Lesions Of Nucleus Basalis Magnocellularis Research Articles

Electrolytic and ibotenic acid lesions of the nucleus basalis magnocellularis interrupt long-term retention, but not acquisition of two-way active avoidance, in rats.

Previous experiments on two-way active avoidance have shown conflicting results after nucleus basalis magnocellularis lesion: disrupting effects with electrolytic lesions and facilitative effects with excitotoxic lesions. To resolve this issue, in this experiment, Wistar rats received pre-training bilateral electrolytic or ibotenic acid lesions and were trained in a massed two-way active avoidance conditioning. In order to test the long-term retention of the learned response, one additional session was conducted 10 days after the acquisition. Results showed that whereas electrolytic lesions did not affect the acquisition, ibotenic acid lesions enhanced it. Retention of active avoidance response was impaired by both electrolytic and ibotenic lesions of the NBM. These results suggest a role of the NBM in the memory consolidation and/or retrieval of two-way active avoidance.

NADPH‐diaphorase activity in the frontal cortex of NBM‐lesioned rats treated with verapamil

AbstractThe effect of the calcium antagonist verapamil on NADPH‐diaphorase activity was studied in the frontal cortex of rats with lesioned nucleus basalis magnocellularis (NBM). Treatment with verapamil (5 mg/kg/12h ip) started 24 h after NBM lesions and lasted 8 days. Animals were sacrificed on day 21 after NBM‐lesions. There were no significant differences between control, saline‐ and verapamil‐treated NBM‐lesioned rats in the total number of neurons expressing NADPH‐diaphorase. However, the number of neurons which show loss of enzymatic reaction in their processes was significantly higher in saline‐treated NBM‐lesioned rats. This may relate to incipient neurodegeneration in these neurons. The obtained reactive decrease of NADPH‐diaphorase staining was abolished by verapamil treatment, which suggests a significant neuroprotective effect of this calcium antagonist.

Effect of vagal autotransplantation on quantitative [ 3H]-vesamicol binding image in rats with unilateral lesions of nucleus basalis magnocellularis

It is considered that nodosal ganglion grafting improves learning and memory disorder in nucleus basalis magnocellularis lesioned rats, and that [ 3H]-vesamicol is one of the mapping agents for presynaptic cholinergic neurons. Quantitative autoradiography was performed using high sensitive imaging plate system to evaluate the effect of neurotransplantation on [ 3H]-vesamicol binding. The affected-side to unaffected-side ratio of [ 3H]-vesamicol in the nucleus basalis magnocellularis lesioned group was significantly lower than that in the sham-operated group at 1, 2 and 4 weeks ( P<0.01). In the transplanted group, the ratio was significantly higher than that in the untreated group at 4 weeks ( P<0.05). [ 3H]-vesamicol binding is one of the most sensitive indicators of nucleus basalis magnocellularis lesions and the effect of the nodosal ganglion grafting.

Effects of Antimuscarinic Drugs on Both Urinary Frequency and Cognitive Impairment in Conscious, Nonrestrained Rats

Recent studies indicate a risk of learning and memory impairments when patients with senile dementia are treated with antimuscarinic drugs. In this study, we compared the effectiveness of propiverine hydrochloride (propiverine) and oxybutynin chloride (oxybutynin) on the increased urinary frequency and cognitive impairment induced by nucleus basalis magnocellularis (nBM) lesioning in conscious and non-restrained rats. For examination of bladder function, nBM-lesioned rats were given total parenteral nutrition regimens for 8 days. Propiverine administered orally at 0.3, 3 and 30 mg /kg on the postoperative day 7 significantly lessened the increase in the frequency of voiding caused by the nBM lesion, whereas oxybuty-nin administration did not show any improvement at 0.1 or 1 mg/kg but did so at 10 mg /kg. To examine the memory impairment, we trained nBM-lesioned rats in an 8-arm radial maze task for 20 days and then evaluated the effectiveness of oral drug administration on 19th and 20th radial maze performance. The higher rate of errors caused by nBM lesioning was significantly aggravated by oxybutynin at 30 and 100 mg/kg. Propiverine showed slight aggravation of errors, but with no statistical significance at any dose, 30, 100 or 300 mg/kg. These results suggest that propiverine has comparatively less effect on the cognitive impairment than oxybutynin.

