Differential alterations of cortical cholinergic and neurotensin markers following ibotenic acid lesions of the nucleus basalis magnocellularis

The present study determined whether cortical cholinergic neurons recover functionally following the loss of afferent projections from the nucleus basalis magnocellularis (nbm). At various points following ibotenic acid lesions of the nbm, choline acetyltransferase (ChAT) activity or the capacity of cortical cholinergic neurons to synthesize [³H]acetylcholine (ACh) from the precursor molecule [³H]choline were measured in the frontoparietal cortex. First, cortical ChAT activity was decreased by 21% and 35% on the side ipsilateral to the lesion at 1 and 2 weeks following the nbm lesion, respectively. By 6 weeks following nbm lesions, cortical ChAT activity returned to control levels and remained at control levels at 10 weeks following nbm lesions. However, by 13 weeks following nbm lesions, we observed a 21% increase in ChAT activity on the side ipsilateral to the lesion. ChAT activity in the nbm remained unchanged over the time course studied. Secondly, there was a parallel reduction (by 43%) in the capacity of frontoparietal cortex slices from the side ipsilateral to the lesion to synthesize [³H]ACh by 2 weeks following nbm lesions. By 13 weeks following the lesion there was a significant increase (29%) in the synthetic capacity of cortical cholinergic neurons compared to the 2 week time point. Third, the content of neurotensin in the frontoparietal cortex was significantly decreased by 25% and 36%, at 2 weeks and 13 weeks following nbm lesions, respectively. Neurotensin levels in the nbm were not affected by ibotenic acid lesions. In contrast, [¹²⁵I]neurotensin binding sites in the frontal or parietal cortex were not altered at 2 weeks following nbm lesions. In summary, the results of the present study provide evidence for functional recovery by cortical cholinergic neurons following selective lesions of the nbm. However, the reduction of cortical cholinergic terminals resulting from the lesion appears to cause irreversible trans-synaptic decreases in cortical neurotensin levels.     

Profound disturbances of spontaneous and learned behaviors following lesions of the nucleus basalis magnocellularis in the rat

It has been shown that a marked decline in the cortical activity of the cholinergic synthesizing enzyme choline-acetyltransferase (ChAT), accompanied by a severe neuronal loss in the nucleus basalis magnocellularis of Meynert occurs in the brains of patients with senile dementia of the Alzheimer type. However, the functional role of these neurons is largely unknown. In fact, very few studies have been done in animals. In this paper we report the behavioral effects of the lesion of the nucleus basalis magnocellularis in the rat either by radiofrequency current or by ibotenic acid injection at the level of the cell bodies. The two kinds of lesion lead to a profound disturbance of spontaneous and learned behaviors. There is a complete disorganization of behavior which is evidenced by an enhanced locomotor activity, an alteration in alimentary and hoarding behavior. In addition, we observed a deterioration of spatial memory and an incapacity to reverse a previously learned response. Biochemical assay showed that radiofrequency and ibotenic acid lesions produced a decrease of ChAT activity in the prefrontal and sensorimotor cortices and in amygdala without affecting the hippocampus or striatum. Ibotenic acid lesions seem to specifically destroy the cell bodies of the nucleus basalis magnocellularis since the dopaminergic and noradrenergic fibers of passage remained intact as measured by the unchanged level of endogenous catecholamine concentration in the terminal region in the prefrontal cortex. Presently, it cannot be said that the behavioral syndrome results solely from the lesion of the cholinergic neurons. Also, it is likely that the lesion of the nucleus basalis magnocellularis in the rat does not exactly reproduce the behavioral syndrome observed in Alzheimer's disease in man. However, this experimental approach in leading to a better knowledge of the functioning of these neurones could improve our understanding of this disease.     

Dementia: animal models of the cognitive impairments following damage to the basal forebrain cholinergic system

The finding that patients with Alzheimer's disease (AD) have significant degeneration of neurons in the basal forebrain cholinergic system (BFCS) stimulated a great deal of research to determine the cognitive impairments resulting from selective damage to this area. The experiments reviewed here indicate that lesions of the nucleus basalis magnocellularis (NBM) and of the medial septal area (MSA) reproduce the behavioral symptoms following lesions of their respective target sites, the frontal cortex (FC) and the hippocampus (HIP). Impairments of recent memory are one of the most striking symptoms in AD patients at the beginning of their disease, and lesions of the BFCS induce similar impairments. Comparisons of the effects of the lesions produced by different neurotoxins, ibotenic (IBO) acid and quisqualic (QUIS) acid, have raised questions about the role of cholinergic and noncholinergic neurotransmitter systems in the basal forebrain. The implications of these data for the cholinergic hypothesis of mnemonic functions are discussed.     

