Region Of Nucleus Basalis Magnocellularis Research Articles

Alterations in α4β2 nicotinic receptors in cognitive decline in Alzheimer’s aetiopathology

Nicotinic acetylcholine receptor subtype α4β2 is considered important in the regulation of attention and memory, and cholinergic degeneration is known as one pathophysiology of Alzheimer's disease. Brain amyloid-β protein deposition is also a key pathological marker of Alzheimer's disease. Recent amyloid-β imaging has shown many cognitively normal subjects with amyloid-β deposits, indicating a missing link between amyloid-β deposition and cognitive decline. To date, the relationship between the α4β2 nicotinic acetylcholine receptor and amyloid-β burden has not been elucidated in vivo. In this study we investigated the relation between α4β2 nicotinic acetylcholine receptor availability in the brain, cognitive functions and amyloid-β burden in 20 non-smoking patients with Alzheimer's disease at an early stage and 25 age-matched non-smoking healthy elderly adults by measuring levels of α4β2 nicotinic acetylcholine receptor binding estimated from a simplified ratio method (BPRI) and Logan plot-based amyloid-β accumulation (BPND) using positron emission tomography with α4β2 nicotinic acetylcholine receptor tracer (18)F-2FA-85380 and (11)C-Pittsburgh compound B. The levels of tracer binding were compared with clinical measures for various brain functions (general cognition, episodic and spatial memory, execution, judgement, emotion) using regions of interest and statistical parametric mapping analyses. Between-group statistical parametric mapping analysis showed a significant reduction in (18)F-2FA-85380 BPRI in the cholinergic projection region in patients with Alzheimer's disease with a variety of (11)C-Pittsburgh compound B accumulation. Spearman rank correlation analyses showed positive correlations of (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region with scores of the Frontal Assessment Battery (a test battery for executive functions and judgement) in the Alzheimer's disease group (P < 0.05 corrected for multiple comparison), and also positive correlations of the prefrontal and superior parietal (18)F-2FA-85380 BPRI values with the Frontal Assessment Battery score in the normal group (P < 0.05 corrected for multiple comparison). These positive correlations indicated an in vivo α4β2 nicotinic acetylcholine receptor role in those specific functions that may be different from memory. Both region of interest-based and voxelwise regression analyses showed a negative correlation between frontal (11)C-Pittsburgh compound B BPND and (18)F-2FA-85380 BPRI values in the medial frontal cortex and nucleus basalis magnocellularis region in patients with Alzheimer's disease (P < 0.05 corrected for multiple comparison). These findings suggest that an impairment of the cholinergic α4β2 nicotinic acetylcholine receptor system with the greater amount of amyloid deposition in the system plays an important role in the pathophysiology of Alzheimer's disease.

Differential modulation of frontal cortex acetylcholine by injection of substance P into the nucleus basalis magnocellularis region in the freely-moving vs. the anesthetized preparation.

In vivo microdialysis was used to assess the effects of unilateral substance P (SP) injection into the nucleus basalis magnocellularis on extracellular levels of acetylcholine (ACh) in the frontal cortex, either in freely moving or urethane-anesthetized rats. The results show that the neurochemical effects of SP are critically dependent on the choice of the experimental preparation: In the freely-moving rat, the injection procedure led to behavioral and concurrent bilateral cholinergic activation in the frontal cortex. This cholinergic activation was ipsilaterally reduced by intrabasalis injection of SP (1 ng), indicating that the peptide exerted an inhibitory influence on the neurochemical effect exerted by handling, intracranial needle insertion, and vehicle injection. In the anesthetized preparation, SP had a biphasic dose-dependent action on cortical ACh: a short-lasting ipsilateral increase immediately after injection (especially with 1 ng), and a delayed bilateral increase after more than 2 h (10, 100 ng). The procedure of inserting the injection needle moderately increased cortical ACh levels. Methodologically, these data are discussed with respect to the importance of using anesthetized vs. freely moving rats and the effects of intraparenchymal injections.

