Nucleus Basalis Lesions Research Articles

Attenuation by the benzodiazepine receptor antagonist, ZK 93 426, of the deficit in spatial navigation induced by nucleus basalis lesions

The effects of the benzodiazepine receptor antagonist, beta-carboline ZK 93,426 treatment were studied both in NB-lesioned (ibotenic acid) and in unoperated Kuo-Wistar rats in a water maze task. The ZK 93,426 administered in the doses of 1 and 5 mg/kg, 30 min prior to the testing in a water maze apparatus, attenuated the NB lesion-induced spatial navigation deficit, although it had no effect on the performance of unoperated rats. The results suggest functional interactions between GABAergic system and ibotenic acid-induced lesion of the basal forebrain in rats.

Basal forebrain cholinergic neurons in aged rat brain are more susceptible to ibotenate-induced degeneration than neurons in young adult brain

Choline acetyltransferase (ChAT) activity, acetylcholinesterase (AChE) activity, and [ 3H]nicotine binding site density were measured in neocortex from unoperated (control) and nucleus basalis (NB)-lesioned young (2–3 months old) and aged (23–24 months old) rats. In control animals, neither enzyme activities nor the density of nicotine binding sites were altered as a function of age. However, age-related differences were apparent 2 weeks following unilateral infusions of ibotenic acid into the right NB. NB lesion-induced decreases by enzyme activities were significantly greater in ipsilateral neocortices from aged rats; ChAT and AChE activities in young animals decreased by 59 and 53%, respectively, while both enzyme activities in aged rats decreased by 72%. NB lesions decreased significantly the density of nicotine binding sites in ipsilateral neocortices from both young and aged rats; binding decreased by 23–26% in young rats and by 31–34% in aged animals. Results indicate that the basal forebrain cholinergic system in the aged rat is more susceptible to ibotenate-induced degeneration than neurons in young animals.

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

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

Nucleus basalis lesions in neonate rats induce a selective cortical cholinergic hypofunction and cognitive deficits during adulthood.

Ibotenic acid was infused into the nucleus basalis magnocellularis (nBM) of 2-day old rats to eliminate immature cholinergic neurons before they develop functional synaptic connections in the neocortex. For bilaterally lesioned neonates, cognitive testing was initiated 2 months after lesioning and animals were sacrificed at 8 or 12 months of age. Lesioned animals exhibited a marked deficit in the retention of passive avoidance behavior, as well as in the acquisition of 2-way active avoidance behavior. Lesioned animals also made significantly more alternation errors than control animals in the Lashley III spatial maze and showed severe impairments in general learning, reference memory and working memory during 17-arm radial maze testing. For all 4 tasks, neonatally lesioned animals did not show any recovery to the performance level of control animals. Histological analysis of the subcortex from lesioned animals during adulthood revealed: (1) a substantial reduction in acetylcholinesterase-positive cells (presumably cholinergic) within the nucleus basalis, (2) decreased acetylcholinesterase staining in neocortex and (3) a gliosis essentially restricted to the globus pallidus. Surrounding brain regions were apparently not damaged as a direct result of excitotoxin infusion. Neurochemically, neonate nBM lesioning produced a long term cholinergic hypofunction as evidenced by significant reductions of 25% and 18% in frontal cortex choline acetyltransferase (CAT) activity at 12 and 8 months of age, respectively. By contrast, prefrontal cortical concentrations of biogenic amines and their metabolites were unaffected, thus indicating a degree of neurochemical specificity for these neonatal nBM lesions. The persistent cortical cholinergic hypofunction in lesioned animals may be related to the long term deficits in learning/memory abilities that were also observed. It is suggested that neonatal nBM lesioning could provide a useful animal model for elucidating the plasticity of the developing brain after cortical anervation.