Lack of sympathetic and cholinergic influences on cerebral vasodilation caused by sciatic nerve stimulation in the rat

We studied the influences of sympathetic and cholinergic mechanisms on pial arteriolar responses during cortical activation in the rat. Adult male Sprague-Dawley rats were anesthetized with alpha-chloralose and urethane and mechanically ventilated. Pial arterioles on the somatosensory cortex were visualized on a video monitor through a closed cranial window. Changes in arteriolar diameter induced by sciatic nerve stimulation (0.2 V, 5 Hz, 5 ms, for 20 s) were measured before and after (a) ipsilateral superior cervical ganglionectomy (n = 5), (b) intravenous (0.5 mg/kg) administration and topical (10(-5) M) application of atropine (n = 5), and (c) lesion of the nucleus basalis magnocellularis (the major source of intracerebral acetylcholine neurons, n = 7). Unilateral nucleus basalis magnocellularis lesions were performed stereotactically by injection of ibotenic acid (25 nmol/microliter). Sensory cortex cholinergic denervation was confirmed histologically. These treatments had no significant effect on arteriolar responses to sciatic nerve stimulation. Thus, the present results suggest that neither sympathetic nor cholinergic mechanisms play a significant role in somatosensory evoked cerebral vasodilation.     

Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis

The role of forebrain cholinergic projections in place navigation learning was assessed in two experiments. Following surgery, rats were required to learn the spatial location of an underwater platform on the basis of distal room cues. Bilateral injections of ibotenic acid into the nucleus basalis magnocellularis depleted choline acetyltransferase (ChAT) from the anterior and temporoparietal cortex but not the hippocampus. Separate histological studies confirmed the accuracy of the lesions and demonstrated a marked loss of cortical acetylcholinesterase. These rats subsequently showed no deficits in spatial learning or memory. In a second experiment, bilateral lesions of the vertical limb of the diagonal band of Broca and medial septum depleted ChAT from the hippocampus and posterior cortex but not the anterior cortex. Histological studies confirmed the accuracy of the lesion and showed a pronounced loss of acetylcholinesterase from the hippocampus. These rats were deficient in spatial learning and showed reduced spatial bias during transfer tests. The data are discussed in the light of the hypothesis that the cholinergic innervation of the hippocampus plays a key role in spatial reference memory processes involved in place navigation.     

Generation of cortical event-related slow potentials in the rat involves nucleus basalis cholinergic innervation

These experiments were conducted to gather information regarding the role of cholinergic innervation to the cortex in the generation of event-related slow potentials. The effects of unilateral drug treatments or lesions on ipsilateral and contralateral frontal cortex slow potential (SP) responses were examined in rats. The SP responses were recorded with silver-silver chloride electrodes and were generated by a 2 sec light cue which preceded rewarding medial forebrain bundle stimulation. The following approaches were used: microinjection of GABA, procaine or saline into the nucleus basalis magnocellularis; microinjection of atropine or saline subdurally in the SP recording area; electrolytic lesion of the nucleus basalis area; and kainic acid lesion of the nucleus basalis area. The following bilateral measurements were obtained lesion studies: choline acetyltransferase (ChAT) in cortex and hippocampus; serotonin in cortex, hippocampus, striatum and nucleus accumbens; norepinephrine in cortex and hippocampus; dopamine in striatum and nucleus accumbens; and metabolites of serotonin, norepinephrine and dopamine in these areas. The cortical SP responses were reduced on the side ipsilateral to the injections of GABA and procaine into the nucleus basalis, and on the side of the subdural atropine injection. With either type of lesion, the SP responses on the lesioned side were significantly reduced as compared to the non-lesioned side. Reductions in cortical ChAT and other measures were observed ipsilateral to the electrolytic lesion, but only cortical ChAT activity was reduced in the kainic acid-lesioned animals. Thus, pharmacological depression of nucleus basalis neurons, blockade of cholinergic muscarinic receptors in the cortex, and nucleus basalis lesions that reduce cortical choline acetyltransferase activity depress event-related slow potentials in the rat frontal cortex. These results provide evidence that cortical slow potential responses in the rat are dependent upon cholinergic innervation from the nucleus basalis.     

