Effects of atipamezole and tetrahydroaminoacridine on nucleus basalis lesion-induced EEG changes.

In the present study the effect of combined anticholinesterase [tetrahydroaminoacridine (THA)] and alpha2-antagonist (antipamezole) treatment were evaluated on nucleus basalis (NB, quisqualic acid) lesion-induced EEG activity changes. THA (1, 3 and 6 mg/kg; an anticholinesterase) and atipamezole (Ati: 3 and 10 mg/kg; an alpha2-antagonist) suppressed dose-dependently NB lesion-induced high-voltage spindle activity and increase in slow/fast activity ratio. A combination of THA (3 mg/kg) and Ati (3 or 10 mg/kg) more effectively suppressed NB lesion-induced HVS activity than either of the drugs alone did. The present results suggest that alpha2-noradrenergic and NB cholinergic systems interact in the regulation of slow wave and HVS activity and that combined stimulation of these systems more effectively stabilize NB lesion-induced EEG changes.     

Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat

The nucleus basalis magnocellularis (NBM) contains cholinergic neurons that project to the neocortex and is densely innervated by excitatory amino acid-containing terminals. A dysfunction in the balance of excitatory inputs or an alteration in the sensitivity of NBM cells to glutamate may underlie the selective vulnerability to aging. Some large NBM neurons contain neurokinin B (NKB) mRNA. The present study investigated whether α-2-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) orN-methyl-d-aspartate (NMDA) differentially destroy NKB-containing, NKB-receptive, or cholinergic NBM cells, and whether this vulnerability is altered by aging. Injections of AMPA or NMDA significantly decreased neocortical ChAT activity, as compared to control levels, across all three age groups, with no interaction between lesion and age group. The results of in situ hybridization histochemistry and NKB receptor studies suggest that NKB-containing neurons in the NBM, and the neurons they innervate, are not vulnerable to NMDA or AMPA in either young or old rats. While NKB mRNA-positive cells were diffusely distributed throughout the basal forebrain, only a small proportion of the large NBM cells contained NKB mRNA. The results suggest that NKB does not extensively colocalize with acetylcholine within the basal forebrain of rats and that NBM NKB neurons do not directly innervate cholinergic cells.     

The nucleus basalis of Meynert in multi-infarct (vascular) dementia

Summary The number and nucleolar volume of nerve cells within the nucleus basalis of Meynert were estimated in 10 patients with Alzheimer's disease, 12 with multi-infarct dementia, 9 with a mixed Alzheimer/multi-infarct dementia and in 10 age-matched controls. As reported previously in Alzheimer's disease, both the number and nucleolar volume of surviving cells was reduced, whereas in multi-infarct dementia no significant change in either measure was noted. In patients with Alzheimer's disease/multi-infarct dementia the loss of nerve cells and reduction in nucleolar volume varied greatly in severity from patient to patient according to the relative balance of Alzheimer and vascular type pathological changes present within each patient.Supported in part by a grant from the North Western Regional Health Authority to one of us (BM)     

伏核毁损对精神分裂症模型大鼠行为和学习记忆能力的影响

目的　探讨毁损伏核对调控精神分裂症行为的有效作用及对学习记忆能力的影响 ,为精神分裂症外科治疗提供参考。方法　给大鼠腹腔内注射苯环己哌啶 (PCP)制作精神分裂症动物模型。采用立体定位仪 ,电极毁损大鼠伏核 ,观察社会行为、刻板行为评分 ,并进行Morris水迷宫实验。结果　毁损伏核组能使精神分裂症模型大鼠刻板行为和运动失调有所减轻 ,与假毁损组比较差异具有显著性 (P <0 .0 5 )。水迷宫实验毁损组在初期空间记忆能力的建立上存在缺陷 ,与假毁损组比较差异具有显著性 (P <0 .0 5 )。结论　伏核毁损能改善精神分裂症症状 ,对大鼠初期学习记忆能力有一定影响     

