Nucleus Basalis Lesions Research Articles

Unilateral and bilateral nucleus basalis lesions: Differences in neurochemical and behavioural recovery

The neurochemical and behavioural recovery following unilateral and bilateral lesions of the nucleus basalis was investigated in adult male Wistar rats 20 days and 6 months after surgery. The lesions were made by stereotaxic injections of ibotenic acid. Twenty days after surgery there was a statistically significant choline acetyltransferase decrease in the frontal and parietal ipsilateral cortex of the unilaterally lesioned rats and in the cortex of both hemispheres after bilateral lesions. Cortical high affinity choline uptake rate was significantly decreased 4 days after lesions but showed a rapid recovery within 20 days post-lesion in unilaterally and bilaterally lesioned rats. However, at this time both groups of lesioned rats showed a marked impairment in the acquisition of passive and active (shuttle-box) avoidance conditioned responses. Six months after surgery the decrease in choline acetyltransferase activity was smaller and statistically significant in the ipsilateral frontal cortex only in the unilaterally lesioned rats and in the frontal and parietal cortex of both hemispheres in the bilaterally lesioned rats. High affinity choline uptake was increased in the contralateral hemispheres of the unilaterally lesioned rats and was significantly larger than in the bilaterally lesioned rats. There was no difference in the acquisition of both passive and active avoidance conditioned responses between the sham operated and unilaterally lesioned rats, while the bilaterally lesioned rats could only negotiate the active avoidance conditioned response. In conclusion, our experiments demonstrate a remarkable neurochemical and behavioural recovery within 6 months in rats with a unilateral lesion of the nucleus basalis and only a limited recovery in the bilaterally lesioned rats.

Cortical hypometabolism and its recovery following nucleus basalis lesions in baboons: a PET study.

The cerebral metabolic rate for glucose was measured serially with positron emission tomography and [18F]fluorodeoxyglucose in five baboons with stereotactic electrocoagulation of the left nucleus basalis of Meynert (NbM). Four days after lesion, a significant metabolic depression was present in the ipsilateral cerebral cortex, most marked in the frontotemporal region, and which recovered progressively within 6-13 weeks. These data demonstrate that adaptive mechanisms efficiently compensate for the cortical metabolic effects of NbM-lesion-induced cholinergic deafferentation. Moreover, unilateral NbM lesions also induced a transient reduction in contralateral cortical metabolic rate, the mechanisms of which are discussed. Explanation of these effects of cholinergic deafferentation in the primate could further our understanding of the metabolic deficits observed in dementia of the Alzheimer's type.

Effects of nucleus basalis lesions on the muscarinic and nicotinic modulation of [3H]acetylcholine release in the rat cerebral cortex.

Presynaptic muscarinic and nicotinic receptors in the cerebral cortex reportedly inhibit and increase acetylcholine (ACh) release, respectively. In this study, we investigated whether these receptors reside on cholinergic nerve terminals projecting to the cerebral cortex from the nucleus basalis magnocellularis (nbm). Adult male rats received unilateral infusions of ibotenic acid (5 micrograms/1 microliter) in the nbm. Two weeks later, cerebral cortical cholinergic markers (choline acetyltransferase activity, high-affinity choline uptake, and coupled ACh synthesis) were significantly reduced in synaptosomes prepared from the lesioned hemispheres compared to contralateral controls. The depolarization-induced release of [3H]ACh from these synaptosomes was also reduced in the lesioned hemispheres, reflecting the reduced synthesis of transmitter. However, the nbm lesions had no effect on the inhibition of release induced by 100 microM oxotremorine. Synaptosomal [3H]ACh release was not altered by nicotine or the nicotinic agonists anabaseine and 2-(3-pyridyl)-1,4,5,6-tetrahydropyrimidine. Nicotine (10-100 microM) did increase [3H]ACh release in control and lesioned hemispheres in cortical minces, but to a similar extent. These results suggest that neither muscarinic nor nicotinic receptors modulating ACh release reside on nbm-cholinergic terminals.

Long-term neuropathological and neurochemical effects of nucleus basalis lesions in the rat.

The long-term effects of excitotoxic lesions in the nucleus basalis magnocellularis of the rat were found to mimic several neuropathological and chemical changes associated with Alzheimer's disease. Neuritic plaque-like structures, neurofibrillary changes, and neuronal atrophy or loss were observed in the frontoparietal cortex, hippocampus, amygdala, and entorhinal cortex 14 months after the lesions were made. Cholinergic markers in neocortex were reduced, while catecholamine and indoleamine metabolism was largely unaffected at this time. Bilateral lesions of the nucleus basalis magnocellularis increased somatostatin and neuropeptide Y in the cortex of the rat by at least 138 and 284 percent, respectively, suggesting a functional interaction between cholinergic and peptidergic neurons that may differ from that in Alzheimer's disease.

Maintenance of cortical somatostatin and monoamine levels in the rat does not require intact cholinergic innervation

Levels of somatostatin, noradrenaline, dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were unchanged in rat neocortex 3 or 6 months after ibotenic acid lesion of the ipsilateral nucleus basalis that reduced cortical choline acetyltransferase levels by over 60%. These results render unlikely the possibility that non-cholinergic neurotransmitter deficits in Alzheimer's disease cortex are the consequence of cholinergic degeneration.