Estrogen replacement does not prevent the loss of choline acetyltransferase-positive cells in the basal forebrain following either neurochemical or mechanical lesions

Recent studies have shown that estrogen replacement can enhance the functional status of basal forebrain cholinergic neurons. Studies have also shown that estrogen has neuroprotective effects both in vitro and in vivo on a variety of cells and against a variety of insults. The present study examined the ability of estrogen replacement to protect basal forebrain cholinergic neurons from the effects of neurochemical and mechanical injury. Ovariectomized Sprague-Dawley rats received either estrogen replacement or sham surgery, and then received either a unilateral injection of ibotenic acid into the nucleus basalis magnocellularis, or unilateral transection of the fimbria fornix. Cholinergic neurons in the medial septum and nucleus basalis were detected and quantified using immunohistochemical techniques. The data show that neither 3 weeks nor 13 weeks of continuous estrogen replacement prevented the loss of choline acetyltransferase (ChAT)-containing cells in the nucleus basalis following a unilateral injection of ibotenic acid. Likewise, estrogen replacement did not prevent a decrease in ChAT-positive cells detected in the medial septum following unilateral transection of the fimbria fornix. Notably, increased numbers of ChAT-positive cells were detected in the contralateral nucleus basalis, and in the ipsilateral and contralateral medial septum, at 2 weeks following a unilateral injection of ibotenic acid into the nucleus basalis; however, these effects were not related to hormone treatment. These data suggest that estrogen replacement does not protect cholinergic neurons in the medial septum and nucleus basalis from the effects of excitotoxic or mechanical injury.     

β-Amyloid(Phe(SO3H))25–35 in rat nucleus basalis induces behavioral dysfunctions, impairs learning and memory and disrupts cortical cholinergic innervation

Long-term behavioral effects, changes in learning and memory functions and aberrations of cholinergic fibers projecting to the parietal cortex were investigated after bilateral injections of β-amyloid(Phe(SO₃H)²⁴)25–35 peptide in rat nucleus basalis magnocellularis (nbm). The β-amyloid peptide used in these experiments contained the original β-amyloid 25–35 sequence which was coupled to a phenylalanine-sulphonate group at position 24. This additional residue serves as a protective cap on the molecule without influencing its neurotoxic properties and results in water-solubility, stability and low rates of peptide metabolism. In this paper, home cage, locomotor and open-field activities, passive shock-avoidance and ‘Morris' water maze learning abilities were assessed throughout a 35-day survival period. Subsequently, acetylcholinesterase (AChE) histochemistry was used to visualize alterations of parietal cortical cholinergic innervation. In response to the neurotoxic action of β-amyloid(Phe(SO₃H)²⁴)25–35, a progressive hyperactivity developed in the rats in their home cages which were maintained throughout the 5-week post-injection period. This was accompanied by a significant hypoactivity in the novel environment of a locomotor arena. β-Amyloid(Phe(SO₃H)²⁴)25–35-treated animals showed greatly impaired cortical memory functions in the step-through passive shock-avoidance paradigm, while spatial learning processes remained unaffected. Moreover, β-amyloid(Phe(SO₃H)²⁴)25–35 injections in the nucleus basalis suppressed explorative behavior in rats and inhibited conditioned stress responses 28 days after surgery. Reductions of cortical cholinergic (AChE-positive) projections provided anatomical substrate for the behavioral changes. This indicated extensive, long-lasting neurodegenerative processes as a result of β-amyloid(Phe(SO₃H)²⁴)25–35 infusion.     

The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus‐specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4‐SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en‐passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.     

Neurochemical recovery in the neocortex after colchicine lesions of the nucleus basalis magnocellularis in rats

Neurochemical recovery was investigated in male, Fischer-344 rats up to 3 months after lesions of the nucleus basalis. Bilateral injections of colchicine (1.0 micrograms/site) into the nucleus basalis magnocellularis (NBM) resulted in a 30% decrease in choline acetyltransferase (ChAT) activity in frontal cortex 4 weeks after surgery, compared to unlesioned controls. ChAT activity in the frontal cortex gradually recovered to control levels by 12 weeks. The loss of ChAT-immunoreactive neurons in the NBM observed 4 weeks after surgery was still evident 12 weeks after surgery. These results suggest that surviving cholinergic neurons in the NBM contribute to recovery of ChAT activity in the neocortex.     

The neural mechanisms underlying cholinergic celldeath within the basal FOREBRAIN

The basal forebrain region includes a large group of cholinergic neurons within themedial septal area and nucleus basalis magnocellularis (NBM) that project to the hippocampusand throughout the neocortex, respectively. This chapter will consider the mechanisms thatinfluence why cholinergic cells within the NBM die and discuss studies that have manipulated thefeatures of these cells that could make them differentially vulnerable to degeneration with agingand Alzheimer^fn3s Disease (AD). This chapter will focus upon the NBM cholinergic system because thisregions typically demonstrates a greater degree of cell loss with aging and AD.     

