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L.j. Thal - One of the best experts on this subject based on the ideXlab platform.
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Short-term and complete reversal of NGF effects in rats with lesions of the Nucleus Basalis Magnocellularis.
Brain research, 1998Co-Authors: J Winkler, A E Power, G A Ramirez, L.j. ThalAbstract:Rats received bilateral quisqualic acid lesions of the Nucleus Basalis Magnocellularis. Three weeks after lesioning, osmotic minipumps were implanted that released recombinant human nerve growth factor or cytochrome c at a dosage of 5.0 microg rat-1 day-1 through intracerebroventricular cannulas for 7 weeks. One quarter of the rats were sacrificed at the end of the treatment, while the rest of the animals were sacrificed 2, 8, and 12 weeks after termination of NGF/cc treatment. ICV administration of nerve growth factor (NGF) transiently reduced weight gain. NGF maximally increased choline acetyltransferase activity in all cortical regions, the olfactory bulb and the hippocampus between 20% and 56% at the end of the treatment. This increase linearly declined and completely regressed during the 12-week withdrawal period both in regions affected and unaffected by the lesion. Administration of NGF induced a short-lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the Nucleus Basalis Magnocellularis (NBM), the horizontal limb of the diagonal band of Broca, and the medial septum. In contrast, QUIS-induced NBM lesions permanently reduced ChAT activity most pronounced in the frontal and parietal cortex up to 45%. Furthermore, QUIS induced a permanent loss of p75NGFr-immunoreactive neurons within the NBM and the DB without affecting the MS. These findings suggest that degenerating cholinergic neurons of the NBM and HDB do not spontaneously recover after lesioning and may require continuous neurotrophic support by NGF to ameliorate cholinergic hypofunctioning.
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LONG LATENCY EVENT-RELATED POTENTIALS IN RATS: EFFECTS OF Nucleus Basalis Magnocellularis LESIONS*
International Journal of Neuroscience, 1998Co-Authors: Patricia Robledo, L.j. Thal, J Winkler, Christine Somes, Cindy L. EhlersAbstract:The effects of AMPA lesions of the Nucleus Basalis Magnocellularis (NBM) on EEG and event-related potentials (ERPs) generated by an auditory discrimination task were examined. The lesions significantly reduced choline acetyl transferase (ChAT) activity in frontal and parietal cortex. NBM lesions produced significantly more errors in the task. Significant increases in EEG spectral power in the fronto-parietal cortex were found, most predominantly in the higher frequencies (8-32 Hz), suggesting increases in arousal in the lesioned animals. Additionally, the lesion resulted in an increase in the area, the standard deviation of the amplitude of the N1 component, as well as instability in the amplitudes of several other ERP components. These results suggest that NBM lesions may impair ability to correctly respond in a discrimination task by a combination of increased arousal and an inability to maintain stable attentional capacity.
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delayed treatment with nerve growth factor improves acquisition of a spatial task in rats with lesions of the Nucleus Basalis Magnocellularis evaluation of the involvement of different neurotransmitter systems
Neuroscience, 1992Co-Authors: L.j. Thal, Ad J. Dekker, Fred H. GageAbstract:Abstract Rats received bilateral lesions of the Nucleus Basalis Magnocellularis by infusion of ibotenic acid. Fourteen days later, osmotic minipumps releasing human recombinant nerve growth factor (0.3 μg/day) were implanted subcutaneously. Starting one month after the lesion, spatial learning of the animals was tested using the Morris water maze. Acquisition of the task was impaired by the lesion, but treatment with nerve growth factor reduced the average latency to find the platform by approximately 9 s, which represents 28% of the lesion-induced behavioral deficit. Retention of this task and spatial acuity, tested in a trial in which the platform was not present, did not show a statistically significant improvement. Lesions of the Nucleus Basalis Magnocellularis reduced the choline acetyltransferase activity in the neocortex, but not in the hippocampus. Treatment with nerve growth factor increased the choline acetyltransferase activity in the neocortex but not in the hippocampus. There was no significant difference in the levels of norepinephrine, dopamine, serotonin or their metabolites in the cortex or hippocampus between nerve growth factor-treated animals and lesioned control animals. There was no significant correlation between any of these neurochemical changes and behavioral performance (acquisition and spatial acuity). Treatment with nerve growth factor did not increase the number or the size of nerve growth factor receptor-immunoreactive neurons in the Nucleus Basalis Magnocellularis. These data suggest that delayed treatment with nerve growth factor results in an improvement of spatial learning in rats with lesions of the Nucleus Basalis Magnocellularis. A possible role for cholinergic mechanisms in this effect is discussed.