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity.

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity.

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity.

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen in control rats but not in nBM-lesioned rats in both the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in DMTS, indicating no impairment after nBM lesions. There were no group differences in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impairment after nBM lesions.

Differential participation of the NBM in the acquisition and retrieval of conditioned taste aversion and Morris water maze

Deficits in both learning and memory after lesions of the cholinergic basal forebrain, in particular the nucleus basalis magnocellularis (NBM), have been widely reported. However, the participation of the cholinergic system in either acquisition or retrieval of memory process is still unclear. In this study, we tested the possibility that excitotoxic lesions of the NBM affect either acquisition or retrieval of two tasks. In the first experiment, animals were trained for two conditioned taste aversion tasks using different flavors, saccharine and saline. The acquisition of the first task was before NBM lesions (to test retrieval) and the acquisition of the second task was after the lesions (to test acquisition). Accordingly, in the first part of the second experiment, animals were trained in the Morris water maze (MWM), lesioned and finally tested. In the final part of this experiment, another set of animals was lesioned, then trained in the MWM and finally tested. All animals were able to retrieve conditioned taste aversion (CTA) and MWM when learned before NBM lesions; however, lesions disrupted the acquisition of CTA and MWM. The results suggest that the NBM and cholinergic system may play an important role in acquisition but not during retrieval of aversive memories.

Immune Responses in Nucleus Basalis Magnocellularis-Lesioned Rats Exposed to Chronic Isolation Stress

The present study was designed to establish the influence of chronic social isolation stress on humoral and cellular immunity in nucleus basalis magnocellularis (NBM)-lesioned rats. Therefore. ten days after bilateral electrolytic lesions of NBM, adult male Wistar rats were immunized with bovine serum albumin in complete Freund' adjuvant (BSA-CFA) and placed individually or in groups of five rats during 21 days. On days 10 and 21 after immunization, the Arthus and delayed hypersensitivity skin reactions to BSA as well as anti-BSA antibody production were determined. On day 10, the diameter and intensity of delayed hypersensitivity skin reaction to BSA were significantly higher in social-isolated rats in comparison with the group-reared ones. On day 21, the diameter and intensity of the Arthus skin reaction were significantly higher in social-isolated rats compared to group-reared rats. Between days 10 and 21, the diameter and intensity of the Arthus skin reaction significantly increased in social-isolated rats, while the diameter of delayed hypersensitivity skin reaction significantly decreased. In contrast to social-isolated rats, there were no significant differences in Arthus and delayed hypersensitivity skin reactions in group-reared rats, between days 10 and 21. Also there were no significant differences in the production of anti-BSA antibody between social-isolated and group-reared rats. The relative spleen weight was significantly lower in social-isolated rats. These data suggest that chronic isolation stress modify humoral and cellular immunity in NBM-lesioned rats.

Effect of acute verapamil treatment on cold restraint-induced gastric lesions in rats with lesioned nucleus basalis magnocellularis

Our recent studies suggested that there were no differences in the number and type of cold restraint-induced gastric lesions (petechiae and erosions) between control and nucleus basalis magnocellularis (NBM)-lesioned rats. Having in mind that calcium antagonists can prevent the development of gastric stress ulcer in control rats, the aim of the present study was directed to compare the effect of verapamil in the prevention of cold restraint-induced gastric lesions in control and NBM-lesioned rats. Therefore, 30 min before the stress, control (intact control and sham-operated) rats as well as rats with bilateral electrolytic lesions of NBM were treated with saline (1 ml/kg s.c.) or verapamil (1.0, 2.5, 5.0 and 10.0 mg/kg s.c.) and exposed to cold restraint for 2 hr. Verapamil, in doses of 5.0 and 10.0 mg/kg, significantly decreased the number and length of gastric erosions (p < 0.05) in control rats, while in NBM-lesioned rats, the same doses of verapamil significantly decreased the number of gastric petechiae (p < 0.01). Since the antiulcer treatment with verapamil express different effects in the prevention of the two types of gastric lesions in control and NBM-lesioned rats, it can be concluded that in NBM-lesioned rats there may exist an alteration of the mechanisms involved in stress-induced gastric petechiae and erosions.