Autoradiographic analysis of muscarinic receptors and choline-uptake mechanisms within foetal basal forebrain transplants

The pharmacological characteristics of both muscarinic receptors and high-affinity choline uptake sites were examined within intracerebral implants of foetal basal forebrain cell suspensions. Approximately 12 weeks after implantation, the transplants were identified by acetylcholinesterase histochemistry. Muscarinic receptors were labelled by [3H]quinuclidinyl benzylate (QNB) autoradiography. The M1 and M2 receptor components of QNB binding were differentiated by pirenzepine competition. The distribution of the high-affinity choline uptake site was examined using [3H]hemicholinium-3 (HC3) autoradiography. Unilateral lesion of the nucleus basalis reduced [3H]QNB (8-25%) and [3H]HC3 (19-43%) binding throughout host frontoparietal cortex ipsilateral to the lesion but did not significantly alter these cholinergic markers within cingulate cortex, subcortical white matter, striatum or septum. Saturation analysis of the implanted tissue revealed the presence of a single population of [3H]QNB and [3H]HC3 binding sites with affinities similar to those of the host tissue (KD = 0.43 nM and 20.4 nM respectively). However, the receptor profile which developed appeared to be intrinsic to the implant; it was unaffected by the site of implantation and was dissimilar to that which ultimately developed in the donor tissue when left in situ.

O-267 - Effects of schizandrin (TJN-103) on brain functional depression induced by nucleus basalis (NB) lesion in rats

O-267 - Effects of schizandrin (TJN-103) on brain functional depression induced by nucleus basalis (NB) lesion in rats

EEG changes induced by acute and chronic quisqualic or ibotenic acid nucleus basalis lesions are stabilized by tacridine

The present study investigated the effects of acute (1 week) and chronic (8 months) quisqualic (quis) and ibotenic (ibo) acid nucleus basalis (NB) lesions on the biochemical activity of the NB cholinergic system (choline acetyltransferase (ChAT) activity) and on neocortical EEG activity. Cortical ChAT activity of quis or ibo NB-lesioned rats did not recover during and 8-month period. Acute and chronic quis and ibo NB lesions increased EEG slow waves and high voltage spindles. Tacridine, an anticholinesterase, dose-dependently suppressed acute and chronic quis and ibo NB lesion-induced EEG changes. The present results suggest that NB cholinergic neurons do not recover after excitotoxin-induced damage during an 8-month period and that cholinergic neuron loss is importantly involved in the acute and chronic lesion-induced EEG changes.

Effects of THA on passive avoidance and spatial performance in quisqualic acid nucleus basalis-lesioned rats

Bilateral quisqualic acid nucleus basalis (NB) lesions impaired passive avoidance (PA) retention. NB lesions did not impair acquisition performance (stable platform location) in the water maze (WM). However, NB-lesioned rats were impaired in learning the new location of the escape platform in WM. Pretraining injections of tacridine (an anticholinesterase, THA) at 3 mg/kg, but not at 1 mg/kg, slightly improved PA retention performance in NB-lesioned rats. THA (1 or 3 mg/kg) did not allecviate NB lesion-induced WM defect. The results further suggest that loss of NB neurons impair PA acquisition and relearning of the new platform location in WM, and that cholinergic neuron loss may be at least partially involved in the NB lesion-induced performance defect.

Lesions of nucleus basalis alter ChAT activity and EEG in rat frontal neocortex

The EEG was recorded from frontal, parietal and visual cortices of sham-operated control rats and rats having ibotenic acid lesions of the nucleus basalis. Recordings were made during a period of rest and during stimulus-evoked desynchronization. Spectral power was determined using a Fast Fourier Transform routine; 3 artifact-free 4 sec epochs of resting activity and two 4 sec epochs of activated EEG were analyzed. Choline acetyltransferase activity (ChAT) was measured in each cortical area and was reduced in lesioned animals an average of 25% in frontal cortex, 19% in the parietal region and 10% in visual cortex. The percent of low frequency activity (1–12 Hz) in the frontal EEG was significantly greater in lesioned animals than in the control group during quiet rest; a significant correlation was found between ChAT activity and power in this band. Desynchronized activity was largely unaffected except for a reduction in 25–31 Hz activity in the frontal cortex of lesioned animals. EEG activity in both the parietal and visual areas was unchanged from control values.