Quantitative morphometric analysis of the neurotoxic effects of the excitotoxin, ibotenic acid, on the basal forebrain

The effects of injections of the excitotoxin, ibotenic acid, into the nucleus basalis magnocellularis (NBM) were quantitatively studied. Besides destroying NBM neurons, ibotenic acid also produced comparable cell destruction within the adjacent medial amygdaloid nucleus and globus pallidus. Since the globus pallidus is spared in victims of senile dementia of the Alzheimer type (SDAT), although the adjacent NBM and amygdala are damaged, these data are not consistent with the theory that the damage to the basal forebrain seen in SDAT victims is produced by elevated levels of endogenous excitotoxin. These data also question the validity of using ibotenic acid-induced NBM lesions as a model of the cholinergic deficit in SDAT.     

Interaction between nerve growth factor and GM1 monosialoganglioside in preventing cortical choline acetyltransferase and high affinity choline uptake decrease after lesion of the nucleus basalis

Monosialoganglioside GM₁ and nerve growth factor (NGF) were administered alone or concomitantly to adult male rats with a unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (NBM). High-affinity choline uptake (HACU) rate and choline acetyltransferase (ChAT) activity were measured, 4 and 21 days after surgery, respectively, in the frontal and parietal cortices of both hemispheres. A 33–34% decrease in HACU rate and a 43-39% decrease in ChAT activity was found in the ipsilateral cortices 4 and 21 days, respectively, after the lesion. If the lesioned rats received NGF (10 μg i.c.v.) twice a week or daily administrations of GM₁ (30 mg/kg, i.p.), beginning immediately after surgery the decrease in HACU rate and ChAT activity was smaller. If NGF and GM, were given concomitantly no decrease in HACU rate and ChAT activity was detected in the lesioned hemisphere and a slight increase occurred in the contralateral hemisphere. However, after the concurrent administration of NGF (10 μg i.c.v.) and the inactive dose of GM₁ 10 mg/kg i.p. no decrease in HACU and ChAT activity was also found in the lesioned rats. The latter finding indicates a potentiation by GM₁ of NGF effects on the cholinergic neurons of the IBM. The two drugs may either antagonize the neurotoxic effects of ibotenic acid or stimulate a compensatory activity in the remaining neurons.     

Effects of combined serotonin depletion and lesions of the nucleus basalis magnocellularis on acquisition of a complex spatial discrimination task in the rat

The purpose of the present experiment was to determine the effects of lesions of cholinergic neurons originating from the nucleus basalis magnocellularis (NBM), alone or in combination with central serotonin depletion, on learning and memory in rats trained in the Stone 14-unit T-maze--a complex, positively-reinforced spatial discrimination task. Lesion of cholinergic neurons within the NBM was accomplished by bilateral infusion of ibotenic acid. Serotonin depletion was accomplished by the systemic administration of p-chloroamphetamine (PCA). The results show that PCA-induced serotonin depletion enhanced learning. This effect was completely prevented by NBM lesions, despite the fact that NBM lesions alone did not affect the performance of rats in this task. The results of this study support the view that the cholinergic and serotonergic systems may functionally interact in learning and memory processes. The significance of this interaction in the etiology and treatment of dementia should be further investigated.     

Choline acetyltransferase activity associated with cerebral cortical microvessels does not originate in basal forebrain neurons

Cerebral cortical microvessels are innervated by cholinergic fibers that are probably involved in the regulation of local cerebral blood flow and blood-brain barrier permeability. The possibility exists that the cholinergic terminals associated with the cortical microvasculature belong to neurons from the nucleus basalis magnocellularis (NBM), where 70% of the cortical cholinergic projections originate. To test this hypothesis, ibotenic acid (25 nmol) was injected unilaterally in the NBM in rats, and 14 days later, choline acetyltransferase (ChAT) activity was measured in the frontoparietal cortex and in a blood vessel fraction isolated from this region. Lesions of the NBM resulted in a 50% decrease of cortical ChAT as compared with control or sham-operated hemispheres; however, no changes were observed in the ChAT activity associated with cortical microvessels. These results indicate that, in rat cerebral cortex, the perivascular cholinergic terminals do not originate in the basal forebrain.     

