The primate nucleus basalis of Meynert: neuronal activity related to a visuomotor tracking task

Summary The activity of neurons in the nucleus basalis of Meynert (nbM), both the compact (nbMc) and interstitial (nbMi) components, has been examined in monkeys trained to perform a visuomotor step-tracking task. This study was carried out in the same animals and with the same task used to examine neuronal activity in the external and internal segments of globus pallidus (GPe and GPi) and ventral pallidum (VP). The presumed interstitial cells that are located within the laminae surrounding GPe and GPi and identified physiologically by their similarity with nbMc neurons, are referred to as border cells. A major finding of this study is that a large proportion of nbMc and border cells were active in relation to either the step-tracking movements or to load application. Moreover, a high proportion of the responses of border neurons were differential for opposite directions of load and movement. The percentages of directionally specific border and nbMc neurons were considerably less than for GP, with border neurons having more directionally specific responses than nbMc neurons. The similarity between border and GP neuronal properties in this task suggests that both may receive similar sensorimotor afferent input. In the compact portion of nbM, nonspecific neuronal responses following each behavioral event in the paradigm were common. These responses appeared to have been modified by and may have been contingent upon association with reinforcement.This work was supported by grants from the U.S. Public Health Service (NIH NS15417 and NIH NS20471)     

Well-maintained responses of acetylcholine release and blood flow in the cerebral cortex to focal electrical stimulation of the nucleus basalis of Meynert in aged rats

Responses of extracellular acetylcholine (ACh) release and blood flow in the cerebral cortex in the parietal lobe following focal electrical stimulation of the nucleus basalis of Meynert (NBM) ipsilateral to the parietal cortex were compared in healthy adult (6–8 months) and aged (27–28 months) Fischer-344 rats anesthetized with halothane. The focal electrical stimulation of the NBM produced an increase in the ACh release and blood flow in the parietal cortex in both the adult and aged rats. The increased responses of ACh and blood flow observed in the healthy, adult rats were well maintained in the aged rats.     

P300-like potential disappears in rabbits with lesions in the nucleus basalis of Meynert

 The nucleus basalis of Meynert (nbM, substantia innominata) in the basal forebrain provides a single major source of cholinergic innervation for the entire cerebral cortex. We tested the effects of nbM lesions on rabbit P300-like potentials. The P300-like event-related potential (ERP) was recorded in 14 female adult white rabbits using a conventional auditory oddball paradigm. The probability of occurrence for the 2-kHz and 1-kHz stimulus tones was 90% (frequent) and 10% (rare), respectively. The nbM was destroyed bilaterally in seven rabbits referred to as the nbM (+) group. In the other seven rabbits [nbM (–) group], putamen nuclei (n=6) or amygdaloid nuclei (n=1) were destroyed bilaterally. The evoked responses were recorded before and 1 week after the destruction. In the nbM (+) group, P300 amplitude to rare stimuli significantly decreased after the lesion. In the nbM (–) group, no component of ERPs showed changes after the lesions. These results indicate that the nbM might be involved in the generation of the rabbit P300. Received: 10 February 1996 / Accepted: 30 September 1996     

Nucleus basalis Meynert neurons contain the vitamin D-induced calcium-binding protein (Calbindin-D 28k)

Summary The neurons of the monkey basal nucleus of Meynert are shown to contain a protein indistinguishable from the chicken intestinal 28kd vitamin D-dependent calcium-binding protein (Calbindin-D 28k; CBP). CBP is thought to shuttle and buffer Ca⁺⁺-ions, thus regulating the intracellular calcium distribution and concentration. Our observation may engender interest in searching for the role of Vitamin D-metabolites, the CBP and calcium-ions in the physiology and pathology of nucleus basalis Meynert neurons.Dedicated to Dr. Ennio Rossetti, Ambri, on occasion of his 66^th birthday     

Microanatomical and electrophysiological changes of the rat dentate gyrus caused by lesions of the nucleus basalis magnocellularis

The effect of unilateral or bilateral lesions of the nucleus basalis magnocellularis (NBM) on the dentate gyrus of the hippocampus were assessed using microanatomical and electrophysiological techniques. NBM is the main cholinergic basal forebrain nucleus that supplies the fronto-parietal cortex. Lesions were induced using the neurotoxin ibotenic acid or a radio-frequency system and did not affect glutamic acid decarboxylase activity both in the frontal cortex and in the hippocampus. At 4 weeks after lesioning, a loss of choline acetyltransferase (ChAT) activity and of ChAT-immunoreactive fibres was observed in the frontal cortex but not in the hippocampus and no changes in the density of granule neurons of the dentate gyrus or in the hippocampal long-term potentiation (LTP) were noticeable. At 8 weeks after lesioning the loss of both ChAT activity and of ChAT-immunoreactive fibres persisted in the frontal cortex of NBM-lesioned rats. Moreover, at this time a significant decrease in the density of granule neurons in the dentate gyrus accompanied by a reduced probability of dentate LTP induction were observed in both ibotenic acid- and radio-frequency-lesioned rats. These findings have shown that although NBM does not send direct cholinergic projections to the hippocampus, lesions of this cholinergic nucleus are accompanied by delayed neurodegenerative changes involving the dentate gyrus. This suggests the occurrence of indirect connections between NBM and the hippocampus, the functional relevance of which should be explored.     

