Further characterizations of the nature of the behavioral and neurochemical effects of lesions to the nucleus basalis of Meynert in the rat

Converging lines of evidence indicate an important role for the basal forebrain cholinergic system in memory processes. The principal origin of the cholinergic projection to the neocortex appears to be the magnocellular neurons in the region of the nucleus basalis of Meynert (NbM). We examined the effects of bilateral lesions of the NbM on retention of shock avoidance training by stereotaxically injecting rats with 0.5 microliter of ibotenic acid (14 micrograms/microliter) into the NbM. Two weeks later rats were given passive avoidance training and tested for retention of the original avoidance habit 5 min, 30 min, or 24 hr later. Rats with lesions of the NbM showed significantly impaired shock avoidance performance compared to non-operated controls at both 30 min and 24 hr, but not at 5 min after training. Lesioned animals also showed a significant decrease in cortical choline acetyltransferase (CAT) and acetylcholinesterase (AChE) activities. No differences in muscarinic receptor binding or plasma cholinesterase activity was observed. The results demonstrate the usefulness of NbM lesions as a model for studying the role of the basal forebrain cholinergic system in memory processes.     

Transplantation of embryonic ventral forebrain neurons to the neocortex of rats with lesions of nucleus basalis magnocellularis--II. Sensorimotor and learning impairments

The cholinergic projection from the nucleus basalis magnocellularis to the neocortex has been implicated in normal memory function and in the dementia of Alzheimer's disease. In order to investigate functions of this cholinergic system of the forebrain, rats with unilateral ibotenic acid lesions of the nucleus basalis magnocellularis have been compared with normal animals and with rats given cortically-placed transplants, either of cholinergic-rich embryonic ventral forebrain cells or of control noncholinergic cells taken from embryonic hippocampus. In the first experiment, lesions of the nucleus basalis magnocellularis led to impairments in step-through passive avoidance and Morris' water-maze tasks, and to locomotor hyperactivity attributable to a reduction in within-trial habituation. The ventral forebrain grafts, but not the noncholinergic hippocampal grafts, significantly ameliorated the deficits of passive avoidance retention, and of water-maze spatial accuracy, but had no effect on the acquisition impairments in either task, nor on the habituation deficit in locomotor activity of the nucleus basalis magnocellularis lesioned rats. In the second experiment, the lesions induced contralateral sensory neglect and ipsilateral turning biases, which were also partially ameliorated by the ventral forebrain grafts. The results support the hypothesis that the basal forebrain-neocortical cholinergic system contributes to certain memory processes, but suggest a more general role for this system in other cortical functions also.     

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.     

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.     

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.     

Atrophy of cholinergic neurons within the rat nucleus basalis magnocellularis following intracortical AF64A infusion

The rat nucleus basalis magnocellularis (nBM) was morphometrically analyzed following multiple intracortical AF64A infusions. At 3 weeks post-infusion, brains were histochemically double-stained for acetyl-cholinesterase and Nissl substance following diisopropylfluorophosphate pretreatment. Intracortical AF64A induced significant atrophy, but not degeneration, of nucleus basalis cholinergic cell bodies. These results suggest that retrograde cellular atrophy is associated with inhibition of presynaptic high-affinity choline transport on cortical terminals of nBM cholinergic neurons.     

Effects of nBM lesions on muscarinic-stimulation of phosphoinositide hydrolysis

The nucleus basalis magnocellularis (nBM) is believed to be the major path of cholinergic innervation to the frontal cortex. The cerebral cortex is known to contain muscarinic receptors that are coupled to the hydrolysis of phosphoinositides (PI) (9,14). Adult male Sprague-Dawley rats were unilaterally and bilaterally lesioned at the nBM with the excitotoxin ibotenic acid and killed at 7 or 21 to 23 days postsurgery. In rats unilaterally lesioned 7 days previously, the carbachol dose-response curves in lesioned fronto-parietal cortex were identical to control fronto-parietal cortices. In rats studied 21 to 23 days postsurgery, carbachol dose-response curves were again identical in control vs. lesioned fronto-parietal cortices. Similar results are obtained when bilaterally lesioned rats are compared to sham-operated controls. For each group, the hydrolysis is linear with respect to time until 15 minutes with a maximum reached at approximately 40 minutes. Receptor density, as measured by [3H]-QNB binding or agonist competition for [3H]-QNB binding, was not changed by any of the lesions studied. These results suggest that the loss of cholinergic innervation from the nBM does not result in compensatory denervation supersensitivity in cerebral fronto-parietal cortical muscarinic receptors.     

