cDepartment of Psychology, Bowling Green State University, Ohio
dFlinders University, Faculty of Health Sciences, Bedford Park, Australia
ABSTRACT: The medial septum, diagonal bands, ventral pallidum, substantia innominata, globus pallidus and internal capsule contains a heterogeneous population of neurons, including cholinergic and non-cholinergic (mostly GABA-containing) corticopetal projection neurons and interneurons. This highly complex brain region, which constitutes a significant part of the basal forebrain has been implicated in attention, motivation, learning, as well as in a number of neuropsychiatric disorders such as Alzheimer's disease, Parkinson's disease, and schizophrenia. Part of the difficulty in understanding the functions of the basal forebrain, as well the aberrant information processing characteristics of these disease states lies in the fact that the organizational principles of this brain area remained largely elusive. On the basis of new anatomical data it is proposed that large part of the basal forebrain corticopetal system be organized into longitudinal bands. Considering the topographic organization of cortical afferents to different divisions of the prefrontal cortex and a similar topographic projection of these prefrontal areas to basal forebrain regions, it is suggested that several functionally segregated cortico-prefronto-basal forebrain-cortical circuits exist. It is envisaged that such specific "triangular" circuits could amplify selective attentional processing in posterior sensory cortical areas.
The term basal forebrain (BF) refers to a heterogeneous collection of structures located close to the medial and ventral surfaces of the cerebral hemispheres. Part of the difficulty in understanding the function of the basal forebrain lies in the anatomical complexity of the region. Using state-of-the-art tracing and immunocytochemical studies, Lennart Heimer1-6 was among the first to parcellate the “unnamed” substance of Reil7 into functional-anatomical compartments, including the ventral pallidum, the core/shell of the nucleus accumbens and the ‘extended amygdala’. Basal forebrain areas, including the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB), sublenticular substantia innominata and peripallidal regions contain cell types different in transmitter-content, morphology and projection pattern8-12. Among these different neuronal populations, the cholinergic corticopetal projection neurons have received particular attention due to their prominent loss in Alzheimer’s and related disorders13. However, cholinergic projection neurons represent only a fraction of the total cell population in these forebrain areas, which also contain various GABAergic and peptidergic neurons.
Mesulam14 proposed the Ch nomenclature to designate different groups of cholinergic neurons. The human basal forebrain-Ch complex extends from the level of the olfactory tubercle to that of the rostral level of the lateral geniculate body, spanning a rostrocaudal length of 19 mm. It attains its greatest medio-lateral width of 18 mm within the substantia innominata. The constituent neurons of the BF-Ch complex can be subdivided into four regions: the Ch1 and Ch2 regions (corresponding to the MS/VDB complex), the Ch3 region (HDB) and the Ch4 region. The latter region, also termed the nucleus basalis of Meynert, can be further subdivided into six sectors that occupy its anteromedial (Ch4am), anterolateral (Ch4al), anterointermediate (Ch4ai), intermediodorsal (Ch4id), intermedioventral (Ch4ai) and posterior (Ch4p) regions. Applying a 3-dimensional-sampling design, Vogels et al.15 estimated the total number of neurons within the human Ch complex to be 1.2 million in each hemisphere. The number of cholinergic neurons were estimated earlier by Arendt et al.16 to be about 220,000 on each side. Experimental neuroanatomical studies in the monkey17 have shown that different cortical regions receive their major input from individual sectors of the BF-Ch complex. Thus, neurons within the MS/VDB complex (Ch1/Ch2) provide the major cholinergic innervation of the hippocampus, and cholinergic cells within the HDB (Ch3) project to the olfactory bulb. The Ch4am provides the major source of input to medial cortical areas including the cingulate gyrus; Ch4al to frontoparietal opercular areas and the amygdala; Ch4i to lateral (pre)frontal, posterior parietal, peristriate, inferotemporal, parahippocampal, orbitoinsular regions, and Ch4p to superior temporal and temporopolar regions.