Xi Can Tang - One of the best experts on this subject based on the ideXlab platform.
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Huperzine A reverses cholinergic and monoaminergic dysfunction induced by bilateral Nucleus Basalis Magnocellularis injection of beta-amyloid peptide (1-40) in rats.
Cellular and Molecular Neurobiology, 2007Co-Authors: Yan Qi Liang, Xiao Tian Huang, Xi Can TangAbstract:(1) Huperzine A, a promising therapeutic agent for Alzheimer’s disease (AD), was tested for its effects on cholinergic and monoaminergic dysfunction induced by injecting β-amyloid peptide-(1–40) into Nucleus Basalis Magnocellularis of the rat. (2) Bilateral injection of 10 μg β-amyloid peptide-(1–40) into Nucleus Basalis Magnocellularis produced local deposits of amyloid plaque and functional abnormalities detected by microdialysis. In medial prefrontal cortex, reductions in the basal levels and stimulated release of acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine were observed. However, oral huperzine A (0.18 mg/kg, once daily for 21 consecutive days) markedly reduced morphologic abnormalities at the injection site in rats infused with β-amyloid peptide-(1–40). Likewise, this treatment ameliorated the β-amyloid peptide-(1–40)-induced deficits in extracellular acetylcholine, dopamine, and norepinephrine (though not 5-hydroxytryptamine) in medial prefrontal cortex, and lessened the reduction in nicotine or methoctramine-stimulated release of acetylcholine and K+-evoked releases of acetylcholine and dopamine. (3) The present results provide the first direct evidence that huperzine A acts to oppose neurotoxic effects of β-amyloid peptide on cholinergic, dopaminergic, and noradrenergic systems of the rat forebrain.
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Huperzine A reverses cholinergic and monoaminergic dysfunction induced by bilateral Nucleus Basalis Magnocellularis injection of beta-amyloid peptide (1-40) in rats.
Cellular and molecular neurobiology, 2007Co-Authors: Yan Qi Liang, Xiao Tian Huang, Xi Can TangAbstract:(1) Huperzine A, a promising therapeutic agent for Alzheimer's disease (AD), was tested for its effects on cholinergic and monoaminergic dysfunction induced by injecting beta-amyloid peptide-(1-40) into Nucleus Basalis Magnocellularis of the rat. (2) Bilateral injection of 10 microg beta-amyloid peptide-(1-40) into Nucleus Basalis Magnocellularis produced local deposits of amyloid plaque and functional abnormalities detected by microdialysis. In medial prefrontal cortex, reductions in the basal levels and stimulated release of acetylcholine, dopamine, norepinephrine, and 5-hydroxytryptamine were observed. However, oral huperzine A (0.18 mg/kg, once daily for 21 consecutive days) markedly reduced morphologic abnormalities at the injection site in rats infused with beta-amyloid peptide-(1-40). Likewise, this treatment ameliorated the beta-amyloid peptide-(1-40)-induced deficits in extracellular acetylcholine, dopamine, and norepinephrine (though not 5-hydroxytryptamine) in medial prefrontal cortex, and lessened the reduction in nicotine or methoctramine-stimulated release of acetylcholine and K(+)-evoked releases of acetylcholine and dopamine. (3) The present results provide the first direct evidence that huperzine A acts to oppose neurotoxic effects of beta-amyloid peptide on cholinergic, dopaminergic, and noradrenergic systems of the rat forebrain.