Anxiolytic-like action of neurokinin substance P administered systemically or into the nucleus basalis magnocellularis region

There is evidence that the neurokinin substance P plays a role in neural mechanisms governing learning and reinforcement. Reinforcing and memory-promoting effects of substance P were found after it was injected into several parts of the brain and intraperitoneally. With regard to the close link between anxiety and memory processes for negative reinforcement learning, the aim of the present study was to gauge the effect of substance P on anxiety-related behaviors in the rat elevated plus-maze and social interaction test. Substance P was tested at injection sites where the neurokinin has been shown to promote learning and to serve as a reinforcer, namely in the periphery (after i.p. administration) and after injection into the nucleus basalis magnocellularis region. When administered i.p., substance P had a biphasic dose–response effect on behavior in the plus-maze with an anxiolytic-like action at 50 μg/kg and an anxiogenic-like one at 500 μg/kg. After unilateral microinjection into the nucleus basalis magnocellularis region, substance P (1 ng) was found to exert anxiolytic-like effects, because substance P-treated rats spent more time on the open arms of the plus-maze and showed an increase in time spent in social interaction. Furthermore, the anxiolytic effects of intrabasalis substance P were sequence-specific since injection of a compound with the inverse amino acid sequence of substance P (0.1 to 100 ng) did not influence anxiety parameters. These results show that substance P has anxiolytic-like properties in addition to its known promnestic and reinforcing effects, supporting the hypothesis of a close relationship between anxiety, memory and reinforcement processes.

The H 1- and H 2-histamine blockers chlorpheniramine and ranitidine applied to the nucleus basalis magnocellularis region modulate anxiety and reinforcement related processes

This study examined the effects of the H 1-antagonist chlorpheniramine and the H 2-antagonist ranitidine on reinforcement and anxiety-parameters following unilateral injection into the vicinity of the nucleus basalis magnocellularis (NBM). In Experiment 1, rats with chronically implanted cannulae were injected with chlorpheniramine or ranitidine (each at doses of 0.1, 1, 10 and 20 μg) and were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. During the test for conditioned corral preference, when provided a choice between the four quadrants, only those rats injected with 10 or 20 μg chlorpheniramine spent more time in the treatment corral, indicative of a positively reinforcing action. None of the other doses of chlorpheniramine or of the H 2-antagonist influenced rats' preference behavior. In Experiment 2, the elevated plus-maze (EPM) was used to gauge possible anxiolytic or anxiogenic effects of intra-basalis injection of chlorpheniramine or ranitidine (each at doses of 0.1, 1, 10 and 20 μg). A single injection of chlorpheniramine at 0.1 or 20 μg as well as ranitidine at 20 μg was found to exert anxiolytic-like effects in the EPM. Both compounds elevated the time spent on the open arms and increased scanning over the edge of an open arm. None of the other doses of the H 1- and H 2-antagonist influenced rats' behavior in the EPM. In sum, these findings show that H 1- and H 2-receptor antagonists differentially modulate reinforcement and fear-related processes in the NBM and thus, provide the first evidence for a behavioral relevance for the histaminergic innervation of this brain site.

Facilitation of learning following injection of the chondroitin sulfate proteoglycan biglycan into the vicinity of the nucleus basalis magnocellularis