Effects of nucleus basalis lesions on cerebral cortical concentrations of corticotropin-releasing hormone (CRH)-like immunoreactivity in the rat

The present study was designed to determine the effects of partial cholinergic denervation on parietal cortical corticotropin-releasing hormone-like immunoreactivity (CRH-LI) in the rat at different ages. Young adult rats received either unilateral or bilateral ibotenic acid infusions into their nucleus basalis, destroying most of the acetylcholinesterase-positive neurons in that region. Parietal cortical levels of CRH-LI were assayed 2.5, 10, 14 and 19 months after placement of nucleus basalis lesions. Parietal CRH-LI was elevated at 10, 14 and 19 months in bilaterally lesioned animals, while unilateral lesions had no effect on CRH-LI.     

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.     

Independent effects of age and nucleus basalis magnocellularis lesion: maze learning, cortical neurochemistry, and morphometry.

The effects of age and lesion of the cholinergic nucleus basalis magnocellularis (NBm) were assessed behaviorally, morphologically, and biochemically. Groups consisted of rats lesioned 1 month before testing, rats lesioned 13 months before testing, and their respective age-matched controls. Both age and lesion independently induced behavioral deficits in performance on two water maze tasks. The combined effect of these two factors produced behavioral deficits equal to the sum of the individual impairments. NBm lesion produced a 28% decrease in anterior cortical choline acetyltransferase activity and a 20% decrease in synaptophysin immunoreactivity in the neocortex that was stable over a 12-month period. Neither neuritic plaque nor neurofibrillary-tanglelike structures were found in the brains of 18-month-old control rats, nor were they found in NBm-lesioned rats examined 15 months postlesion. There was an age-related decrease in homovanillic acid levels in both control and NBm groups, which suggests a decrease in dopamine turnover. These results show a lack of biochemical and behavioral recovery after NBm lesion and suggest that the effects of age on behavior are independent of NBm-cortical dysfunction.     

Nucleus basalis magnocellularis lesions: lack of biochemical and immunocytochemical recovery and effect of cholinesterase inhibitors on passive avoidance

Lesions of the rat nucleus basalis magnocellularis (nBM) result in a marked decrease in cortical choline acetyltransferase (CAT) and in behavioral deficits. After unilateral ibotenic acid (IBO) lesions of the nBM in rats, there was a significant ipsilateral loss of frontal and parietal CAT, which did not recover for 3 months following surgery and was accompanied by a loss of CAT immunoreactivity in the peripallidal region. Bilateral ibotenate nBM lesions resulted in a marked deficit of one-trial step-through passive avoidance (PA) at 24 hours. Cholinesterase inhibitors including physostigmine, N-ethylaklylphenyl carbamate (RA-6), and N,N-methylethylphenyl carbamate (RA-7) were administered in separate experiments, for 2 days before retrieval testing or for 3 consecutive days during consolidation immediately following training. Nonsignificant improvements in PA latency were produced using 0.32 mg/kg physostigmine and 2.5 mg/kg RA-6 administered before retrieval testing. The results suggest that destruction of cholinergic neurons in the nBM are involved in the PA deficit, but does not exclude the possibility that damage to other neuronal systems may contribute to the observed behavioral deficit.     

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.     

Effects of nerve growth factor and GM1 ganglioside on the number and size of cholinergic neurons in rats with unilateral lesion of the nucleus basalis

Four groups of rats with a unilateral ibotenic acid lesion of the nucleus basalis were treated with saline, nerve growth factor (NGF) 10 micrograms administered intracerebroventricularly twice per week, sialoganglioside GM1 30 m/kg daily i.p. and NGF twice per week plus GM1 10 mg/kg i.p. daily, respectively, beginning immediately after lesioning. Twenty-one days later the rats treated with saline showed a marked impairment in negotiating a 'step through' passive avoidance conditioned response, a 32% decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the lesioned nucleus basalis and a 12% decrease in their areas. The rats treated with NGF and NGF plus GM1 showed no difference from sham-operated rats. In the GM1-treated rats a 12% decrease only in the number of ChAT-positive neurons was detected while performance and neuronal areas were normal. These findings indicate that NGF and GM1 prevent the cholinergic deficit by protecting the cholinergic neurons of the nucleus basalis from ibotenic acid neurotoxicity.     

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.     

Nucleus basalis lesions attenuate aquisition,but not retention,of Pavlovian heart rate conditioning and have no effect on eyeblink conditioning

Summary Rabbits with lesions of the anterior nucleus basalis of Meynert (nBM) were compared with animals with sham lesions or unoperated control animals on a classical conditioning task in which heart rate (HR) and eyeblink (EB) conditioned responses (CRs) were as sessed. The nBM lesions impaired the magnitude of the decelerative HR CR, but had no effect on the EB CR. A second experiment, in which animals were lesioned af ter acquisition was complete, showed that anterior nBM lesions had no effect on retention of either the HR or EB CR. These data suggest that the anterior nBM may participate in the early stages of information processing in which stimuli are evaluated for their significance based on their association with a reinforcer. However, the ante rior nBM is apparently not involved in the selection of a somatomotor response to deal effectively with such changing stimulus contingencies.     