Transplantation of embryonic ventral forebrain grafts to the neocortex of rats with bilateral lesions of nucleus basalis magnocellularis ameliorates a lesion-induced deficit in spatial memory

Embryonic ventral forebrain grafts containing developing cholinergic cells were transplanted to the neocortex of rats with bilateral quisqualic acid lesions of the nucleus basalis magnocellularis. A lesion-induced deficit on performance of a spatial alternation test of memory was reduced by such transplants. When the same animals were treated with the acetylcholinesterase inhibitor physostigmine (0.05 mg/kg), however, performance on the behavioral task was not further promoted, and therefore, under these conditions, the cholinergic cortical transplants appear not to be subject to modulation by anticholinesterase drugs.     

Comparison of the effects of acute and chronic ibotenic and quisqualic acid nucleus basalis lesioning

The present study examines the effects of acute (1 month recovery) and chronic (8 month recovery) bilateral quisqualic (quis) and ibotenic (ibo) acid nucleus basalis (NB) lesioning on the activity of cholinergic neurons and on passive avoidance (PA) and water-maze (WM) performance. Our data demonstrate that A: The activity of choline acetyltransferase (ChAT) in cortical tissue and the number of ChAT positive neurons in the NB were decreased 1 and 8 months after quis or ibo NB lesioning. B: Ibo NB lesioning produced a greater nonspecific subcortical cell loss than quis NB lesioning. C: PA retention was impaired by acute and chronic quis and ibo NB lesioning. D: Acute ibo NB lesioning impaired acquisition and reversal learning in WM performance whereas chronic ibo NB lesioning impaired only reversal WM learning. Acute and chronic quis NB lesioning impaired reversal WM learning. The present results suggest that NB cholinergic neurons do not recover spontaneously from excitotoxin-induced damage and that they may be importantly involved in inhibitory avoidance and spatial reversal learning performance.     

Neuropathological study on the nucleus basalis of Meynert in Pick's disease

Summary The pathological changes in the nucleus basalis of Meynert (nbM) in 10 autopsied cases with Pick's disease were studied in comparison with 15 agematched controls. Both the number and density of nerve cells and the degree of fibrillary gliosis were examined at the anterior, intermediate, and posterior divisions of the nbM. In only 2 of the 10 Pick cases was the number of neurons significantly reduced, with moderate fibrillary gliosis at the anterior division (case 5: reduced by 64%, case 8: reduced by 46%). This neuronal loss in the anterior nbM division may not be a retrograde degeneration secondary to the cortical lesions, since there were some cases without neuronal loss in the nbM despite the presence of much more severe cortical lesions than in these two cases. In all Pick cases except case 1, mild to moderate fibrillary gliosis was found without an apparent neuronal loss at the posterior division of the nbM. This change in the posterior nbM division may be due to secondary retrograde degeneration, since there was a parallel relationship between the degree of fibrillary gliosis in the posterior nbM division and the severity of cortical lesions in the temporal tip and the superior temporal gyrus, to which the cholinergic fibers are known to project from the posterior division of the nbM. The present study suggests that the mild degeneration of the nbM in most cases with Pick's disease may be secondary, but that there are also some cases of Pick's disease with a primary degeneration in the nbM.     

Changes in cortical EEG and cholinergic function in response to NGF in rats with nucleus basalis lesions

We examined whether recovery of cholinergic function in response to nerve growth factor (NGF) results in restoration of electrocortical activity. Rats received unilateral lesions of the nucleus basalis and were infused intracerebroventricularly (i.c.v.) over 3 weeks with NGF or vehicle. Cortical electrical activity was assessed at postoperative days 4, 7, 14, and 21 from 8 epidural electrodes. On day 21, choline acetyl transferase (ChAT) activity was measured in cortical tissue underlying each electrode site. Lesions resulted in increases in slow-wave (δ) power and decreases in high-frequency (β₂) power in the lesioned, as well as the non-lesioned hemisphere. Changes correlated topographically and in magnitude with losses of ChAT activity and suggested that regional electrocortical function was affected by cholinergic activity originating in the ipsilateral, as well as the contralateral hemisphere. NGF attenuated changes in cholinergic and electrocortical function bilaterally, though in the lesioned hemisphere, function did not return to control levels. Likewise, intact animals receiving NGF showed increases in β₂-power, as well as modest increases in ChAT activity. Changes in brain electrical activity in response to NGF occurred within 4–7 days without significant changes during the 2 weeks thereafter. Our results suggest that outcomes of future animal and human trials using unilateral i.c.v. infusions of NGF need to consider the reciprocal influences of hemispheric cholinergic function, as well as possible effects of NGF on intact brain.     