Age-related alterations in responses of the nucleus basalis magnocellularis neurons to frontal cortex stimulation in rats

The present study investigated the age-related alterations in responses of the nucleus basalis magnocellularis (nbM) neurons to frontal cortex (FCX) stimulation. Single unit extracellular recording from the nbM neurons were obtained with glass micropipettes in urethane-anesthetized rats. A total of 137 units were located within the nbM in the three age groups (young, 3 months; adult, 12 months; old, 24 months). FCX stimulation elicited responses in 91% of the 137 neurons. Most of them were excited. The frequency of occurrence of excitatory responses in the nbM neurons was decreased with aging. The thresholds and latencies of excitatory responses evoked by FCX stimulation were increased in old rats. The mean peak-firing rate of exciting phase was gradually reduced with aging. These findings indicate that there might be some functional changes in the nbM neurons with aging.     

Correlation between cortical plaque count and neuronal loss in the nucleus basalis in Alzheimer's disease

In order to substantiate the hypothesis of a cholinergic matrix for neuritic plaque formation in Alzheimer's disease (AD), the relationship between the loss of cholinergic neurons in the basal forebrain and formation of neuritic plaques in the cerebral cortex was studied in 5 cases of neuropathologically verified AD. Quantitative evaluation of the number of neuritic plaques in the cerebral cortex as calculated from 6 areas showed a strong correlation with the loss of neurons in the nucleus basalis of Meynert (NbM). This finding indicates that changes in cortical cholinergic innervation which arise from the neurons of the NbM are an important feature in the pathogenesis of neuritic plaques.     

慢性酒精中毒大鼠学习记忆及Meynert基底核胆碱能神经元的变化

目的研究酒精致大鼠学习记忆障碍与Meynert基底核(NBM)胆碱能神经元变化的关系。方法将24只雄性Wister大鼠随机均分成对照组和酒精中毒组,酒精中毒组大鼠隔日胃内注入含酒精(2.5 g/kg)的蒸馏水2 ml共90d,对照组则注入不含酒精的蒸馏水2 ml。然后采用Morris水迷宫和免疫组织化学技术,分析大鼠Meynert基底核胆碱能神经元、额叶皮层星形胶质细胞数的变化和学习记忆能力的关系。结果酒精中毒组大鼠Morris水迷宫潜伏期明显延长,Meynert基底核胆碱能神经元数目明显减少,额叶皮层星形胶质细胞数目反应性增生。结论酒精致大鼠学习记忆能力障碍与Meynert基底核胆碱能神经元减少有关。     

Cholinergic stimulation of the nucleus basalis of Meynert and reticular thalamic nucleus affects spike-and-wave discharges in WAG/Rij rats

The role of the cholinergic innervated nucleus basalis of Meynert (NB) and reticular thalamic nucleus (RT) in the generation or modulation of spontaneously occurring spike-and-wave discharges (SWDs) was investigated in the WAG/Rij rat model of absence epilepsy. The cholinergic agonist carbachol and the muscarinic antagonist scopolamine were injected in the NB and RT in the doses of 0.55 and 5.5 nmol while the EEG was recorded. Carbachol injected in the NB decreased the number and the mean duration of SWDs. Scopolamine alone had no influence on SWDs, but could antagonize the effects of carbachol if administered simultaneously in NB. Injections of carbachol in the RT inhibited the occurrence of SWDs, but did not affect the mean duration. Scopolamine administered in the RT had no influence on seizure activity. It is concluded that cholinergic stimulation of the NB or the RT inhibits the cortical synchronous activity characterizing SWDs.     

Modulatory action of cholinergic drugs on N-methyl-d-aspartate response in dissociated rat nucleus basalis of Meynert neurons

The effect of cholinergic drugs on N-methyl-d-aspartate (NMDA)-activated responses in neurons dissociated freshly from the nucleus basalis of Meynert (nBM) of immature and mature rats were investigated with the whole-cell patch-clamp technique. The NMDA (10⁻⁴ M)-evoked inward current (I_NMDA) consisted of transient peak and successive steady-state components. In mature neurons, the peak component was suppressed by pretreatment with acetylcholine (ACh, 10⁻¹²–10⁻⁵ M) but facilitated by higher concentrations (> 10⁻⁵ M). Regardless of the concentration, ACh had no effect on I_NMDA of immature neurons. The results suggest that ACh behaves as either inhibitory or excitatory modulator of glutaminergic transmission in nBM neurons of adult mammals depending on ACh concentration.     

