broadly implicated in the regulation of attention. Disruptions in the function of this system produce impairments in many attentional functions, including the performance of well-learned responses under increased attentional load and the surprise-induced enhancement of learning rate. Similarly, lesions of the amygdala central nucleus (CeA) have been found to impair attentional function in some circumstances. In the present article, the effects of lesions that disconnected CeA from the cholinergic substantia innominata/nucleus basalis magnocellularis (SI/nBM) on performance are examined in a modified 5-choice serial reaction time (5CSRT) task, thought to assess selective or sustained attention. The lesions impaired performance under conditions of increased attentional load, suggesting that a circuit that includes CeA and SI/nBM regulates these aspects of attention.     

Disconnection of the amygdala central nucleus and substantia innominata/nucleus basalis disrupts increments in conditioned stimulus processing in rats

Rats with a neurotoxic lesion of the amygdala central nucleus (CN) in one hemisphere and a 192 immunoglobulin G (192IgG)-saporin lesion of cholinergic neurons in the contralateral substantia innominata/nucleus basalis (SI/nBM) failed to show the enhanced attentional processing of a conditioned stimulus (CS) observed in sham-operated rats when that CS's predictive value was altered. Performance of these asymmetrically lesioned rats was poorer than that of rats with a unilateral lesion of either structure or with a symmetrical lesion of both structures in the same hemisphere. These results implicate connections between the CN and SI/nBM in the incremental attentional processing of CSs, extending previous research that has shown similar effects of bilateral lesions of either the CN or the SI/nBM.     

Loss of cholinergic neurons in the nucleus basalis induces neocortical electroencephalographic and passive avoidance deficits.

The present experiments were designed to examine the hypothesis that the degeneration of cholinergic nucleus basalis is related to the cognitive and neurophysiological deficits found in old age. Aged (26 months) rats were impaired both in the acquisition of spatial (water-maze) task and retention of passive avoidance task. During aging, neocortical electroencephalographic fast activity was decreased and high-voltage spindles increased. Loss of choline acetyltransferase-positive neurons correlated with the high-voltage spindle incidence and passive avoidance retention deficit. Unilateral ibotenate nucleus basalis lesioning decreased choline acetyltransferase activity in the cortex and produced a large nonspecific subcortical cell loss in young rats. Ibotenate-lesioned rats were impaired in spatial learning and passive avoidance retention in young rats. Quisqualic acid produced a greater decrease in cortical choline acetyltransferase activity and smaller nonspecific subcortical cell loss than ibotenate lesioning. Spatial learning was not impaired, but passive avoidance performance was disrupted. Slow waves and high-voltage spindles were increased and beta activity decreased on the side of either quisqualate or ibotenate nucleus basalis lesioning. These results demonstrate that age-related neurophysiological and cognitive deficits result partially from the loss of cholinergic neurons in the nucleus basalis and that quisqualic acid nucleus basalis-lesioning in young rats may be used as a pharmacological model of the age-related cholinergic neuron loss.     

Learning and memory deficits after lesions of the nucleus basalis magnocellularis: reversal by physostigmine

The role of the cholinergic nucleus basalis magnocellularis in spatial learning and memory was studied in the rat. Animals received bilateral injections of ibotenic acid (5 micrograms/microliters) into the region of the nucleus basalis magnocellularis. Six weeks postoperatively they were deprived of food and trained for 5 weeks in a 16-arm radial maze in which 9 of the arms were baited with food. The nucleus basalis magnocellularis-lesioned animals showed significant deficits in the acquisition of the task. Further analysis of the data indicated that this was due primarily to a deficit in reference (long-term) as opposed to working (short-term) memory. After the 5-week training period the nucleus basalis magnocellularis-lesioned animals received intraperitoneal injections of physostigmine sulphate (0.5 mg/kg) 30 min before each daily trial for 1 week. This treatment resulted in a significant improvement in the performance of the spatial memory task on all three measures. The ibotenate lesions reduced the activity of choline acetyltransferase by about 40% in the anterior cortex and by 15% in the posterior cortex. Hippocampal choline acetyltransferase activity was not affected, indicating that the septohippocampal cholinergic projection was spared by the lesions. The activity of glutamate decarboxylase was not affected in any of these regions. These results suggest that the cholinergic projections of the nucleus basalis magnocellularis play an important role in the acquisition of a spatial memory task.     

Influence of ascending noradrenergic fibers on the neurotensin-like immunoreactive neurons in the rat paraventricular nucleus

The topographic organization of cells containing choline-acetyltransferase (CAT) and located within the magnocellular nuclei of the basal forebrain was studied by correlating maximum CAT decrease in one or another cortical region with a given localization of the cell lesions. Lesions were made by using ibotenic acid. Lesions affecting the ventral pallidum decreased CAT activity in the antero-medial prefrontal cortex and lesions of the internal and ventral borders of the pallidum decreased CAT activity in sensori-motor and parieto-temporal cortices. None of these lesions produced a decrease of CAT activity in the hippocampus. These results suggest that it is possible to show the presence of a specific cholinergic projection from the basal forebrain to the medial-associative prefrontal cortex of the rat.     