The number of cholinergic neurons in one hemisphere of the rat brain has been estimated to be between 18,000-20,000.10 Tracing studies in rodents established that cholinergic neurons in the BF innervate the entire cortex, including the hippocampus and amygdala according to a rough medio-lateral and antero-posterior topography.12,18-25 The dendrites of cholinergic neurons extend in an apparent random fashion for several hundred microns and often constitute overlapping fields (Fig. 1). However, using a computerized mapping system, the primary and secondary dendrites tend to show characteristic orientation according their location in the BF (J. Somogyi and Záborszky, in preparation).
The density of cholinergic cells is not uniform; they often form clusters consisting of 3-15 tightly packed cell bodies. Computational studies (Záborszky, Nadasdy, Somogyi, in preparation) suggest that the location of these clusters is unexpected based upon random distribution. Moreover, it appears that in the monkey a proportionally larger population of cholinergic cells is located in such clusters than in rodents (Fig. 2). At present, it is not known whether or not the diffusely located cholinergic cells and the clusters project to different or similar layers in the cortex. Their separate projection would explain, in part, how the BF can participate in both general (e.g. arousal) and more specific functions, including sensory processing or selective attention (see below).
It was earlier suggested that in both rodents20 and monkeys26 about 90% of the neurons that project to the neocortex are cholinergic, although this ratio would be smaller for septohippocampal cells (50-70%). More recent studies in rats27, however, questioned the validity of such data, showing that the proportion of cholinergic cells in some areas of the substantia innominata may be as low as 10%, and that cholinergic projection neurons make up only about half of the total projection to the somatosensory and prefrontal corticis.28,29 In a quantitative study10, it was calculated that the total number of GABAergic neurons in one side of the basal forebrain is 38,579 as compared to 18,236 cholinergic neurons, which would suggest, on the average, a 2:1 ratio for GABAergic/cholinergic neurons. Using calbindin (CB), calretinin (CR) and parvalbumin (PV) as markers for different classes of GABAergic neurons, we30 found a much higher GABAergic/cholinergic ratio of 3.8:1 (Fig. 4). Individual structures show different ratios. In the MS/VDB, HDB, ventral pallidum and the internal capsule the total GABAergic/cholinergic ratio is 3-4:1, however in the globus pallidus and the ‘extended amygdala’ (bed nucleus of stria terminals and substantia innominata) an even higher ratio of 8:1 is found. Although at this point it is unclear what proportion the above defined different GABAergic populations participate in the cortical projections, our preliminary studies suggest that at least a portion of CB, CR and PV neurons indeed project to various cortical areas (Figs. 7, 8, 9).
As Figures 3 and 4 suggest, the four cell types show hetereogeneous distribution across different structures. However, looking from a 3-dimensional perspective, these four cell types seem to construct longitudinal, obliquely (latero-medially) oriented, partially overlapping bands, or columns (Fig. 5). In the caudal two thirds of the basal forebrain, the latero-medial order of cells is PV-ChATg-CR-CB, while in the septum31 this pattern is clearly reversed. Located most medially are the parvalbumin cells and most laterally are the calbindin neurons. Cholinergic and calretinin cells are deposited in between. If this reverse-banded pattern is confirmed, this would suggest that the different cell ‘columns’ should be twisted in the area of the HDB. Interestingly, evidence that this “twisted pattern” in the longitudinal organization of the basal forebrain may exist is clearly visible from our study, showing how the medio-lateral portions of the hypothalamus innervate different latero-medially located cholinergic cells in the septum.32
Because most of the studies used only a few sections to map the distribution of retrogradely labeled cells, it remains to be tested in systematic 3-dimensional reconstruction studies whether or not corticopetal projection neurons in the BF are also organized according to rostro-caudal ‘bands’, and how these ‘bands’ relate to functionally or developmentally different cortical areas. According to a partial reconstruction of the neurons projecting to the prefrontal cortex and different sensory areas in rats, it is apparent (Fig. 6) that occasional retrograde labeled cells are distributed along bands in the whole rostro-caudal extent of the BF. The majority of projection neurons are confined, however, to specific regions of the BF. For example, the largest proportion of cells projecting to the auditory cortex are located around 2.5-2.8 mm behind the bregma, while the bulk of the neurons innervating the somatosensory (S1) cortex are located between 1.6-2.0 mm behind the bregma. On the other hand, the prefrontal cortex seems to receive projections from extended portions of the basal forebrain (Fig. 6). Comparing different cases or using double labeling, however, suggests that neurons projecting to functionally different cortical areas (e.g. somatosensory/versus visual) are segregated only by a narrow space of 50-200 m from each other in extended portions of the BF.
