The septal area, the diagonal band nuclei, and the nucleus basalis of the substantia innominata are components of the basal forebrain. These structures lack a true cortical organization but can be said to have a "corticoid" architecture because of their location on the surface of the cerebral hemispheres (Mesulam, 2000). The basal forebrain projects to many different regions, using excitatory amino acids, GABA, and acetylcholine as the transmitters. Its single most important output is a cholinergic projection directed to the hippocampus, amygdala, and all other parts of the cerebral cortex (see Figure 1). The projections from the septal and diagonal band nuclei to the hippocampus travel in the fornix. In the human brain, the massive projections from the nucleus basalis to the cerebral cortex travel in the external and extreme capsules, the uncinate fasciculus, and the cingulum (Selden et al., 1998).
The medial septal nucleus of the primate brain is an inconspicuous structure containing relatively small neurons. Less than half of the medial septal neurons are cholinergic and correspond to the Ch1 sector of the basal forebrain. A second group of somewhat larger cholinergic neurons is embedded within the vertical nucleus of the diagonal band of Broca, a nucleus that is usually considered a component of the septal complex. Approximately three-quarters of the neurons of the vertical limb nucleus are cholinergic and constitute the Ch2 sector. The substantia innominata (or the subcommissural gray) is a complex region composed of the ventral globus pallidus, the nucleus basalis of Meynert, and the horizontal nucleus of the
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diagonal band. A small percentage (a tenth or less) of the neurons in the horizontal limb nucleus are cholinergic and constitute the Ch3 sector. These neurons tend to be hypochromic on Nissl stains and are shaped like a spindle.
The most conspicuous group of cholinergic neurons in the primate brain is found within the nucleus basalis of Meynert. Approximately 90 percent of the larger neurons in the nucleus basalis of the monkey and human brain are cholinergic and constitute the Ch4 sector (see Figure 2). In the human brain, each hemisphere may contain approximately 200,000 nucleus basalis neurons, about 90 percent of which belong to Ch4 (Arendt, Bigl, Tennstedt, and Arendt, 1985). The anteroposterior extent of the human Ch4 complex is 1.5 to 2 centimeters. In addition to the cholinergic neurons within the cytoarchitectonic confines of the nucleus basalis, there are interstitial cholinergic neurons embedded within the anterior commissure, the ansa peduncularis, the ansa lenticularis, and the internal capsule (Mesulam and Geula, 1988). These neurons can be considered part of the Ch4 complex on the basis of morphological, cytochemical, and hodological criteria.
Gorry (1963) pointed out that the nucleus basalis displays a progressive evolutionary trend, becoming more and more extensive and differentiated in more highly evolved species, especially in primates and cetaceans. Observations of the brains of turtles, mice, rats, squirrel monkeys, rhesus monkeys, and humans are consistent with this general view. There are considerable interspecies differences in the organization of these cholinergic pathways. The rodent cerebral cortex contains intrinsic cholinergic interneurons whereas the primate does not, making it entirely dependent on afferents from the basal forebrain for its cholinergic innervation. Furthermore, the Ch4 neurons of the primate express calbindin, whereas those of the rodent do not.
The Ch4-nucleus basalis complex displays a partial overlap with surrounding cell groups of the pre-optic area, hypothalamus, striatum, diagonal band of Broca, amygdala, and globus pallidus. There is no strict delineation between nuclear aggregates and passing fiber tracts. As noted above, many Ch4 neurons are embedded within the internal capsule, the diagonal bands of Broca, the anterior commissure, the ansa peduncularis (inferior thalamic peduncle), and the ansa lenticularis. In fact, previous designations
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for the nucleus basalis included "nucleus of the ansa peduncularis" and "nucleus of the ansa lenticularis." The physiological implication of this intimate association with fiber bundles is unknown. In addition to this open nuclear structure, the neurons of Ch4 are of variable shape and have an isodendritic morphology with overlapping dendritic fields. These characteristics, also present in the nuclei of the brain-stem reticular formation, have led to the suggestion that the Ch4 complex could be conceptualized as a telencephalic extension of the brain-stem reticular core (Ramon-Moliner and Nauta, 1966).