Interaction between raphe dorsalis and nucleus basalis magnocellularis in the regulation of high-voltage spindle activity in rat neocortex

In the present study we compared the effects of an ibotenic acid lesion of the nucleus basalis magnocellularis (NBM), a 5,7-dihydroxytryptamine lesion of the raphe dorsalis (RD) and a combined RD and NBM lesion on the regulation of neocortical electrical activity in freely moving rat. NBM lesions (choline acetyltransferase decrease: frontal cortex 29%, occipital cortex 23%) increased both slow wave amplitudes and waking immobility-related high-voltage spindles (HVS). Although RD lesions (serotonin decrease: frontal cortex 67%, occipital cortex 68%) alone did not affect neocortical electrical activity, the lesion aggravated the increase of HVSs induced by an NBM lesion. The present results demonstrate an interaction between the RD and NBM in regulating cortical functions.     

AMPA-induced Lesions of the Basal Forebrain Differentially Affect Cholinergic and Non-cholinergic Neurons: Lesion Assessment Using Quantitative In Situ Hybridization Histochemistry

The direct and transynaptic effects of lesions of the basal forebrain induced by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and ibotenic acid were investigated using quantitative in situ hybridization histochemistry. Probes complementary to the sequences of choline acetyltransferase mRNA, glutamate decarboxylase mRNA and preproenkephalin mRNA were used to assess direct lesion effects within the basal forebrain and probes for postsynaptic M-1 and M-3 muscarinic receptors were used to assess long-term changes in neocortical muscarinic receptor mRNA expression following cholinergic deafferentation. AMPA-induced basal forebrain lesions destroyed significantly more neurons that expressed choline acetyltransferase mRNA than ibotenic acid-induced lesions (90 versus 60%), but significantly fewer neurons which expressed either glutamate decarboxylase or preproenkephalin mRNA (61 versus 83% reduction in glutamate decarboxylase mRNA and 56 versus 79% reduction in preproenkephalin mRNA). AMPA-induced lesions did, however, destroy a significant proportion of the neurons which expressed glutamate decarboxylase and preproenkephalin mRNA (-60%). The neurons spared following AMPA-induced lesions were typically situated dorsolaterally within the dorsal pallidum, although neurons expressing glutamate decarboxylase or preproenkephalin mRNA were frequently observed within the areas of greatest cholinergic neuronal loss, i.e. the region of the nucleus basalis magnocellularis. These findings suggest that there is a population of non-cholinergic pallidal neurons which are insensitive to AMPA but not to ibotenic acid, reflecting a possibly heterogeneous distribution of NMDA and non-NMDA subtypes of glutamate receptors within the rat basal forebrain. AMPA-induced lesions of the basal forebrain were, however, without significant effect on the levels of expression of M-1 and M-3 muscarinic receptor mRNAs in the cerebral neocortex.     

Effect of delayed treatment with nerve growth factor on choline acetyltransferase activity in the cortex of rats with lesions of the nucleus basalis magnocellularis: dose requirements.

Rats received bilateral ibotenic acid-lesions of the nucleus basalis magnocellularis. Starting two weeks after the lesion, cytochrome c (0.3 micrograms/rat/day) or 0.01, 0.1, 1 or 10 micrograms/rat/day human recombinant nerve growth factor (NGF) was infused into the lateral ventricle. The highest dose of NGF reduced the weight gain of the animals. Six weeks, but not two weeks of treatment with 10 micrograms/rat/day NGF increased choline acetyltransferase (ChAT) activity in the frontal cortex, parietal cortex and hippocampus, predominantly on the side of the ventricular cannula. The 1 microgram/rat/day dose only increased ChAT activity in the frontal cortex on the infused side. Six weeks of treatment with 10 micrograms/rat/day NGF increased the size, but not the number of NGF-receptor-immunoreactive neurons in the nucleus basalis. This treatment did not affect the levels of dopamine, norepinephrine and serotonin in any of the brain regions studied. These data suggest that prolonged treatment with relatively high doses of NGF is necessary to increase ChAT activity in cortical regions of nucleus basalis-lesioned rats. This treatment will also increase ChAT activity in the intact septohippocampal system, but does not affect the levels of several non-cholinergic neurotransmitters.     

Lack of recovery of cortical cholinergic function following quinolinic or ibotenic acid injections into the nucleus basalis magnocellularis in rats

Cortical cholinergic markers fail to recover following injection of quinolinic or ibotenic acid into the rat nucleus basalis magnocellularis.     

Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats

Summary A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 g, twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained.Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.