Short- and long-term effects of nucleus basalis magnocellularis lesions on cortical levels of somatostatin and its receptors in the rat

Cognitive and histological alterations in human Alzheimer's disease (AD) are correlated with selective neuronal loss in nucleus basalis of Meynert. In search of an animal model of AD-linked neurochemical deficits, we examined the effects of short- (2 weeks) and long- (3 and 6 months) term lesions of the nucleus basalis magnocellularis (NBM) on somatostatinergic parameters in rat forebrain. NBM lesions were performed by unilateral injection of ibotenic acid into the NBM. Cortical cholineacetyl transferase (ChAT) activity and acetylcholinesterase staining in the NBM remained significantly decreased ipsi- as compared to contralaterally up to 6 months after the placement of the lesion. Somatostatin (SRIF) content was increased by 120% in the ipsilateral frontal cortex 6 months post-lesion but not at shorter time intervals. Levels of neuropeptide Y (which is extensively co-localized with SRIF in the forebrain) were not significantly altered after unilateral NBM lesions at any time point. A 30% decrease in SRIF binding capacity as well as a marked reduction of SRIF inhibition of adenylate cyclase, indicative of a loss of functional SRIF receptors, was observed in ipsilateral versus contralateral frontal cortex on brain tissue homogenates after short-term unilateral NBM lesion. By film radioautography, the loss in SRIF binding sites was localized to both superficial and deep layers of the frontal cortex. This loss persisted up to 3 months but was no longer apparent after 6 months due to a decrease in SRIF binding capacity on the contralateral side.     

Investigations of neurotoxicity and neuroprotection within the nucleus basalis of the rat

The present study investigated the specific ways by which cytotoxicity due to glutamate receptor stimulation could be attenuated by the administration of agonists and antagonists of the ionotropic and metabotropic glutamate receptors within the nucleus basalis magnocellularis (NBM) of rats as measured by cortical choline acetyltransferase activity. The results of these studies suggest that (1) the cytotoxicity of ibotenate to NBM cholinergic cells is not dependent upon stimulation of metabotropic glutamate receptors, but results from activation of (NMDA) receptors, (2) the cytotoxicity of quisqualate to cholinergic cells within the NBM is not dependent upon stimulation of NMDA or metabotropic receptors, and (3) the cytotoxicity of NMDA was prevented by administration (i.p.) of the un-competitive NMDA antagonist memantine (30 mg/kg), resulting in plasma levels of 2.5 μg/ml, a concentration known to block efficiently NMDA receptors in vitro. Finally, performance of a food-motivated, delayed-alternation task on a T-maze was impaired by injections of NMDA into the NBM, but was prevented by co-administration of NMDA with memantine.     

Nicotinic, muscarinic and dopaminergic actions in the ventral hippocampus and the nucleus accumbens: effects on spatial working memory in rats