Ultrastructural localization of gold particles within neural grafts labeled with gold-filled sendai viral envelopes

The ability to discriminate between host and donor cells is required to interpret the organization of neural grafts at the electron microscopic (EM) level. Using light microscopy, Ardizzoni et al. (Ardizzoni, S.C., Michaels A., and Arendash, G.W. [1988] Science 239:635-637) described a method, using gold-filled Sendai viral envelopes, for labeling cell suspensions prior to grafting. As the colloidal gold used in this procedure is especially attractive for use with EM, we have examined the ultrastructural distribution and character of this label with transplanted cells. Cell suspensions taken from the nucleus basalis of fetal rats were labeled using gold-filled Sendai viral envelopes and grafted into the dorsal neocortex of adult host rats with nucleus basalis lesions. After varying survival times ranging from 1 to 14 months, grafts and surrounding host tissue were examined using standard EM techniques. Within the graft site, gold particles ranging from 10-200 nm were found associated with various membranes throughout the cytoplasm of both neurons and glia. Gold particles of similar size were also found within the nuclei of neuronal and non-neuronal cells. Host cells near the graft site contained some small gold particles (10-40 nm). Control injections of non-viable, gold-labeled cells or colloidal gold alone resulted in similar patterns of small gold particles which were readily discriminable from the larger virally inserted gold particles found in viable labeled donor cells. We conclude that this method allows discrimination between closely associated host and donor cells.

The effects of THA on scopolamine and nucleus basalis lesion-induced EEG slowing

The effectiveness of THA (an anticholinesterase) on scopolamine (0.4 mg/kg) and nucleus basalis (NB) lesion-induced change in neocortical spectral electroencephalography (EEG) were investigated. Scopolamine increased the amplitudes of all the spectral components in waking-immobility. In the movement-related EEG spectral values, only the alpha power was increased. THA 7.5 mg/kg, but not THA 3 mg/kg, could reverse scopolamine-induced amplitude change. NB lesioning increased delta and theta amplitudes, but decreased beta amplitude. Delta amplitude was increased during movement recordings in NB-lesioned rats. THA 7.5 mg/kg and pilocarpine 10 mg/kg, but not THA 3 mg/kg, could partially reverse the increase of delta and theta amplitudes induced by NB lesions. However, the beta power decrease could not be restored with cholinomimetics. This study demonstrates that quantitative EEG activity analysis may reflect the THA-induced restoration of the function of the cholinergic nucleus basalis.

Serotonin influences the behavioral recovery of rats following nucleus basalis lesions

The present study investigated the effects of serotonergic depletion upon the performance of rats with lesions of the nucleus basalis magnocellularis (NBM) in a nonspatial memory task. NBM lesions were made by injections of ibotenic acid. Serotonin was depleted by systemic injections of p-chloroamphetamine (PCA). After four weeks of testing, the choice accuracy of PCA rats was not different from that of control rats (CON), while the choice accuracy of NBM rats and rats with combined treatment (NBM + PCA) was significantly lower than CON rats, but not different from each other. After prolonged testing, performance improved in NBM rats, but not in NBM + PCA rats indicating that simultaneous loss of both cholinergic and serotonergic neurotransmission produced a significantly longer lasting behavioral deficit than the loss of cholinergic neurotransmission alone.

Nucleus basalis lesions decrease α-and α-bungarotoxins binding in rat cortex

A unilateral ibotenic acid lesion of the nucleus basalis magnocellularis in the rat, which is known to produce a reduction in cortical choline acetyltransferase activity and acetylcholine release, produces a decrease of 125I-alpha-bungarotoxin and 125I-kappa-bungarotoxin binding sites in the frontoparietal cortex of the lesioned hemisphere. This decrease can be observed at two weeks following the lesion and persists for up to twelve weeks. The results suggest that a population of bungarotoxin binding sites may have a presynaptic localization.