Powell and his coworkers33 proposed that different cortical areas receive their input from longitudinally curved, partially overlapping bands of cells in the basal forebrain. They also noticed that functionally interrelated areas of the prefrontal, sensory or motor areas of the cortex receive their projections from partially overlapping areas from the BF. Data from anterograde and retrograde studies and the distribution pattern of ChAT-PV-CR-CB suggests that a large part of the BF is organized into longitudinally oriented bands. This would be an extension of the original notion of Niewenhuys et al.34 that the different fiber components in the medial forebrain bundle retain their 3-dimensional spatial relationship across the entire length of the forebrain. Of course, the consequence of these data would be that neurons in these ‘twisted’ parallel bands may have a separate input-output pattern, and thus, may participate in different functions.
Cholinergic varicosities are present in all cortical layers38 and a varying proportion of them were reported to form clearly identifiable synapses (15% in rat parietal cortex39; 44% in monkey prefrontal cortex40 and 67% in human temporal cortex41), innervating pyramidal, spiny stellate and GABAergic neurons. There are marked laminar variations in the density of cholinergic synapses and the identity of their postsynaptic targets. For example, the proportion of GABA-positive postsynaptic elements are highest in layer IV and lowest in layers V-VI in the visual cortex.42 Due to distribution on various postsynaptic neurons that in turn may have different cholinergic receptors and specific intracortical connections, cholinergic activation may have a complex effect in cortical information processing. For example, acetylcholine (ACh) has been shown to excite layer V low-threshold spike (LTS) GABAergic cells through nicotinic receptors, whereas it elicites hyperpolarization in fast spiking (FS) GABAergic neurons in the same layer through muscarinic receptors.43 Axons of LTS cells mainly distribute vertically to upper layers (I-III), and those of FS cells are primarily confined to layer V pyramidal neurons. Activation of the cholinergic system could thus reduce, in the least, some forms of intralaminar inhibition (via FS cells) and together, with direct muscarinic depolarization of layer V pyramidal cells,44 increase pyramidal to pyramidal recurrent excitation and thus enhance the transfer of information between cortical columns. By contrast, nicotinic excitation of LTS cells would promote intracolumnar inhibition and enhance the inhibitory control of specific excitatory synaptic inputs to the pyramidal cells. Therefore, cholinergic activation may change the direction of information flow within cortical circuits, which may be important in enhanced response selectivity in cortical sensory processing that is observed during arousal or attention.45-49
GABAergic Innervation Pattern
GABAergic projection neurons in the basal forebrain seem to exclusively innervate various inhibitory neurons in the cortex.50 Since these GABAergic axons establish multiple contacts with inhibitory neurons, it is assumed that they can control a large population of principal cells. A recent electrophysiological study51 lends some credence to this assumption.
Because no individual corticopetal cholinergic or GABAergic axons have been identified thus far, their spatial distribution in a cortical column is unclear. Interestingly, the distribution of muscarinic and GABAA receptors in the visual cortex show segregated but partially overlapping columns (Zilles, personal communication). If these receptor distributions reflect the spatial arrangement of cholinergic and GABAergic axons arising from the BF, one can hypothesize that the somewhat segregated cholinergic and non-cholinergic ‘columns’ in the BF (see Fig. 6, AUD) would relate to separate cortical modules. This would further strengthen the idea that a subpopulation of BF neurons and specific cortical areas are interlinked through selective circuitries.