Acetylcholine receptors in dissociated nucleus basalis of Meynert neurons of the rat

Electrical and pharmacological properties of acetylcholine (ACh)-induced currents in neurons dissociated from the nucleus basalis of Meynert (nBM) of immature (2-week-old) rats were investigated with the whole-cell mode of the patch-clamp technique. At a holding potential (V_H) of −50 mV, ACh (10⁻⁴M) evoked a transient inward current mimicked by nicotine (I_nACh), followed by a sustained outward current mimicked by carbamylcholine (I_mACh). The K_D values were 1.2 × 10⁻⁴ M for I_nACh) and 8.7 × 10⁻⁷ M for I_mACh. The reversal potenial of I_mACh was close to E_K. The I_mACh was determined to be elicited via the M₂ muscarinic receptor, based on the differences in sensitivity to muscarinic antagonists such as pirenzepine and AF-DX-116.     

Monkey nucleus basalis is enriched with choline acetyltransferase

The nucleus basalis of Meynert, which projects directly and diffusely to the cerebral cortex, was histologically identified in Nissl- and acetylcholinesterase-stained sections of the forebrain of Rhesus monkeys. Adjacent 1 mm thick sections were microdissected in 2 mm² blocks and assayed for choline acetyltransferase activity. The results demonstrate a marked enrichment of choline acetyltransferase activity in samples containing the nucleus basalis of Meynert and strongly suggest that this nucleus is a cholinergic nucleus in the primate.     

Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical ³H-acetylcholine (³H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of ³H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of ³H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. Th results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimer's type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm. The cortical slice preparation from quinolinic acid-treated animals showing impairment of ³H-ACh release, may be useful in assessing the action of drugs designed to improve cholinergic function.     

Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical ³H-acetylcholine (³H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of ³H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of ³H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. Th results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimer's type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm. The cortical slice preparation from quinolinic acid-treated animals showing impairment of ³H-ACh release, may be useful in assessing the action of drugs designed to improve cholinergic function.     

Muscarinic modulation of acetylcholine release from slices of guinea pig nucleus basalis magnocellularis

Spontaneous and electrically evoked endogenous acetylcholine release and [³H]-choline efflux from slices of guinea pig nucleus basalis magnocellularis (nbM) were studied. Tetrodotoxin reduced the spontaneous endogenous release by 55%, while the Ca²⁺-free medium reduced it by about 30%. Evoked [³H]-choline efflux was Na⁺ and Ca²⁺ dependent and frequency related. Physostigmine, 30 μM, nearly halved the stimulation-evoked efflux; atropine, 0.15 μM, not only antagonized, but even reversed this effect into facilitation. Pirenzepine, 1 μM, and AFDX 116, 1 μM, were less effective than atropine, and reversed the inhibitory effect of physostigmine only when applied together. 4-DAMP, 0.01 μM, was ineffective. These findings indicate that acetylcholine release in guinea pig nbM slices is inhibited by the cooperation of muscarinic autoreceptors, possibly belonging to the M₁ and M₂ subclasses.     

Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer's disease

In order to substantiate the hypothesis of a cholinergic pathogenesis of neuritic plaques in Alzheimer's disease the relationship between the loss of cholinergic neurons in six subdivisions of the nucleus basalis of Meynert and density of neuritic plaques in five neocortical target areas and hippocampus was studied in five cases with Alzheimer's disease. Distribution of plaques in different cortical areas as well as degeneration pattern of neurons within the subpopulations of the nucleus basalis were markedly different in the cases of Alzheimer's disease. Quantitative evaluation of the number of neuritic plaques in the five cortical areas revealed a strong correlation with the loss of neurons in those subpopulations of the nucleus basalis which give rise to the cholinergic innervation of the affected cortical areas. The nonlinearity of this correlation may reflect two different modes of plaque formation. Either plaque formation is a self-perpetuating process with an increasing rate depending on the number of plaques already formed or additional mechanisms, with an increasing rate of influence during plaque formation are induced. The shape of the regression function is different for the various cortical regions and their corresponding subpopulations of the nucleus basalis suggesting a different dependency of neuritic plaque formation on the neuronal loss in the nucleus basalis. This might reflect a different density of cholinergic fibers within these areas, a different degree of collateralization of the fibers or other factors not yet known. The findings indicate that degeneration of cortical cholinergic afferents from the neurons of the nucleus basalis is an important feature in the pathogenesis of neuritic plaques.     