Cerebrovascular responsiveness to hypercapnia in intracerebral tissue transplants

Cerebral blood flow was measured using [ 14C]iodoantipyrine quantitative autoradiography in rats which had previously undergone unilateral ibotenate-induced nucleus basalis lesion followed by intracortical implantation of foetal basal forebrain cell suspensions. Transplants had no effect upon host cortical blood flow, although within the transplant itself, blood flow was significantly lower than the contralateral site. Both the transplant and host cortex exhibited a similar degree of hyperaemia in response to hypercapnia.

Sprouting of cholinergic axons does not occur in the cerebral cortex after nucleus basalis lesions

Different doses of the excitotoxin quisqualate were used to make lesions in the caudal part of the ferret nucleus basalis, i.e. the part that projects to the visual cortex. The higher doses of the excitotoxin destroyed all nerve growth factor receptor-immunoreactive cells in the caudal nucleus basalis and gave rise to up to 75% loss of acetylcholinesterase-containing axons in the visual cortex. In sections stained for Nissl substance there was generalized tissue damage around the injection sites and extensive loss of all neuron types in areas surrounding the caudal nucleus basalis. Lower doses of the excitotoxin damaged only a proportion of the nerve growth factor receptor-immunoreactive neurons in the caudal nucleus basalis and produced a much lower depletion of acetylcholinesterase-positive fibres in the visual cortex. The only damage seen in sections stained for Nissl substance was a loss of magnocellular neurons in the vicinity of the injection sites. A quantitative morphological approach was used to show that either one week or three months after the lesions there was a linear correlation between the proportion of acetylcholinesterase-positive axons lost in the visual cortex and the proportion of nerve growth factor receptor-immunoreactive cells that had disappeared from the caudal nucleus basalis. Since the correlation lines for the short-term (one week) survival and the long-term (three months) survival experiments coincided, this indicated that no collateral sprouting of cholinergic axons had occurred in the visual cortex of the long-term survival animals regardless of size of the lesion in the nucleus basalis.

Clinicopathologic Study of Dementia in Parkinson Disease

We attempted to correlate dementia to histopathologic lesions in 15 autopsy patients with Lewy body type Parkinson disease (PD) by semiquantitative analysis of Alzheimer pathology, cortical Lewy bodies, locus ceruleus, nucleus basalis and vascular lesions. Ten out of the 15 patients were demented and consisted of 6 with PD alone, 2 with PD and marked Alzheimer pathology, 1 with PD, marked Alzheimer pathology and diffuse Lewy body disease and 1 with multiple cerebral infarcts, PD and marked Alzheimer pathology. The degeneration of the locus ceruleus was prominent in 2 patients with marked dementia but without any significant cortical pathology. Our findings are consistent with previous observations suggesting that the cause of dementia in PD is heterogeneous and further indicate that degeneration of the locus ceruleus may contribute to the pathogenesis of dementia in a subgroup of PD patients.

The effect of γ-vinyl-GABA on the performance of nucleus basalis-lesioned rats in spatial navigation task

The present study investigates whether the stimulation of γ-aminobutyric acid (GABA)ergic system affects spatial navigation deficits induced by the lesioning of the nucleus basalis (NB). Thus, the effect of γ-vinyl-GABA treatment which elevates the GABA levels in brain was studied on water maze task both in unoperated and NB-lesioned (ibotenic acid) rats. The subchronic administration of γ-vinyl-GABA aggravated dose-dependently NB lesion-induced deficits, although it did not impair the performance of unoperated rats in this task. The imbalance between GABAergic system and cholinergic or non-cholinergic systems of the NB may contribute to spatial navigation deficits in rats.