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.     

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.     

Selective optogenetic stimulation of cholinergic axons in neocortex

Acetylcholine profoundly affects neocortical function, being involved in arousal, attention, learning, memory, sensory and motor function, and plasticity. The majority of cholinergic afferents to neocortex are from neurons in nucleus basalis. Nucleus basalis also contains projecting neurons that release other transmitters, including GABA and possibly glutamate. Hence, electrical stimulation of nucleus basalis evokes the release of a mixture of neurotransmitters in neocortex, and this lack of selectivity has impeded research on cholinergic signaling in neocortex. We describe a method for the selective stimulation of cholinergic axons in neocortex. We used the Cre-lox system and a viral vector to express the light-activated protein channelrhodopsin-2 in cholinergic neurons in nucleus basalis and their axons in neocortex. Labeled neurons depolarized on illumination with blue light but were otherwise unchanged. In anesthetized mice, illumination of neocortex desynchronized the local field potential, indicating that light evoked release of ACh. This novel technique will enable many new studies of the cellular, network, and behavioral physiology of ACh in neocortex.     

Protective effects of the alpha 2-adrenoceptor antagonist,dexefaroxan, against degeneration of the basalocortical cholinergic system induced by cortical devascularization in the adult rat

It has been hypothesized [Colpaert, F.C., 1994. In: Briley, M., Marien, M. (Eds.), Noradrenergic Mechanisms in Parkinson's Disease. CRC Press, Boca Raton, FL, pp. 225-254] that a deficiency in the noradrenergic system originating from the locus coeruleus is a decisive factor in the progression of central neurodegenerative disorders including Alzheimer's disease, and that treatments which boost noradrenergic transmission (e.g. via blockade of alpha(2)-adrenoceptors) could provide both symptomatic and trophic benefits against the disease. Studies in the rat in vivo demonstrating that the selective alpha(2)-adrenoceptor antagonist dexefaroxan increases acetylcholine release in the cortex, improves measures of cognitive performance and protects against excitotoxin lesions, support this concept. As a further test of the hypothesis, we investigated the effect of dexefaroxan in a rat model of unilateral cortical devascularization that induces a loss of the cortical cholinergic terminal network and a retrograde degeneration of the cholinergic projections that originate in the nucleus basalis magnocellularis. Lesioned and sham-operated rats received a 28-day subcutaneous infusion of dexefaroxan (0.63 mg/rat/day) or vehicle, delivered by osmotic minipumps implanted on the day of the cortical devascularization procedure. In lesioned rats, the dexefaroxan treatment was associated with a significantly higher number and size of vesicular acetylcholine transporter-immunoreactive boutons in comparison to the vehicle treatment; this effect was most marked within cortical layer V. Dexefaroxan also significantly reduced the atrophy of cholinergic neurons within the nucleus basalis magnocellularis. Dexefaroxan had no observable effect on any of these parameters in sham-operated cohorts. These results show that systemically administered dexefaroxan mitigates cholinergic neuronal degeneration in vivo, and provide further evidence for a therapeutic potential of the drug in neurodegenerative diseases such as Alzheimer's disease, where central cholinergic function is progressively compromised.     

Regional decreases of cortical choline acetyltransferase after lesions of the septal area and in the area of nucleus basalis magnocellularis

Choline acetyltransferase and [³H]choline uptake have been measured in neocortical regions and hippocampus one week after lesions which destroyed the septum bilaterally, and after unilateral lesions in the area of nucleus basalis magnocellularis. Lesions of the septal area, which severely decreased choline acetyltransferase in hippocampus, only moderately decreased choline acetyltransferase in a posterior cortical region and had no effect in frontal and parietal regions. In contrast, lesions which included nucleus basalis magnocellularis decreased choline acetyltransferase markedly in frontal and parietal regions and had less of an effect in the posterior cortical regions. Lesion-induced decreases of [³H]choline uptake paralleled those of choline acetyltransferase. Lesions which included nucleus basalis magnocellularis had no effect on choline acetyltransferase in hippocampus, nucleus accumbens, olfactory tubercle, midbrain or pons-medulla.These results suggest the existence of topographically distinct cholinergic inputs to neocortex. In agreement with previous studies, cholinergic projections from the peripallidal region of nucleus basalis magnocellularis are predominantly to frontal and parietal neocortex. In contrast to previous suggestions, cholinergic projections to neocortex from the septal area are limited to the posterior regions of neocortex.