Acetylcholine (ACh) systems have been widely shown to be important for memory. In particular, ACh hippocampal neurons are critical for memory formation, though ACh innervation of other areas such as the nucleus accumbens may also be important. There has also been increasing interest in ACh and dopaminergic (DA) interactions with regard to short-term spatial memory. In a series of studies, we have found that ACh and DA agonists and antagonists given systemically interact to influence memory. The critical neural loci of these interactions are not currently known. In the present study, we used local infusion techniques to examine the role of ACh and DA transmitter systems in the nucleus accumbens and the ventral hippocampus on radial-arm maze (RAM) working memory performance. Into the nucleus accumbens of rats, we infused the nicotinic ACh agonist nicotine, the nicotinic ACh antagonist mecamylamine, the DA agonist apomorphine, or the DA antagonist haloperidol. Into the ventral hippocampus, we infused nicotine, mecamylamine, the muscarinic ACh agonist pilocarpine, or the muscarinic ACh antagonist, scopolamine. The nicotinic ACh and DA interaction was tested by a hippocampal infusion of mecamylamine alone or together with the DA D₂ agonist quinpirole given via subcutaneous injection. The results confirmed that both nicotinic and muscarinic ACh receptors in the ventral hippocampus play a significant role in spatial working memory. Blockade of either nicotinic or muscarinic ACh receptors caused significant impairments in RAM choice accuracy. However, infusion of either nicotinic or muscarinic agonists failed to improve choice accuracy. The interaction of DA D₂ systems is different with hippocampal nicotinic blockade than with general nicotinic blockade. Systemic administration of quinpirole potentiated the amnestic effect of mecamylamine infused into the ventral hippocampus, whereas it was previously found to reverse the amnestic effect of systemically administered mecamylamine. In contrast to the significant effects of mecamylamine in the hippocampus, no effects were found after infusion into the nucleus accumbens. Nicotine also was not found to have a significant effect on memory after intra-accumbens infusion. Neither the DA agonist apomorphine nor the DA antagonist haloperidol had a significant effect on memory after infusion into the nucleus accumbens. This study provides support for the involvement of nicotinic and muscarinic receptors in the ventral hippocampus in memory function. Ventral hippocampal nicotinic systems have significant interactions with D₂ systems, but these differ from their systemic interactions. In contrast, nicotinic ACh and DA systems in the nucleus accumbens were not found in the current study to be important for working memory performance in the RAM.     

Neuroprotective effects of 2,4-dimethoxybenzylidene anabaseine (DMXB) and tetrahydroaminoacridine (THA) in neocortices of nucleus basalis lesioned rats

The nicotinic α7 agonist dimethoxybenzilidene anabaseine (DMXB) and cholinesterase inhibitor tetrahydroaminoacridine (THA) were investigated in a trans-synaptic model for neocortical atrophy and degeneration following nucleus basalis lesions. Bilateral lesions reduced parietal neuronal density in layers II–V 8 months later. DMXB administered i.p. daily to rats for 3 months attenuated this loss in layers II–V at a 1 mg/kg i.p. dose. A lower, 0.2 mg/kg i.p. dose, was neuroprotective in layer IV only. THA (1 mg/kg i.p.) also protected against neocortical Nissl-staining deficits.     

Interaction between raphe dorsalis and nucleus basalis magnocellularis in spatial learning

We compared the effects on spatial learning of an ibotenic acid lesion of the nucleus basalis magnocellularis (NBM), a 5, 7-dihydroxytryptamine lesion of the raphe dorsalis (RD) and a combined NBM and RD lesion. The RD lesion reduced serotonin levels, and the NBM lesion reduced cholineacetyltransferase (ChAT) activity in the cortex. Although RD lesions alone did not affect spatial learning in the water-maze, the lesion aggravated the spatial navigation deficit produced by NMB lesioning. The current results suggest a functional interaction between the RD and NBM in spatial navigation.     

Changes in cortical acetylcholine output induced by modulation of the nucleus basalis

The modulatory inputs of the cholinergic neurons of the nucleus basalis have been investigated in midpontine transected and freely moving rats by measuring acetylcholine release from the cerebral cortex using the cortical cup technique. Acetylcholine release was found to be the same in both groups of rats indicating similar levels of activity of the cholinergic neurons ascending to the cortex. The electrical stimulation of the nucleus basalis was always followed by an increase in acetylcholine release. Conversely, in some experiments only the stimulation of the midbrain reticular formation enhanced acetylcholine output. The stimulation of the nucleus accumbens prevented the increase in acetylcholine release elicited by amphetamine. The dose-dependent increase in acetylcholine output following IP administration of amphetamine was also prevented by the 6-hydroxydopamine induced degeneration of the dopaminergic fibres. However injection of apomorphine in the nucleus basalis did not modify acetylcholine output. Direct injection of the GABAergic agonist muscimol resulted in a decrease in acetylcholine output which was prevented by picrotoxin. In conclusion, the cholinergic neurons ascending to the cortex can be inhibited by GABA receptors located in the nucleus basalis and stimulated indirectly by dopaminergic fibres.     