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effects of huperzine a on Nucleus Basalis Magnocellularis lesion induced spatial working memory deficit
Acta Pharmacologica Sinica, 1998Co-Authors: Zhiqi Xiong, Dong Hang Cheng, Xi Can TangAbstract:AIM: To study the effects of huperzine A on Nucleus Basalis Magnocellularis (NBM) lesion-induced spatial working memory impairment. METHODS: A delayed-non-match-to-sample radial arm maze task was used to study spatial working memory. The choline acetyltransferase (ChAT) activity was determined by the conversion of [3H]acetyl-CoA to [3H]ACh. RESULTS: Unilateral NBM lesion by kainic acid 0.02 mumol impaired rat's ability to perform this working memory task as evidenced by fewer correct choices after different delay intervals and more total errors to complete the task. This behavioral impairment associated with a decrease in the activity of ChAT by about 40% in the ipsilateral cerebral cortex. Huperzine A (0.2 mg.kg-1 i.p. 30 min before testing) ameliorated this spatial working memory impairment. Physostigmine (0.2-0.3 mg.kg-1 i.p. 20 min before testing) also attenuated the NBM lesion-induced memory deficit. CONCLUSION: The integrity of NBM is critical for spatial working memory processing, and this working memory impairment induced by NBM lesion can be ameliorated by huperzine A and physostigmine.
James L. Mcgaugh - One of the best experts on this subject based on the ideXlab platform.
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Phthalic acid amygdalopetal lesion of the Nucleus Basalis Magnocellularis induces reversible memory deficits in rats.
Neurobiology of learning and memory, 2002Co-Authors: Ann E. Power, James L. McgaughAbstract:Abstract The basolateral amygdala (BLA) is extensively implicated in emotional learning and memory. The current study investigated the contribution of cholinergic afferents to the BLA from the Nucleus Basalis Magnocellularis in influencing aversive learning and memory. Sprague-Dawley rats were given permanent unilateral phthalic acid (300 ng) lesions of the Nucleus Basalis Magnocellularis and were chronically implanted with cannulas aimed at the ipsilateral BLA. Lesioned rats showed a pronounced inhibitory avoidance task retention deficit that was attenuated by acute posttraining infusions of the muscarinic cholinergic agonist oxotremorine (4 ng) or the indirect agonist physostigmine (1 μg) into the BLA. Continuous multiple-trial inhibitory avoidance training and testing revealed that lesioned rats have a mild acquisition deficit, requiring approximately 1 additional shock to reach the criterion, and a pronounced consolidation deficit as indicated by a shorter latency to enter the shock compartment on the retention test. Because lesioned rats did not differ from sham-operated controls in performance on a spatial water maze task or in shock sensitivity, it is not likely that the memory impairments produced by the phthalic acid lesions are due to any general sensory or motor deficits. These findings suggest that the dense cholinergic projection from the Nucleus Basalis Magnocellularis to the BLA is involved in both the acquisition and the consolidation of the aversive inhibitory avoidance task.
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Serotonergic input to cholinergic neurons in the substantia innominata and Nucleus Basalis Magnocellularis in the rat.
Neuroscience, 1999Co-Authors: Antonella Gasbarri, Antonio Sulli, Claudio Pacitti, James L. McgaughAbstract:The aim of the present study was to determine, at the light microscopic level, whether the serotonergic fibers originating from the dorsal raphe Nucleus (B7), median raphe Nucleus (B8) and ventral tegmentum (B9) make putative synaptic contacts with cholinergic neurons of the Nucleus Basalis Magnocellularis and substantia innominata. For this purpose, we utilized: (i) the anterograde transport of Phaseolus vulgaris leucoagglutinin combined with choline acetyltransferase immunohistochemistry; (ii) choline acetyltransferase/tryptophan hydroxylase double immunohistochemistry; and (iii) the FluoroGold retrograde tracer technique combined with tryptophan hydroxylase immunohistochemistry. Following iontophoretic injections of Phaseolus vulgaris leucoagglutinin in the dorsal raphe Nucleus, labeling was observed primarily in the ventral aspects of the Nucleus Basalis Magnocellularis and in the intermediate region of the substantia innominata. When Phaseolus vulgaris leucoagglutinin was combined with choline acetyltransferase immunohistochemistry, a close association between the Phaseolus vulgaris leucoagglutinin-positive fibers and cholinergic neurons was observed, even though the majority of the Phaseolus vulgaris leucoagglutinin-immunoreactive terminals seemed to establish contact with non-cholinergic elements. Following Phaseolus vulgaris leucoagglutinin injection in the median raphe Nucleus, very few labeled fibers with no evident close contact with Nucleus Basalis Magnocellularis and substantia innominata cholinergic neurons were observed. After tryptophan hydroxylase/choline acetyltransferase double immunohistochemistry, a plexus of serotonergic (tryptophan hydroxylase-positive) fibers in the vicinity of choline acetyltransferase-immunoreactive neurons of the substantia innominata and Nucleus Basalis Magnocellularis was observed, and some serotonergic terminals have been shown to come into very close contact with the cholinergic cells. Most of the tryptophan hydroxylase-immunoreactive terminals seem to establish contacts with non-cholinergic cells. Following FluoroGold injection in the Nucleus Basalis Magnocellularis and substantia innominata, the majority of retrogradely labeled neurons was observed mainly in the ventromedial cell group of the dorsal raphe Nucleus. In this area, a minority of the FluoroGold-positive neurons was tryptophan hydroxylase immunoreactive. These findings show that serotonergic terminals, identified in very close association with the cholinergic neurons in the substantia innominata and Nucleus Basalis Magnocellularis, derive primarily from the B7 serotonergic cell group of the dorsal raphe Nucleus, and provide the neuroanatomical evidence for a direct functional interaction between these two neurotransmitter systems in the basal forebrain.