The aim of this study was to examine the effects of biglycan, a small chondroitin sulfate proteoglycan with neurotrophic activity, on memory and reinforcement upon unilateral injection into the region of the nucleus basalis magnocellularis (NBM). In experiment 1, rats with chronically implanted cannulas were injected with biglycan and tested on the uphill avoidance task, which involves punishment of a high-probability turning response on a tilted platform (negative geotaxis). Immediately after the training trial, that is, after a tail-shock was administered upon performing the response, rats received one microinjection (0.5 μl) of substance P (SP) in a reference dosage of 0.74 pmol or biglycan (doses ranging from 1.3 to 1300.0 nmol) into the NBM region. When tested 24 h later, rats treated with SP (0.74 pmol) or biglycan (2.1 and 2.6 nmol) had significantly longer uphill latencies than vehicle (PBS) controls, indicative of superior learning of the avoidance response. In experiment 2, a test for possible proactive effects of post-trial biglycan on performance during the retention trial was performed. Furthermore, the uphill avoidance task was combined with a conditioned place preference task to assess possible reinforcing effects of biglycan. Rats were injected with either 2.6 or 130.0 nmol biglycan immediately after the training trial of the uphill task. One control group received 2.6 nmol biglycan 5 h after the trial, a second group was sham-operated. Additional groups were included which received biglycan (2.6 or 130.0 nmol), SP (0.74 pmol) or PBS after the training trial but no tail-shock. After training these rats were placed into one of four restricted quadrants of a circular open field (closed corral) for a single conditioning trial. When tested 24 h later on the uphill task, rats injected with 2.6 nmol biglycan again exhibited significantly longer uphill latencies than did vehicle-injected rats. Retention latencies for the rats of the biglycan 5-h delay group did not differ from those of the vehicle-injected animals, ruling out proactive effects of biglycan on performance. Rats receiving biglycan or vehicle but no tail-shock showed poor retention performance on the uphill task. Subsequent tests for conditioned place preference in the open corral revealed that, unlike SP, injection of biglycan had no positively reinforcing effects upon injection into the NBM. In summary, these findings indicate that biglycan facilitates memory processing when injected into the NBM region.

Relationship between dopamine release in nucleus accumbens and place preference induced by substance P injected into the nucleus basalis magnocellularis region.

The activity of the neurotransmitter dopamine in the nucleus accumbens is considered to be an important element in the central processing of reinforcement. Unilateral administration of the neurokinin substance P into the area of the nucleus basalis magnocellularis of rats was found to be reinforcing, as assessed by the conditioned place preference paradigm. Simultaneous in vivo microdialysis showed that administration of substance P into the area of the nucleus basalis magnocellularis could increase extracellular concentrations of dopamine in the contralateral nucleus accumbens. Only those animals in which the administration of substance P induced this increase in dopamine levels acquired place preference. Furthermore, the changes in extracellular dopamine levels after substance P administration had a bimodal time course with an acute increase (to about 160% of baseline) during the first hour after injection, with a low (to 120-130%) and enduring increase occurring thereafter. Interestingly, during this second increase there were indications for positive correlations with the degree of place preference induced by substance P. Further positive correlations with place preference were found in the levels of the serotonergic metabolite 5-hydroxyindoleacetic acid. In contrast to dopamine, these were observed ipsi- and contralateral to the side of substance P administration. By combining the methods of in vivo microdialysis and conditioned place preference it was shown that the reinforcing effect induced by unilateral substance P injection in the nucleus basalis magnocellularis is related to dopaminergic (and possibly serotonergic) mechanisms in the nucleus accumbens.

Stimulation of mono- and diacylglycerol lipase activities in ibotenate-induced lesions of nucleus basalis magnocellularis

Ibotenic acid was injected into the nucleus basalis magnocellularis region of rat brain in order to study whether an elevation of lipase activities was associated with the degeneration of cholinergic neurons in this potential animal model of Alzheimer's disease. Two plasma membrane fractions were prepared from different regions of ibotenate injected (right hemisphere) and non-injected (left hemisphere) rat brain. One plasma membrane fraction was from synaptosomes (SPM) and the other from glial and neuronal cell bodies (PM). Activities of mono- and diacylglycerol lipases in these plasma membrane fractions were markedly increased (3- to 5-fold) in hippocampus, midbrain and frontal cortical regions of rat brain at 10 days after the injection of ibotenate. The activity of choline acetyltransferase was decreased in frontal cortex but unchanged in hippocampus and midbrain. Our results suggest that the increase in lipase activity is much more widespread and non-specific than is the decrease in cholinergic function.