In vivo imaging of cortical membrane remodeling in rats with chronic unilateral ablation of nucleus basalis magnocellularis: use of radiolabeled palmitic acid

Membrane remodeling was imaged in vivo in brains of rats with a 2-week-old right-sided ablation of the nucleus basalis magnocellularis (NBM). To do this, [9,10-³H]palmitic acid ([³H]PAM) was injected intravenously and regional brain incorporationk^* of tracer was determined with quantitative autoradiography after 20 min circulation. In NBM-lesioned animals,k^* was elevated significantly (by up to 17%) in 11 ipsilateral frontal or parietal cortical regions, more so in layer I than in layers IV and V. Unoperated animals showed no right-left difference ink^*, whereas sham-operated animals showed some unilateral effects of damage due to the needle track. Circulating [³H]PAM is incorporated intosn-1 positions of brain phospholipids, mainly phosphatidylcholine, and its rate of turnover is thought to reflect turnover of neuronal and glial membranes. These results, when related to published evidence of altered cortical phospholipid metabolism in NBM-lesioned rats, suggest that images of increased [³H]PAM incorporation into ipsilateral cortex reflect increased membrane remodeling involving phospholipids.     

Negative and positive effects of intracerebroventricular scopolamine on memory in mice undergoing passive avoidance and escape tests

The effects of intracerebroventricular administration of scopolamine on memory and learning in the conscious, freely moving mouse were evaluated using step-down passive avoidance and water maze tests. A new technique was used that allows convenient injection into the cerebral ventricles without disturbing the animal's behavior. No significant changes in locomotor activity were observed after low doses of scopolamine (0.1 and 1.0 μg). However, 10 μg produced an increase in locomotor activity, while 100 μg caused an initial decrease followed by an increase in activity. In the passive avoidance test, scopolamine significantly impaired memory acquisition at doses higher than 1.0 μg, consolidation at a dose of 100 μg, and retrieval at doses of 10 and 100 μg. In contrast, a dose of 0.1 μg significantly improved consolidation and retrieval. In the water maze with a bridge, scopolamine either impaired memory acquisition, consolidation, and retrieval, or had no significant effect in the dose range tested. These results suggest that there are differences in the process of memory formation in the passive avoidance and escape tests.     

Age-related alterations in responses of nucleus basalis magnocellularis neurons to peripheral nociceptive stimuli

The present study investigated the effects of peripheral noxious stimuli on the spontaneous activity of the nucleus basalis magnocellularis (nbM) neurons in young, adult and old rats. Single unit extracellular recordings from the nbM neurons were obtained with glass micropipettes in urethane-anesthetized rats. A total of 104 units were antidromically identified as nbM-cortical neurons. Noxious but not innocuous mechanical stimulation elicited responses in 72% of the 104 neurons. Most of them were excited. The receptive fields were usually very large and bilateral. Most of the neurons also responded to noxious thermal, chemical and electrical stimuli. No marked differences were observed in the incidence of neurons having different spontaneous firing rates, firing patterns and response type among the three age groups. However, the latency of responses evoked by noxious thermal or electrical stimulation and the threshold of excitatory responses evoked by electrical stimulation were increased with aging. The duration and peak-firing rate of excitatory responses evoked by noxious thermal, chemical or electrical stimulation were decreased in old rats. These findings indicate that there might be some functional changes in the nbM neurons and its projection pathway with aging, which impair their responsive ability to peripheral nociceptive stimuli.     

Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia

The present study correlates the severity of dementia in Alzheimer’s disease with the degree of neuropathology present in the nucleus basalis of Meynert. We assessed neurofibrillary tangles, neuronal loss and morphometric changes in 21 patients with Alzheimer’s disease who underwent extensive neuropsychological testing before death. We report a highly significant correlation between scores in the psychological tests and all of the neuropathological markers examined within the nucleus basalis of Meynert. The test that correlated most closely with these morphological measures was Folstein’s Mini Mental State. Among the different neuropathological changes, the number of neurofibrillary tangles was strongly correlated with the degree of dementia. We also provide evidence for a differential involvement of the three subdivisions of the nucleus basalis in Alzheimer’s disease neuropathology. The posterior subdivision, which provides a substantial cholinergic input to the parahippocampal gyrus, was the more profoundly affected. Taken together, these results point to an important participation of the nucleus basalis in dementia of the Alzheimer type. In addition, the strong correlation between neuropathological changes and neuropsychological scores indicates the reliability of these tests in assessing the progression of the disease. Received: 22 June 1998 / Revised: 22 October 1998 / Accepted: 5 January 1999     

The link between sleep and depression: The effects of antidepressants on EEG sleep

The assumption that sleep dysregulation is more than a mere epiphenomenon of depression is based on several observations: sleep disturbances are strongly associated with the depressive state; a number of sleep manipulations can alleviate symptoms of depression in some patients; and the majority of antidepressants bring about remarkable changes in sleep polygraphic variables. An obvious question is whether changes in sleep physiological processes are intimately involved in the pathogenesis and recovery from depression. One way to elucidate the link between sleep and depression is to examine whether the influence of antidepressants on sleep is related to clinical improvement in depressives. For that purpose, the effects of antidepressants on EEG sleep and their importance for the treatment of depression are summarized against the background of two existing hypotheses concerning the link between sleep and depression: one hypothesis concerning the role of REM; the other concerning the role of non-REM sleep. EEG sleep studies on the use of antidepressants in depressives have not produced clear evidence of the involvement of REM sleep or non-REM sleep in the mechanisms underlying clinical change. Furthermore, the role of sleep physiological mechanisms during treatment with antidepressants is still unclear. To interpret the effects of antidepressants on EEG sleep in terms of sleep physiological processes more fundamental sleep research is necessary. Also, more comparative studies of antidepressants with similar therapeutic effects but different pharmacological profiles are needed in both healthy and depressed subjects to further quantify the impact of EEG sleep modification in the recovery from depression and to differentiate between pharmacological and sleep-related aspects.     

Behavioral impairments after lesions of the nucleus basalis by ibotenic acid and quisqualic acid

Ibotenic acid (IBO) or quisqualic acid (QUIS) was infused into the region of the nucleus basalis magnocellularis (NBm) in F344 rats in order to behaviorally and biochemically characterize the effects of these two neurotoxins. QUIS infusion resulted in a slightly higher depletion of choline acetyltransferase (ChAT) activity in both anterior and posterior regions of cortex than did lesions caused by infusion of IBO. Both QUIS- and IBO-treated rats demonstrated significantly longer latencies than controls to find a hidden platform in a Morris water maze task. In addition, QUIS-treated rats performed significantly better than IBO-treated rats in the water maze. Analysis of swim speed and open field behavior did not show significant differences in general motor activity. Passive avoidance retention was unaffected by either neurotoxin. Cortical amino acid levels, [3H]neurotensin binding, dopamine, norepinephrine, and serotonin levels were unaffected by either neurotoxin. The levels of HVA and 5-HIAA in the IBO and QUIS groups were significantly reduced compared to controls, but were not significantly different from each other. Histological examination showed greater damage to non-NBm structures with IBO than with QUIS, including the basolateral nucleus of the amygdala and the reticular formation of the thalamus. The greater behavioral deficit seen after IBO lesions may be due to damage to other areas rather than differences in the extent of depletion of corticai ChAT, amino acids, catecholamines or indolamines.