Involvement of Cholinergic and GABAergic Systems in the Reversal of Memory Disruption by NS-105, a Cognition Enhancer

The effects of (+)-5-oxo- d-prolinepiperidinamide monohydrate (NS-105) on the scopolamine-, electrolytic lesion of the nucleus basalis magnocellularis (NBM)-, AF64A-, baclofen-, cerebral ischemia- and electroconvulsive shock (ECS)-induced memory disruption in the passive avoidance response or radial arm maze tasks were investigated in rats. The effects of NS-105 were compared with those of aniracetam, bifemelane, idebenone, and indeloxazine in two tasks of the passive avoidance response. Furthermore, effects of NS-105 on in vivo release of acetylcholine (ACh) in the cerebral cortex, high-affinity choline uptake (HACU) of the cerebral cortex in rats with lesion of NBM, HACU of the hippocampus in rats treated with pentobarbital and activity of choline acetyltransferase (ChAT) of the cerebral cortex in rats with lesion of NBM were examined. NS-105 showed antiamnestic actions in a variety of animal models of cholinergic dysfunction employed in this study. Aniracetam improved memory disruption caused by scopolamine, but bifemelane, idebenone, and indeloxazine did not. NS-105 (10 mg/kg) showed the increase of ACh release from the cerebral cortex and the enhancement of HACU both in the cerebral cortex and hippocampus, but showed no change in activity of ChAT. NS-105 also reversed memory disruption induced by baclofen, a potent GABA B receptor agonist, but all of reference drugs did not. These results suggest that antiamnestic action of NS-105 is due to the facilitation of cholinergic neuronal activity and the suppression of GABA B receptor-mediated responses.

The effect of sequential lesioning in the basal forebrain on cerebral cortical glucose metabolism in rats. An animal positron emission tomography study

We studied the effect of the cortical projection from the basal forebrain on the cerebral cortical metabolism using positron emission tomography (PET) with [ 18F ] fluorodeoxyglucose. Unilateral damage of the nucleus basalis magnocellularis (NBM) did not cause a permanent reduction of cortical metabolism: recovery was observed 4 weeks after the operation. Destruction of the contralateral side after recovery from unilateral damage produced persistent bilateral suppression of glucose metabolism, with partial recovery. We speculate that recovery from the unilateral NBM lesions is partly ascribable to the cholinergic projection from the contralateral NBM, and partly due to non-cholinergic systems, and conclude that bilateral damage might be responsible for persistent cortical glucose metabolism suppression.

Selective lesion of the cholinergic basal forebrain causes a loss of cortical neuropeptide Y and somatostatin neurons