Stability of numbers but not size of mouse forebrain cholinergic neurons to 53 months

In normal mammalian aging there is a reduction of cholinergic markers in a variety of regions. To determine whether this reduction is related to reduced numbers of basal forebrain cholinergic neurons, we counted the number and measured the sizes of the magnocellular acetylcholinesterase-positive neurons in this region of 7, 15, and 53-month-old C57B1/6NNIA mice. Data were collected from coded slides containing the medial septum, nucleus of the diagonal band, magnocellular preoptic nucleus, and nucleus basalis magnocellularis. There was no decline in numbers of basal forebrain acetylcholinesterasepositive neurons in any of the regions studied. However, cell sizes showed a progressive age-related decline which was greatest in the nucleus basalis magnocellularis.     

Physiologic effects of nucleus basalis magnocellularis stimulation on rat barrel cortex neurons

Cholinergic neurons in the nucleus basalis magnocellularis (NBM) project to the cerebral cortex and are thought to play an important role in learning and memory, and other cognitive functions. In the present study, we examined the effects of NBM stimulation on the response properties of individual cortical neurons in layer V of the rat somatosensory cortex. Seventy-three neurons were studied before and after a brief electrical stimulation of NBM. Transient changes in spontaneous activity were observed in 60% of the cells, and in most cases this background activity decreased. Recordings lasting more than 1 h stimulation were obtained from 56 cells. Because some NBM stimulation-induced effects lasted several hours, neurons were evaluated in two groups, NBM1 and NBM2. NBM1 neurons were those exposed to either the first NBM stimulation of the day or an NBM restimulation following a more than 5 h stimulation-free period. Neurons exposed to NBM restimulation following a stimulation free interval of less than 5 h were classified as NBM2. Sixty-nine percent of the 32 NBM1 neurons displayed marked decreases in spontaneous activity and/or increases in the response evoked by deflecting a contralateral facial vibrissa. NBM1 stimulation caused some units to respond to previously minimally effective whisker stimuli. Stimulation effects often lasted several hours. By contrast, long-lasting changes were observed in only 25% of the 24 NBM2 neurons, and the only consistent effect was on spontaneous, not stimulus-evoked, activity. Systemic injection of atropine blocked NBM stimulation-induced changes in spontaneous and stimulus-evoked activities. Control neurons, studied without NBM stimulation, failed to display consistent alterations in their response properties during the course of 1 h or more. Results demonstrate that NBM activation produces long-lasting, cholinergically mediated alterations in the response properties of somatosensory cortical neurons. Effects were complex, being influenced by factors such as the time interval between successive stimulations during an experiment. The complexity of these NBM mediated effects should be considered when designing therapies for neurodegenerative disorders characterized by loss of NBM neurons.     

The basal nucleus of Meynert in patients with progressive supranuclear palsy

Unilateral inoculation of hamster substantia nigra (SN) with scrapie agent led to an early decrease in tyrosine hydroxylase (TH) activity in the corresponding striatum, which was detectable by the 5th day. This decrease was accompanied by an increase in glutamate decarboxylase (GAD) observed on the 20th day. Local phenomena related to administration of the agent were investigated by intrastriatal inoculation followed by local measurement of TH, GAD and choline acetyltransferase (ChAT) activities. A rise in GAD activity was observed 20 days later. The decrease in TH activity which occurred 5 days after inoculation of the substantia nigra with scrapie agent constitutes an extremely early indication in hamsters of the slow pathological processes at work: at clinical and behavioural levels, these can be detected at best only 80 days after the intracerebral inoculation.     

Desynchronized (REM) sleep inhibition induced by carbachol microinjections into the nucleus basalis of Meynert is mediated by the glutamatergic system

The aim of this paper was to study the effects of microinjections of carbachol, a mixed cholinergic agonist, into the nucleus basalis of Meynert (NBM) of rats on the wake-sleep cycle. Carbachol (2.74 nmol) was able to increase wakefulness (W) and decrease desynchronized sleep (DS). To verify the hypothesis that the effects of carbachol are at least partially mediated by the glutamatergic system, the NMDA antagonist 2-amino-5-phosphonopentanoic acid and the non-NMDA antagonist d--glutamylaminomethanesulfonic acid were injected into the NBM before carbachol. Pretreatment with these glutamate receptor antagonists counteracted the effect of carbachol on DS. The effect of carbachol on W was not modified by the pretreatment with the glutamate receptor antagonists. This is the first study showing that carbachol injected into the NBM increases W and decreases spontaneous DS in the rat. Moreover, our results tend to indicate that the decrease in DS following the injection of carbachol into the NBM is related to the release of endogenous glutamate.