Leon J Thal - One of the best experts on this subject based on the ideXlab platform.
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Short-term and complete reversal of NGF effects in rats with lesions of the Nucleus Basalis Magnocellularis.
Brain Research, 1998Co-Authors: Jürgen Winkler, Ann E. Power, G A Ramirez, Leon J ThalAbstract:Abstract Rats received bilateral quisqualic acid (QUIS) lesions of the Nucleus Basalis Magnocellularis (NBM). Three weeks after lesioning, osmotic minipumps were implanted that released recombinant human nerve growth factor (NGF) or cytochrome c at a dosage of 5.0 μ g rat −1 day −1 through intracerebroventricular (ICV) cannulas for 7 weeks. One quarter of the rats were sacrificed at the end of the treatment, while the rest of the animals were sacrificed 2, 8, and 12 weeks after termination of NGF/cc treatment. ICV administration of NGF transiently reduced weight gain. NGF maximally increased choline acetyltransferase (ChAT) activity in all cortical regions, the olfactory bulb and the hippocampus between 20% and 56% at the end of the treatment. This increase linearly declined and completely regressed during the 12-week withdrawal period both in regions affected and unaffected by the lesion. Administration of NGF induced a short-lasting hypertrophy of low affinity NGF receptor immunoreactive neurons within the Nucleus Basalis Magnocellularis (NBM), the horizontal limb of the diagonal band of Broca, and the medial septum (MS). In contrast, QUIS-induced NBM lesions permanently reduced ChAT activity most pronounced in the frontal and parietal cortex up to 45%. Furthermore, QUIS induced a permanent loss of p75NGFr-immunoreactive neurons within the NBM and the DB without affecting the MS. These findings suggest that degenerating cholinergic neurons of the NBM and HDB do not spontaneously recover after lesioning and may require continuous neurotrophic support by NGF to ameliorate cholinergic hypofunctioning.
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Grafting of nerve growth factor-producing fibroblasts reduces behavioral deficits in rats with lesions of the Nucleus Basalis Magnocellularis
Neuroscience, 1994Co-Authors: Ad J. Dekker, Leon J Thal, Jürgen Winkler, Jasodhara Ray, Fred H. GageAbstract:Abstract Rats received bilateral lesions ot the Nucleus Basalis Magnocellularis by infusion of biotenic acid. Two weeks after the lesion, a suspension of genetically modified primary rat fibroblasts was grafted dorsal to the Nucleus Basalis Magnocellularis (2 × 10 5 cells per side). The fibroblasts were either infected with the gene for human β-nerve growth factor or Escherichia coli β-galactosidase. The nerve growth factor-producing fibroblasts released 67 ng nerve growth factor /10 5 cells per day in vitro . Two weeks after implantation of the fibroblasts, spatial learning was tested in the Morris water-maze. Nerve growth factor-producing fibroblasts, but not β-galactosidase-producing fibroblasts ameliorated the deficit in acquisition of the water-maze task. In addition, spatial acuity was improved to near-normal levels by the nerve growth factor-producing grafts. Choline acetyltransferase activity in cortical areas and hippocampus was not affected by the nerve growth factor-producing grafts. Both grafted groups showed a similar reduction in the level of dopamine, but not homovanillic acid or 3-methoxytyramine, in the frontal cortex. Levels of norepinephrine, epinephrine and serotonin and their metabolites in the neocortex and hippocampus were not affected by the lesion or the grafts. Nerve growth factor-producing grafts increased the size of remaining nerve growth factor-receptor (p75) immunoreactive neurons in the Nucleus Basalis Magnocellularis by 25%. Nucleus Basalis Magnocellularis lesions reduced the integrated optic density of choline acetyltransferase-positive fiber staining in the ventral neocortex by 46%, but nerve growth factor-producing grafts restored this area to 86% of control. These data suggest that nerve growth factor-producing grafts can cause a marked behavioral improvement, probably through the partial restoration of the lesioned projection from Nucleus Basalis Magnocellularis to neocortex.