Degeneration of the cholinergic basal forebrain (CBF) and changes in cortical neuropeptide levels have been reported in Alzheimer's disease. In the present study, we sought to determine if a selective cholinergic lesion of nucleus basalis magnocellularis (Nbm) could affect the number and distribution of neuropeptide Y (NPY) and somatostatin (SS) immunoreactive neurons in the frontoparietal and occipital cortices of rats. Brain sections were evaluated at survival times of 1, 2, 4, 8, 12, 24, 48, 78 and 100 weeks after intraventricular injection of 192-saporin, an immunotoxin directed at the low affinity neurotrophin receptor (p75 NGFr), that selectively destroys the CBF. Following the immunotoxin lesion of the Nbm, the number of NPY-labeled neurons decreased 33% in the frontoparietal cortex and 60% in the occipital cortex compared to age-matched normal controls at most survival time points. A significant loss of SS-labeled neurons in both cortical regions was seen 12 weeks after 192-saporin injection with no further change up to 100-week survival time. The effect of age on neuropeptidergic populations was evaluated in normal control rats. The number of NPY and SS immunoreactive neurons in aged rats (21–26 months) decreased by 42% in the frontoparietal cortex and 27% in the occipital cortex when compared with young (3–6 months) and middle-age (9–14 months) rats. When both non-lesioned and lesioned animals with different ages were pooled for linear regression, a significant correlation was found between the number of cortical NPY- and SS-labeled neurons and cortical acetylcholinesterase (AChE) histochemical staining intensity. These findings indicate that: (1) cholinergic denervation of the Nbm is associated with an irreversible loss of neocortical NPY and SS immunoreactive neurons analogous to that observed in Alzheimer's disease and aging; (2) the degree of the loss of cortical NPY and SS immunoreactive neurons seems to be related to the extent of the reduction of cortical AChE intensity in both toxin-injected and normal aged rats. These findings may reflect a trophic dependence of NPY and SS neurons on cortical cholinergic input.

Chronic sparing of delayed alternation performance and choline acetyltransferase activity by CEP-1347/KT-7515 in rats with lesions of nucleus basalis magnocellularis

Peripheral injection of the indolocarbazole CEP-1347/KT-7515 into rats that have sustained ibotenic acid lesions of the nucleus basalis magnocellularis has been shown to prevent the loss of cortically-projecting neurons in that basal forebrain region. The present study tested whether this neuroprotective activity would lead to chronic sparing of a behaviour known to be impaired by that lesion, as well as to chronic maintenance of cholinergic activity in cortical target regions of the nucleus basalis. CEP-1347/KT-7515 was injected into adult rats that had sustained bilateral ibotenic acid lesions of the nucleus basalis magnocellularis; the first injection occurred 18–24 h after lesioning, with subsequent injections of CEP-1347/KT-7515 occurring every other day over 12 days. One day following the last injection the animals were tested for retention of a previously-learned delayed alternation task. Animals that received CEP-1347/KT-7515 committed significantly fewer errors than lesioned animals receiving vehicle. These same animals were tested again eight to 10 weeks later (which was 10–12 weeks post-dosing), without receiving further drug or behaviour training during the test–retest interval. The animals that had received CEP-1347/KT-7515 continued to commit significantly fewer errors than vehicle animals. Furthermore their performance at this time point was indistinguishable from normal controls. Analysis of errors showed that CEP-1347/KT-7515 prevented a lesion-induced increase in perseverative errors, suggesting the drug improved attention in the lesioned animals. Choline acetyltransferase activity in the frontal cortex of the behaviourally tested animals that received CEP-1347/KT-7515 three months previously showed a significant 40% recovery of the lesion-induced loss seen in the vehicle animals. These results demonstrate that treatment with CEP-1347/KT-7515 over 12 days following excitotoxic damage to the nucleus basalis magnocellularis produces long-term sparing of an attention-demanding behaviour.

Short-term and complete reversal of NGF effects in rats with lesions of the nucleus basalis magnocellularis

Rats received bilateral quisqualic acid (QUIS) lesions of the nucleus basalis magnocellularis (NBM). Three weeks after lesioning, osmotic minipumps were implanted that released recombinant human nerve growth factor (NGF) or cytochrome c at a dosage of 5.0 μg rat −1 day −1 through intracerebroventricular (ICV) cannulas for 7 weeks. One quarter of the rats were sacrificed at the end of the treatment, while the rest of the animals were sacrificed 2, 8, and 12 weeks after termination of NGF/cc treatment. ICV administration of NGF transiently reduced weight gain. NGF maximally increased choline acetyltransferase (ChAT) activity in all cortical regions, the olfactory bulb and the hippocampus between 20% and 56% at the end of the treatment. This increase linearly declined and completely regressed during the 12-week withdrawal period both in regions affected and unaffected by the lesion. Administration of NGF induced a short-lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the nucleus basalis magnocellularis (NBM), the horizontal limb of the diagonal band of Broca, and the medial septum (MS). In contrast, QUIS-induced NBM lesions permanently reduced ChAT activity most pronounced in the frontal and parietal cortex up to 45%. Furthermore, QUIS induced a permanent loss of p75NGFr-immunoreactive neurons within the NBM and the DB without affecting the MS. These findings suggest that degenerating cholinergic neurons of the NBM and HDB do not spontaneously recover after lesioning and may require continuous neurotrophic support by NGF to ameliorate cholinergic hypofunctioning.