Studies using monkeys (based on the concurrent demonstration of perikaryal cholinergic markers and retrograde transport) have shown that each group of cholinergic cells projects widely but also with some degree of topographical specificity. According to these studies, Ch1 and Ch2 collectively provide the major source of cholinergic input for the hippocampal formation, Ch3 provides the major cholinergic input to the olfactory bulb, and Ch4 provides the major cholinergic innervation for the amygdala and all neocortical regions. The primate Ch4 can be divided into anteromedial (Ch4am), anterolateral (Ch4al), intermediate (Ch4i), and posterior (Ch4p) subsectors. Each cortical area receives its cholinergic input primarily (but not exclusively) from a specific subsector of Ch4. For example, Ch4am is the major source of cholinergic innervation for the cingulate gyrus and adjacent medial cortical areas; the Ch4al subsector is the major source of cortical innervation for the amygdala and the frontoparietal operculum; the Ch4i sub-sectors provide the major cholinergic innervation for peristriate, inferotemporal, and lateral frontoparietal cortex; and the Ch4p subsector provides the major source of cholinergic innervation for the superior temporal gyrus and the temporopolar area. Not all cortical areas receive an equal density of cholinergic fibers. There is a much more intense cholinergic innervation in limbic and paralimbic areas than in association and primary sensory-motor areas. Cholinergic drugs may therefore be expected to have their greatest impact on limbic and paralimbic areas.
Limbic and cortical areas of the primate brain contain several different types of postsynaptic muscarinic and nicotinic receptors. The dominant species is the pirenzepine-sensitive m1 subtype of muscarinic receptor. The regional distribution of this receptor subtype shows a relatively good agreement with the regional distribution of presynaptic cholinergic fibers (Mash, White, and Mesulam, 1988). Electron microscopic examinations of immmunostained tissue shows that incoming cholinergic fibers make traditional synaptic contact predominantly on dendritic spines of cortical pyramidal neurons (Smiley, Morrell, and Mesulam, 1997). At m1 muscarinic receptor sites, the acetylcholine that is released by cortical cholinergic fibers reduces the potassium conductance of the post-synaptic membrane and promotes the activation of cholinoceptive neurons by other excitatory inputs (Krnjevic, 1981). These physiological properties have led to the designation of acetylcholine as an excitatory neuromodulator.
The cholinergic Ch4 neurons receive cholinergic, glutamatergic, GABAergic, noradrenergic, serotonergic, and dopaminergic inputs (Záborszky, Cullinan, and Luine, 1993; Smiley, Morrell, and Mesulam, 1999). All cortical areas receive cholinergic input, but only limbic and paralimbic areas send substantial neural projections back to the nucleus basalis-Ch4 complex (Mesulam and Mufson, 1984). This anatomical arrangement indicates that most cortical areas have no direct feedback control over the cholinergic innervation that they receive, whereas limbic and paralimbic areas have powerful feedback control over the cholinergic input that they receive and over the cholinergic input directed to other parts of cortex. The Ch4 complex may thus act as a cholinergic relay for rapidly shifting cortical activation in a way that reflects the emotional-motivational state encoded by the limbic system. A restricted corticofugal control of widely distributed corticopetal pathways appears to be a feature common to other transmitter-specific systems (e.g., monoaminergic) that are also implicated in setting global behavioral states.
Single-unit studies indicate that neurons in the nucleus basalis of the rhesus monkey are sensitive to sensory information that signals the delivery of reward (Wilson and Rolls, 1990). Cholinergic projections may thus help to enhance the cortical impact of motivationally relevant events. Such an effect would influence both selective attention and learning. Experiments in various animal models are consistent with this dual role of cortical cholinergic innervation (Berger-Sweeney et al., 1994; Sarter and Bruno, 2000; Voytko et al., 1994). Cholinergic projections from the basal forebrain also influence learning-induced physiological and structural plasticity within the cerebral cortex (Kilgard and Merzenich, 1998).
The vast majority of Ch4 neurons express the p75 NGF receptor (NGFr). These neurons are dependent on NGF retrogradely transported from the cerebral cortex for survival. This makes them particularly vulnerable to cortical diseases such as Alzheimer's disease (AD). The few NGFr-negative Ch4 neurons selectively project to the amygdala and adjacent structures (Heckers and Mesulam, 1994). There is an age-related loss of calbindin in human Ch4 neurons (Wu, Mesulam, and Geula, 1997). This may contribute to their vulnerability to neurofibrillary degeneration in AD. Neurofibrillary tangles in Ch4 and a severe loss of cortical cholinergic innervation are hallmarks of AD neuropathology. Cholinesterase-inhibiting drugs are used to treat AD, with the aim of reversing some of this cholinergic depletion.
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