Synaptic connections formed by grafts of different types of cholinergic neurons in the host hippocampus

The present experiment was performed to determine whether different types of grafted central cholinergic neurons are able to form synaptic contacts with host hippocampal neurons. Grafts from the septal-diagonal band area, which contain the neurons that normally innervate the hippocampal formation, were compared to those from the nucleus basalis magnocellularis region (NBM), the striatum, the pontomesencephalic tegmentum of the brain stem, and the spinal cord. The regions were dissected from 14- to 16-day-old rat fetuses, and the same number of viable cells (35 × 10 4) from each of the different regions was stereotaxically injected as a cell suspension into the hippocampus of rats subjected to a complete fimbria-fornix lesion, transecting the intrinsic septohippocampal pathways. At 14 to 17 weeks after transplantation, the brains were processed for choline acetyltransferase (ChAT) immunocytochemistry at the light and electron microscopic levels and acetylcholinesterase (AChE) histochemistry at the light microscopic level. There was a great variation in the number of surviving ChAT-positive cells among the different graft types. The septal grafts contained the highest number of ChAT-positive cells, and the striatal grafts showed the lowest numbers. The NBM, brain stem, and spinal cord grafts were inbetween. The differences in the number of ChAT-positive neurons between the groups matched, in general, the differences found in the magnitude of graft-derived AChE-positive fiber growth into the host hippocampal formation. At the electron microscopical level, all types of grafts were capable of forming synaptic contacts with host elements, however, with vast differences in the number of synapses found. The septal grafts produced the highest number of contacts, whereas the striatal and spinal cord grafts produced very few contacts. The ultrastructure of the cholinergic fibers from grafts obtained from the forebrain areas, i.e., septum, NBM, and striatum all appeared normal, whereas brain stem and spinal cord grafts produced different types of anomalies. The results show that grafted cholinergic neurons, that normally do not innervate the hippocampus, can send axons and form synaptic contacts in the host hippocampus. The ability to reinnervate the denervated hippocampal target appears to be shared by the embryologically closely related forebrain cholinergic neuron types, i.e., the septal, NBM, and striatal neurons. The marked differences in overall fiber ingrowth and number of synapses observed between these different types of grafts could be explained largely on the basis of differences in survivability of each grafted neuron type. By contrast, the reinnervation obtained from the grafted brain stem and spinal cord neurons were both quantitatively and qualitatively abnormal. This indicates that neuronal properties beyond the transmitter type are of importance in the formation of graft-host connectivity.

Regional decreases of cortical choline acetyltransferase after lesions of the septal area and in the area of nucleus basalis magnocellularis

Choline acetyltransferase and [ 3H]choline uptake have been measured in neocortical regions and hippocampus one week after lesions which destroyed the septum bilaterally, and after unilateral lesions in the area of nucleus basalis magnocellularis. Lesions of the septal area, which severely decreased choline acetyltransferase in hippocampus, only moderately decreased choline acetyltransferase in a posterior cortical region and had no effect in frontal and parietal regions. In contrast, lesions which included nucleus basalis magnocellularis decreased choline acetyltransferase markedly in frontal and parietal regions and had less of an effect in the posterior cortical regions. Lesion-induced decreases of [ 3H]choline uptake paralleled those of choline acetyltransferase. Lesions which included nucleus basalis magnocellularis had no effect on choline acetyltransferase in hippocampus, nucleus accumbens, olfactory tubercle, midbrain or pons-medulla. These results suggest the existence of topographically distinct cholinergic inputs to neocortex. In agreement with previous studies, cholinergic projections from the peripallidal region of nucleus basalis magnocellularis are predominantly to frontal and parietal neocortex. In contrast to previous suggestions, cholinergic projections to neocortex from the septal area are limited to the posterior regions of neocortex.