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behavioral effects of concurrent lesions of the Nucleus Basalis Magnocellularis and the dorsal noradrenergic bundle
Experimental Neurology, 1992Co-Authors: Donald J. O'connor, Philip J Langlais, Suzan Dietz, Leon J ThalAbstract:Abstract The effects of separate and concurrent lesions to the cholinergic and noradrenergic (NE) systems were assessed in two water mazes. Lesion of the Nucleus Basalis Magnocellularis (NBM) decreased performance in a spatial memory task (Morris water maze) while lesions of the dorsal NE bundle (DNB) enhanced the acquisition of this task independent of the NBM effects. Both lesions impaired performance on a water-escape motivated T-maze; however, the deficits induced by the combined lesion did not differ from the effects of either lesion alone. Neither lesion, nor their combination, had significant effects on open field activity. Biochemical analyses revealed almost total loss of NE in the cortex and hippocampus after DNB lesion, with relatively minor changes in other catecholamines or metabolites. Choline acetyltransferase activity was not significantly altered by the DNB lesion but was decreased in the cortex by the NBM lesion. These results suggest a task-specific effect of DNB lesion that is detectable under conditions of mild stress when floor effects are minimized.
Martina Ballmaier - One of the best experts on this subject based on the ideXlab platform.
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Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in Nucleus Basalis Magnocellularis
Neuroscience, 2002Co-Authors: Martina Ballmaier, Fiorella Casamenti, Michele Zoli, Giancarlo Pepeu, Carla Scali, R. Mazzoncini, Pf SpanoAbstract:Impairments of cortical cholinergic inputs from the Nucleus Basalis Magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the Nucleus Basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-Nucleus Basalis Magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the Nucleus Basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.
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Selective immunolesioning of cholinergic neurons in Nucleus Basalis Magnocellularis impairs prepulse inhibition of acoustic startle.
Neuroscience, 2001Co-Authors: Martina Ballmaier, Fiorella Casamenti, Michele Zoli, Giancarlo Pepeu, Pierfranco SpanoAbstract:Information processing and attentional abnormalities are prominent in neuropsychiatric disorders. Since the cholinergic neurons located in the Nucleus Basalis Magnocellularis have been shown to be involved in attentional performance and information processing, recent efforts to analyze the significance of the basal forebrain in the context of schizophrenia have focused on this Nucleus and its projections to the cerebral cortex. We report here that bilateral selective immunolesioning of the cholinergic neurons in the Nucleus Basalis Magnocellularis is followed by significant deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex in adult rats. This behavioral approach is used in both humans and rodents and has been proposed as a valuable model contributing to the understanding of the neurobiological substrates of schizophrenia. The disruption of prepulse inhibition persisted over repeated testing. The selective lesions were induced by bilateral intraparenchymal infusions of 192 IgG saporin at a concentration having minimal diffusion into adjacent nuclei of the basal forebrain. The infusions were followed by extensive loss of choline acetyltransferase-immunopositive neurons. Our results show that the cholinergic neurons of the Nucleus Basalis Magnocellularis represent a critical station of the startle gating circuitry and suggest that dysfunction of these neurons may result in impaired sensorimotor gating characteristic of schizophrenia.