Basal forebrain cholinergic lesions enhance conditioned approach responses to stimuli predictive of food.

This study examined the effects of lesions to different neuronal populations within the basal forebrain on reward-related learning. Rats received bilateral alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) or quinolinate lesions that preferentially destroy the cholinergic nucleus basalis magnocellularis (NBM) or noncholinergic ventral pallidal neurons, respectively. Both lesions enhanced conditioned approach responses to stimuli predictive of food but did not increase the locomotor stimulating effect of d-amphetamine. Although both lesions disrupted the discriminative control over behavior by a conditioned stimulus, they did not impair the subsequent acquisition of instrumental responding with conditioned reinforcement (CR). Indeed, both lesions were associated with an increased responding with CR following intra-accumbens infusions of d-amphetamine (0, 1, 3, 10, and 20 microg). Quinolinate lesions also increased responses on an inactive control lever. Neither lesion altered consummatory responses to food or sucrose. Results suggest that NBM lesions may disrupt the balance between cortical and subcortical dopamine levels, and/or produce a deficit in attentional mechanisms that is manifested as increased responding to specific stimuli.

Cold Restraint-Induced Gastric Lesions in Individual-and Group-Stressed rats in an Experimental Model of Alzheimer's Disease

Ten days after bilateral electrolytic lesions of the nucleus basalis magnocellularis (NBM) (an experimental model of Alzheimer's disease), adult male Wistar rats were exposed to cold restraint stress in individual and social condition. Therefore, rats were placed into individual or group restraint boxes (composed of six single boxes) and exposed during 2 hr to the cold (4°C). The results showed that: 1) there were no differences in type and intensity of stress-induced gastric lesions between single-stressed intact control (IC), sham-operated (SO) and NBM-lesioned rats, 2) the incidence, number and length of gastric erosions were significantly higher in group-stressed NBM-lesioned rats than in IC and SO rats, 3) the individual-stressed IC and SO rats have significantly higher incidence, number and length of gastric erosions as well as ulcer index than IC and SO group-stressed rats, and 4) there were no significant differences in intensity and type of acute gastric lesions between single- and group-stressed NBM-lesioned rats. It could be concluded that NBM lesions induce significant changes in social behavior in rats.

Egg phosphatidylcholine combined with vitamin B 12 improved memory impairment following lesioning of nucleus basalis in rats

We investigated the effects of egg phosphatidylcholine (PC) combined with vitamin B 12 on memory in the Morris water maze task, and on choline and acetylcholine (ACh) concentrations in the brain of rats. Animals with nucleus basalis Magnocellularis (NBM) lesion received intragastric administration of egg PC or vitamin B 12, or both for 18 days. Memory acquisition and retention were remarkably impaired in NBM lesioned rats compared with in shamoperated control. NBM lesioned group had lower choline and ACh concentrations than control group in the frontal cortex. High dose of egg PC alone significantly increased choline concentration, but did not change ACh concentration in the frontal cortex. High dose of vitamin B 12 alone did not change choline and ACh concentrations in the brain. Either egg PC or vitamin B 12 did not improve memory acquisition and retention. However, low dose of egg PC combined with vitamin B 12 significantly increased ACh concentration and improved memory acquisition and retention in the NBM lesioned rats. We concluded that egg PC combined with vitamin B 12 improved the memory impairment of NBM lesioned rats through the action on the cholinergic neurons.

