Cholinergic innervation of cortex by the basal forebrain: Cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (Substantia innominata), and hypothalamus in the rhesus monkey

Authors

  • M.-Marsel Mesulam,

    1. Bullard and Denny-Brown Lclboratories and Behavioral Neurology Section, Harvard Neurology Department and Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215
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  • Elliott J. Mufson,

    1. Bullard and Denny-Brown Lclboratories and Behavioral Neurology Section, Harvard Neurology Department and Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215
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  • Allan I. Levey,

    1. Departments of Pathology and Pediatrics and Joseph P. Kennedy Jr. Mental Retardation Research Center, University of Chicago, Chicago, Illinois 60637
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  • Bruce H. Wainer

    1. Departments of Pathology and Pediatrics and Joseph P. Kennedy Jr. Mental Retardation Research Center, University of Chicago, Chicago, Illinois 60637
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Abstract

The organization of projections from the cholinergic neurons of the basal forebrain to neocortex and associated structures was investigated in the rhesus monkey with the help of horseradish peroxidase transport, acetyl-cholinesterase histochemistry, and choline acetyltransferase immunohis-tochemistry. Four groups of neurons contained cholinergic perikarya and were designated as Chl-Ch4. The Ch1 group corresponds to the medial septal nucleus; about 10% of its neurons are cholinergic, and it provides a substantial projection to the hippocampus. The Ch2 group corresponds to the vertical nucleus of the diagonal band; at least 70% of its neurons are cholinergic, and it is the major source of innervation that the hippocampus and hypothalamus receive from the Chl-Ch4 complex. The Ch3 group most closely corresponds to the horizontal nucleus of the diagonal band; only 1% of its neurons can definitely be shown to be cholinergic, and it is the major source of Chl-Ch4 projections to the olfactory bulb. The Ch4 group most closely corresponds to the nucleus basalis of Meynert; at least 90% of its neurons are cholinergic, and it has projections to widespread areas of cortex and to the amygdala. In fact, the Ch4 group provides the single major source of cholinergic innervation for the entire cortical surface. In this respect, it is analogous to the raphe nuclei and to the nucleus locus coeruleus, which constitute the major sources of widespread cortical serotonergic and nor-adrenergic innervation, respectively.

The extensive Ch4 group can be divided into several subdivisions. Each subdivision has a preferential set of targets for its projections even though the connection patterns contain considerable overlap. The anteromedial subdivision of Ch4 is the major source of cholinergic projections to areas on the medial aspect of the cerebral hemispheres; the anterolateral Ch4 sub-division is the major source of cholinergic projections to frontoparietal op-ercular areas and to the amygdala; the intermediate Ch4 subdivision pro-vides the major cholinergic input for a variety of dorsal prefrontal, insular, posterior parietal, inferotemporal, and peristriate areas; and the posterior subdivision of Ch4 provides the major cholinergic innervation of superior temporal and immediately adjacent areas.

The basal forebrain in the human contains a cytoarchitechture analogous to that of the monkey. The Ch4 group (nucleus basalis) of the human is very extensive and can be subdivided into the same components that were identfied in the monkey brain. Pathological changes in Ch4 neurons have been described in a variety of human disease. In Alzheimer's disease, the relatively selective depression of neocortical cholinergic innervation may be closely associated with the neuronal loss in Ch4, which has also been described inthis condition.

In the rhesus monkey, all types of cortical areas receive substantial projections from the hippocampus. Virtually all of this hypothalamic input into neocortex arises from acetylcholinesterase-rich neurons which lack choline acetyltransferase. The hypothalamocortical pathway is therefore acetylcholinesterase-rich but not cholinergic.

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