The nucleus basalis magnocellularis: The origin of a cholinergic projection to the neocortex of the rat

The cells of origin of a neocortical cholinergic afferent projection have been identified by anterograde and retrograde methods in the rat. Horseradish peroxidase injected into neocortex labelled large, acetylcholinesterase-rich neurons in the ventromedial extremity of the globus pallidus. This same group of neurons underwent retrograde degeneration following cortical ablations. The region in which cell depletion occurred also showed significant decreases in the activities of choline acetyltransferase and acetylcholinesterase. Discrete electrolytic and kainic acid lesions restricted to the medial part of the globus pallidus each resulted in significant depletions of neocortical choline acetyltransferase and acetylcholinesterase. Hemitransections caudal to this cell group did not result in such depletions. Taken together these observations suggest that the acetylcholinesterase-rich neurons lying in the ventromedial extremity of the globus pallidus, as mapped in this study, constitute the origin of a major subcortical cholinergic projection to the neocortex. The utility of acetylcholinesterase histochemistry in animals pretreated with di-isopropylphosphorofluoridate in identifying cholinergic neurons is discussed in the light of this example; specifically, it is proposed that high acetylcholinesterase activity 4–8 h after this pretreatment is a necessary, but not sufficient, criterion for the identification of cholinergic perikarya.The neurons in question appear to be homologous to the nucleus basalis of the substantia innominata of primates, and are thus termed ‘nucleus basalis magnocellularis’ in the rat. No evidence was obtained to support the hypothesis that nucleus of the diagonal band projects to neocortex. However, striking similarities in size and acetylcholinesterase activity were observed among the putative cholinergic perikarya of the nucleus basalis magnocellularis, the nucleus of the diagonal band, and the medial septal nucleus.Kainic acid lesions of the neocortex produced uniform and complete destruction of neuronal perikarya. These lesions decreased neocortical glutamic acid decar?ylase activity, suggesting that there are GABAergic perikarya in the neocortex. However, the same lesions did not affect neocortical choline acetyltransferase. This observation suggests that there are no cholinergic perikarya in the neocortex, a conclusion that is consistent with the absence of intensely acetylcholinesterase-reactive neurons in the neocortex.     

Delayed treatment with nerve growth factor improves acquisition of a spatial task in rats with lesions of the nucleus basalis magnocellularis: evaluation of the involvement of different neurotransmitter systems.

Rats received bilateral lesions of the nucleus basalis magnocellularis by infusion of ibotenic acid. Fourteen days later, osmotic minipumps releasing human recombinant nerve growth factor (0.3 micrograms/day) were implanted subcutaneously. Starting one month after the lesion, spatial learning of the animals was tested using the Morris water maze. Acquisition of the task was impaired by the lesion, but treatment with nerve growth factor reduced the average latency to find the platform by approximately 9 s, which represents 28% of the lesion-induced behavioral deficit. Retention of this task and spatial acuity, tested in a trial in which the platform was not present, did not show a statistically significant improvement. Lesions of the nucleus basalis magnocellularis reduced the choline acetyltransferase activity in the neocortex, but not in the hippocampus. Treatment with nerve growth factor increased the choline acetyltransferase activity in the neocortex but not in the hippocampus. There was no significant difference in the levels of norepinephrine, dopamine, serotonin or their metabolites in the cortex or hippocampus between nerve growth factor-treated animals and lesioned control animals. There was no significant correlation between any of these neurochemical changes and behavioral performance (acquisition and spatial acuity). Treatment with nerve growth factor did not increase the number or the size of nerve growth factor receptor-immunoreactive neurons in the nucleus basalis magnocellularis. These data suggest that delayed treatment with nerve growth factor results in an improvement of spatial learning in rats with lesions of the nucleus basalis magnocellularis. A possible role for cholinergic mechanisms in this effect is discussed.     

Basal forebrain neurons provide major cholinergic innervation of primate neocortex

In 3 monkeys, lesions were made in the basal forebrain by microinjections of ibotenic acid into the nucleus basalis. Bilateral samples of multiple neocortical gyri were assayed for the activity of choline acetyltransferase. Compared to control hemispheres, enzyme activity was reduced up to 69% in the neocortex ipsilateral to the lesion; in addition, acetylcholinesterase staining was decreased at the lesioned site and in the ipsilateral cortex. These results support the concept that the principal cholinergic innervation of the primate neocortex is derived from axons and nerve terminals of neurons whose perikarya are located in the basal forebrain, particularly the nucleus basalis.