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Basal forebrain neurons project to microvessels and the somata of nitric oxide (NO) synthase‐containing neurons in the cerebral cortex, and their stimulation results in increases in cortical perfusion. γ‐Aminobutyric acid (GABA) is the second major neurotransmitter synthesized by these neurons and it has also been reported to modify cerebromicrovascular tone. We thus investigated by light and electron microscopy the association of GABA neurons (labeled for glutamic acid decarboxylase [GAD]) with cortical microvessels and/or NO neurons (identified by nicotinamide adenine dinucleotide [NADPH‐D] histochemistry) within the frontoparietal and perirhinal cerebral cortex in the rat. On thick and semithin sections, a high density of GAD puncta was observed, several surrounded intracortical blood vessels and neuronal perikarya. In contrast, NADPH‐D cell somata and proximal dendrites were only occasionally contacted by GAD nerve terminals. Perivascular and perisomatic GAD appositions were identified at the ultrastructural level as large (0.44–0.50 μm2) neuronal varicosities located in the immediate vicinity of, or being directly apposed to, vessels or unstained neuronal cell bodies. In both cortical areas, perivascular GAD terminals were located at about 1 μm from the vessels and were seen to frequently establish junctional contacts (synaptic frequency of 25–40% in single thin sections) with adjacent neuronal but not vascular elements. Ibotenic or quisqualic acid lesion of the substantia innominata did not significantly affect the density of cortical and perivascular GAD terminals, suggesting that they mostly originated locally in the cortex. These results suggest that GABA terminals can interact directly with the microvascular bed and that the somata and proximal dendrites of NO neurons are not a major target for cortical GABA neurotransmission. However, based on the colocalization of GABA and NADPH‐D in a subset of cortical neurons, we suggest that these interneurons could be implicated in the cortical vascular response elicited by stimulation of basal forebrain neurons. J. Comp. Neurol. 421:161–171, 2000. © 2000 Wiley‐Liss, Inc.

We earlier reported that electrical stimulation of the rat nucleus basalis of Meynert (NBM) induces large cerebral blood flow increases, particularly in frontal cortical areas but also in some subcortical regions. The present study was designed to address the issue of blood flow control exerted by NBM projections. To this aim, we have determined whether these flow increases were associated with proportionate changes in metabolic activity as evaluated by cerebral glucose utilization (CGU) strictly under the same experimental conditions in the conscious rat. An electrode was chronically implanted in a reactive site of the NBM as determined by laser-Doppler flowmetry (LDF) of the cortical circulation. One to two weeks later, while the cortical blood flow was monitored by LDF, we measured CGU using the [14C]2-deoxyglucose autoradiographic technique during unilateral electrical stimulation of the NBM, and analyzed the local flow-metabolism relationship. The large increases in cortical blood flow induced by NBM stimulation, exceeding 300% in various frontal areas, were associated with at most 24% increases in CGU (as compared with the control group) in one frontal area. By contrast, strong increases in CGU exceeding 150% were observed in subcortical regions ipsilateral to the stimulation, especially in extrapyramidal structures, associated with proportionate CBF changes. Thus, none of the blood flow changes observed in the cortex can be ascribed to an increased metabolic activity, whereas CBF and CGU were coupled in many subcortical areas. This result indicates that different mechanisms, which do not necessarily involve any metabolic factor, contribute to the regulation of the cerebral circulation at the cortical and subcortical level. Because the distribution of the uncoupling is coincident with that of cholinergic NBM projections directly reaching cortical microvessels, these data strongly support the hypothesis that NBM neurons are capable of exerting a neurogenic control of the cortical microcirculation.

This study sought to determine whether the cortical cholinergic projections from Meynert's nucleus are actually the target of the cholinesterase inhibitor physostigmine, which presents the ability to increase cortical blood flow. To this aim, the multiregional cerebrovascular effects of physostigmine in rats with and without lesion of the substantia innominata (SI), the equivalent of Meynert's nucleus of primates, were investigated. Unilateral SI lesions were made using ibotenic acid in three groups of rats. Four to 11 days later, the cortical choline acetyltransferase (ChAT) activity was measured in one group to assess the efficacy of the lesion. In the two other groups, the regional cerebral blood flow was measured using the [¹⁴C]iodoantipyrine technique, under physostigmine (0.2 mg/kg/h iv) or control conditions. SI lesion induced 27-59% fall in cortical ChAT activity in the ipsilateral hemisphere with the frontal area most affected. Despite these large biochemical differences, the lesion had little cerebrovascular effects. Side-to-side blood flow differences did not exceed 11% and did not strictly overlap the ChAT depletion. Physostigmine increased flow (38-66%) in all cortical areas, with no frontal predominance. Despite these considerable vasodilations, there were no significant differences between the lesioned and the intact hemisphere, nor any significant interaction between physostigmine and SI lesion. Thus, physostigmine does not actually activate the SI neuron terminals. This result suggests that cholinesterase inhibitors cannot be used as presynaptic markers of the cholinergic activity of this nucleus and casts doubts on their specificity as enhancement therapeutic agents in Alzheimer's disease. Copyright 1993, 1999 Academic Press