Acetylcholine-rich neuronal grafts in the forebrain of rats: Effects of environmental enrichment, neonatal noradrenaline depletion, host transplantation site and regional source of embryonic donor cells on graft size and acetylcholinesterase-positive fibre outgrowth

The importance of several factors influencing the survival of cholinergic-rich embryonic tissue transplanted to the adult rat forebrain and the extent of acetylcholinesterase-positive fibre innervation of the host brain was investigated in 3 experiments. In the first two experiments, embryonic ventral forebrain tissue was grafted to the neocortex of rats in which the intrinsic cortical cholinergic innervation had been removed by nucleus basalis lesions. Housing the host rats in an enriched environment produced a temporary enhancement of fibre outgrowth 4 weeks after transplantation, but this was not maintained after 10 weeks. Fibre outgrowth was greater when the grafts were transplanted to the noradrenaline-depleted neocortex than to the intact neocortex. Neither environmental enrichment nor noradrenaline depletion influenced graft survival or size. In the third experiment, the embryonic donor tissue was dissected to separate regions containing precursors of the nucleus basalis cholinergic cells from regions containing precursors of the septal cholinergic cells, and transplanted to either the neocortex following nucleus basalis lesions or to the hippocampus following fimbria-fornix lesions. Nucleus basalis grafts showed greater growth in size than septal grafts, and grafts placed into the hippocampus showed greater growth in size than grafts placed into the neocortex. More interestingly, the extent of fibre outgrowth depended on the appropriateness of the donor tissue to the host transplantation site: nucleus basalis tissue showed greater acetylcholinesterase-positive outgrowth than septal tissue in the neocortex, whereas septal tissue showed greater outgrowth than nucleus basalis tissue in the hippocampus.

Generation of cortical event-related slow potentials in the rat involves nucleus basalis cholinergic innervation

These experiments were conducted to gather information regarding the role of cholinergic innervation to the cortex in the generation of event-related slow potentials. The effects of unilateral drug treatments or lesions on ipsilateral and contralateral frontal cortex slow potential (SP) responses were examined in rats. The SP responses were recorded with silver-silver chloride electrodes and were generated by a 2 sec light cue which preceded medial forebrain bundle stimulation. The following approaches were used: (1) microinjection of GABA, procaine or saline into the nucleus basalis magnocellularis; (2) microinjection of atropine or saline subdurally in the SP recording area; (3) electrolytic lesion of the nucleus basalis area; and (4) kainic acid lesion of the nucleus basalis area. The following bilateral measurements were obtained in the lesion studies: choline acetyltransferase (ChAT) in cortex and hippocampus; serotonin in cortex, hippocampus, striatum and nucleus accumbens; norepinephrine in cortex and hippocampus; dopamine in striatum and nucleus accumbens; and metabolites of serotonin, norepinephrine and dopamine in these areas. The cortical SP responses were reduced on the side ipsilateral to the injections of GABA and procaine into the nucleus basalis, and on the side of the subdural atropine injection. With either type of lesion, the SP responses on the lesioned side were significantly reduced as compared to the non-lesioned side. Reductions in cortical ChAT and other measures were observed ipsilateral to the electrolytic lesion, but only cortical ChAT activity was reduced in the kainic acid-lesioned animals. Thus, pharmacological depression of nucleus basalis neurons, blockade of cholinergic muscarinic receptors in the cortex, and nucleus basalis lesions that reduce cortical choline acetyltransferase activity depress event-related slow potentials in the rat frontal cortex. These results provide evidence that cortical slow potential responses in the rat are dependent upon cholinergic innervation from the nucleus basalis.

Comparative effects of cholinergic drugs and lesions of nucleus basalis or fimbria-fornix on delayed matching in rats.

To provide a more specific test of memory impairments following lesions to central cholinergic systems, rats were trained on an operant delayed matching task. Ibotenic acid lesions of the nucleus basalis produced a disruption of performance at all delay intervals (a parallel downward shift in the delay-performance curve). By contrast, fimbria-fornix transections had no effects at short delays, but produced a progressively greater impairment as the delays lengthened (an increased downward slope of the delay-performance curve). Scopolamine produced a dose-dependent disruption of performance, apparent at the shortest delays but greater at longer delays, that was similar to the two lesion deficits combined, whereas physostigmine induced a mild but significant enhancement of performance. The results support the hypothesis that disruption of hippocampal circuitries, including cholinergic afferents via the fimbria-fornix, produces short-term or working memory impairments, whereas disruption of the cortical cholinergic system implicates more stable long-term aspects of task performance. Peripherally administered cholinergic drugs produce both types of effect and thus may influence both systems.

Selective memory loss following nucleus basalis lesions: Long term behavioral recovery despite persistent cholinergic deficiencies

Rats were trained for several months to perform a radial arm maze task and then given either sham or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), the primary cholinergic projection to the neocortex. The lesion produced a profound and apparently selective disturbance in memory for recent events. Further testing revealed that although the memory deficit persisted for several weeks, a gradual but complete recovery eventually occurred. Moreover, when these functionally recovered rats were later tested on a passive avoidance task that is normally sensitive to lesions of the NBM, no deficit was found. Thus, the post-lesion recovery of function generalized to a different memory test, upon which no post-lesion practice had been given. Post-mortem determinations revealed that the lesions caused marked neurodegeneration of the NBM, and decreases in both cortical choline acetyltransferase activity and high affinity choline uptake, but had no effect on density of muscarinic receptors. No evidence of neuronal recovery or neurochemical compensatory changes in the cholinergic system was found in the cortical projection areas, lesion site, or in parallel cholinergic systems terminating in the hippocampus or olfactory bulb. These results support the idea that the cortically-projecting cholinergic cells of the NBM normally play an important role in mediating recent memory. However, they also demonstrate that any simple relationship between the function of this brain region and the mediation of recent memory is unlikely. Finally, the results of this study direct attention toward issues related to the mechanisms involved with the recovery of function, and the extent to which degeneration of this brain area may contribute directly to the severe disturbance of cognitive function associated with certain neurodegenerative diseases (e.g., Alzheimer's, Pick's and Parkinson's disease).