Effect of alpha 2 antagonists and an agonist on EEG slowing induced by scopolamine and lesion of the nucleus basalis

In the present study, the effects of an alpha 2 agonist (clonidine, 1.0 mg/kg, i.p.) and two antagonists (atipamezole, 1 and 10 mg/kg s.c. and yohimbine, 3.0 mg/kg i.p.) were studied on the EEG activity of naive rats, pretreated with either saline or scopolamine (0.8 mg/kg), or rats receiving lesioning of the nucleus basalis. The alpha 2 antagonists increased fast activity (alpha and beta). Clonidine increased slow wave activity (increased in spectral amplitudes) during periods of immobility and mobility. The EEG slowing, induced by scopolamine, was not alleviated by atipamezole or yohimbine, but in immobile rats, an increase in the delta and theta amplitudes was augmented by clonidine. In nucleus basalis-lesioned rats, the increase in delta activity was partially normalised by the alpha 2 antagonists. The decrease in the beta amplitude, induced by lesioning of the nucleus basalis, was not alleviated with either atipamezole or yohimbine. Clonidine increased the slow wave activity in nucleus basalis-lesioned rats and induced an increase in delta and theta bands during immobility. No changes were induced by clonidine in the EEG recorded from rats with lesions of the nucleus basalis.

Excitotoxin lesion of nucleus basalis causes a specific decrease in Go mRNA in cerebral cortex: Sensitivity to MK-801

Lesions of the ascending cholinergic pathway from nucleus basalis are known to have profound effects on cortical function. In particular, a substantial potentiation of carbachol-stimulated polyphosphoinositide turnover is detected from 1 day after lesion and is maintained for several days before returning to normal by 1 month. In this study the effect of this lesion was investigated on levels of three G-protein α-subunit mRNAs. Excitotoxin lesion of the nucleus basalis caused a selective reduction in the levels of Goα mRNA in cerebral cortex ipsilateral to the lesion, G5α and Giα mRNA being unaffected. The maximal effect was obtained at 3 days after lesion where levels of Goα mRNA were decreased by 40% compared to sham-operated animals. Levels of Goα mRNA returned to normal values by 28 days. Treatment with MK-801 caused a significant attenuation of the decrease in Goα mRNA, indicating the involvement of NMDA receptors in this response.

Induction of Ornithine Decarboxylase in Cerebral Cortex by Excitotoxin Lesion of Nucleus Basalis: Association with Postsynaptic Responsiveness and N‐Methyl‐d‐Aspartate Receptor Activation

The major cholinergic innervation of the rat cerebral cortex arises from the nucleus basalis in the basal forebrain. Introduction of the excitotoxins kainate or ibotenate into the nucleus basalis by stereotaxic injection results in degeneration of the cholinergic cells. We have investigated the effect of this excitotoxic action on ornithine decarboxylase (ODC) activity and cholinergic responsiveness in the cerebral cortex. A massive and rapid induction of ODC activity was seen in ipsilateral cortex after injection of excitotoxin. A maximal increase in ODC activity of 268 times the control value was seen in ipsilateral cerebral cortex 8 h after lesioning. Thereafter, ODC activity declined but remained significantly greater than control levels for 32 h. Pretreatment of animals with the irreversible ODC inhibitor difluoromethylornithine prevented the induction of ODC by kainate. Tissue content of the ODC product putrescine showed a marked increase in cerebral cortex ipsilateral to the lesion, increasing sevenfold at 24 h, the maximal concentration reached. After 24 h, the level of putrescine decreased but remained significantly elevated above control values for 5 days. Levels of the polyamines spermidine and spermine were unaffected by lesioning. Increases on ODC activity of much smaller magnitude were also seen in brain regions not directly innervated from the ipsilateral nucleus basalis. However, the response in ipsilateral cortex was found to be dependent on an intact projection from nucleus basalis to cortex. The induction of ODC was shown to be prevented by treatment of rats with MK-801, a result indicating the involvement of N-methyl-D-aspartate (NMDA) receptors.(ABSTRACT TRUNCATED AT 250 WORDS)