Long Latency Event-Related Potentials In Rats: Effects of Nucleus Basalis Magnocellularis Lesions

The effects of AMPA lesions of the nucleus basalis magnocellularis (NBM) on EEG and event-related potentials (ERPs) generated by an auditory discrimination task were examined. The lesions significantly reduced choline acetyl transferase (ChAT) activity in frontal and parietal cortex. NBM lesions produced significantly more errors in the task. Significant increases in EEG spectral power in the fronto-parietal cortex were found, most predominantly in the higher frequencies (8-32 Hz), suggesting increases in arousal in the lesioned animals. Additionally, the lesion resulted in an increase in the area, the standard deviation of the amplitude of the N1 component, as well as instability in the amplitudes of several other ERP components. These results suggest that NBM lesions may impair ability to correctly respond in a discrimination task by a combination of increased arousal and an inability to maintain stable attentional capacity.

Effect of Trasina, an ayurvedic herbal formulation, on experimental models of Alzheimer's disease and central cholinergic markers in rats.

Trasina is a herbal formulation of some Indian medicinal plants classified in Ayurveda, the classic Indian system of medicine, as Medhyarasayanas or drugs reputed to improve memory and intellect. Earlier experimental and clinical investigations have indicated that the formulation has a memory-facilitating action. In this investigation, the effect of Trasina, after subchronic administration for 21 days, was assessed on two rodent models simulating some biochemical features known to be associated with Alzheimer's disease (AD). The models, in rats, included intracerebroventricularly (i.c.v.) administered colchicine (15 micrograms/rat) and lesioning of nucleus basalis magnocellularis (nbm) by ibotenic acid (10 micrograms/rat). Retention of an active avoidance response was used as the memory parameter. In addition, the effect of Trasina was evaluated on i.c.v. colchicine-induced depletion of acetylcholine (ACh) concentrations, reduction in choline acetyltransferase (ChAT) activity, and decrease in muscarinic cholinergic receptor (MCR) binding in rat brain frontal cortex and hippocampus. The behavioral and biochemical investigations were done 7, 14, and 21 days after colchicine or ibotenic acid lesioning. Trasina (200 and 500 mg/kg) was administered orally (p.o.) once daily for 21 days, the first drug administration being given just prior to lesioning. Colchicine and ibotenic acid induced marked retention deficit of active avoidance learning that was attenuated in a dose-dependent manner by Trasina after 14 and 21 days of treatment. Frontal cortical and hippocampal ACh concentrations, ChAT activity and MCR binding was significantly reduced after colchicine treatment. Trasina (200 and 500 mg/kg) reversed these deficits after 14 and 21 days of treatment. The findings indicate that the herbal formulation exerts a significant nootropic effect after subchronic treatment that may be due to reversal of perturbed cholinergic function.

Effects of selective catechol- O-methyltransferase inhibitors on single-trial passive avoidance retention in male rats

The effects of new selective catechol- O-methyltransferase (COMT) inhibitors entacapone (mainly peripheral effect) and tolcapone (acting also in the brain) on normal and impaired cognitive functions were studied in aversively motivated inhibitory avoidance using a single-trial passive avoidance paradigm in young adult rats. Passive avoidance retention latency was shortened by either scopolamine (1.0 mg/kg) or bilateral lesions to nucleus basalis magnocellularis (NBM) caused by infusions of ethylcholine aziridinium (AF64A). Entacapone (30 mg/kg) administered once before training or before the retention test, 24 h after training, prevented the effect of scopolamine but did not alter extinction in these rats. However, entacapone (30 mg/kg) prolonged lag time when given during the extinction process to intact rats after training. Tolcapone administered once before training (10 mg/kg) counteracted the effect of scopolamine. It prolonged retention latency of the intact rats when given after training (10 mg/kg). Tolcapone (3 mg/kg) also prolonged lag time when given during extinction to rats bearing NBM lesions. The effect of scopolamine on extinction and retrieval was not prevented by tolcapone. Only entacapone improved memory storage. Collectively, the present results indicate that COMT inhibitors prolong retention latencies in a single-trial passive avoidance test assessed at several memory phases.