Cholinergic and other BF neurons are located in the way station for several ascending and descending pathways and thus may receive diverse input. For example, light microscopic tracer studies in rodents, carnivores and nonhuman primates52-60 suggest that basal forebrain areas receive input from non-isocortical paralimbic cortical areas (orbitofrontal-prefrontal, temporopolar, insular, parahippocampal and cingulate), the amygdala, the hypothalamus, and various brainstem cell groups. Indeed, electron microscopic studies in the rat confirmed the presence of synaptic input to BF cholinergic neurons from the amygdala, dorsal and ventral striatum, hypothalamus, locus coeruleus, and midbrain dopaminergic cell groups.61-69 Furthermore, based upon electron microscopic double labeling studies in rats, it has been found that cholinergic neurons in the ventral pallidum receive a massive GABAergic input.70 Additionally, cholinergic neurons receive restricted input from enkephalin,71,72 somatostatin,73 NPY,73 substance P,74 cholinergic,75 and CGRP76 axon terminals. In a recent electron microscopic study in the monkey77, the presence of GABAergic, cholinergic and catecholaminergic synapses on cholinergic neurons was confirmed, indicating a similarity in the afferent organization of cholinergic neurons between rodents and primates.
Because the painstaking electron microscopic studies confirmed most of what previous light microscopic studies suggested, it was a surprise that glutamatergic axons from the prefrontal cortex seem to terminate exclusively on non-cholinergic neurons, including parvalbumin-containing GABAergic cells,78 indicating some selectivity in the innervation pattern of BF neurons. Parvalbumin-containing neurons in the BF also receive dopaminergic input from the ventral tegmental area79 and synaptic input from the mesopontine tegmentum (Figs. 10-11). The transmitter character of this latter input is currently under investigation.
Although the noradrenergic and dopaminergic axons contact cholinergic neurons in extensive portions of the BF, the majority of afferents (cortical, striatal, peptidergic) appear to have a preferential distribution on subsets of BF neurons, as discussed in earlier reviews.80,81 Thus, the emerging view is that different subsets of BF neurons may receive different combinations of afferents according to their location in the BF. If this afferent topography would be retained in their efferent channels to the cortex, it would imply that subdivisions of the BF modulate selective cortical areas through certain restricted inputs.
Immuno- and histochemical studies also support the notion that BF neurons are neurochemically compartmentalized.82-89 However, it is unclear how the chemical signature of the neurons relate to their input-output pattern.
The suggestion that various non-cholinergic neurons may participate in different circuitries and thus contributing to functional compartments in the BF is implicated by our preliminary electrophysiological studies. Figure 12 shows the location of nine morphologically identified non-cholinergic neurons in the BF that were examined for their response to substantia nigra-ventral tegmental area (SN-VTA) or locus coeruleus (LC) stimulation. These neurons expressed different patterns of spontaneous activity and a wide range of firing rates. Stimulation of the SN or LC resulted in complex responses (Table 1). The morphology and axonal arborization pattern of these neurons were also heterogeneous. From this small pool of recorded neurons it is apparent that SN-VTA stimulation elicits responses from both projection neurons (identified antidromically from the cortex or having long projection axons without local collaterals) and putative interneurons (having rich local axonal arborizations with no noticeably long axons). Interestingly, none of the three interneurons (#1-3, Fig. 12 and Table 1) responded to LC stimulation. Whether noradrenergic input in the BF would indeed affect primarily projection neurons while the dopaminergic system could influence both local and projection neurons remains to be established in much larger samples.
Careful monitoring the behavioral effect of selective lesions indeed suggests that compartments of the basal forebrain together with specific cortical areas may participate in different cognitive operations.90 For example, the septohippocampal projection may be involved in short-term spatial (working) memory processes, the diagonal band-cingulate cortex cholinergic projection impacts on the ability to utilize response rules through conditional discrimination, the nucleus basalis-neocortical projection is involved in visual attention, and the nucleus basalis-amygdala cholinergic projection may have a role in the retention of affective conditioning (also see chapters of Sarter, Everitt and Gallagher, this volume). It is unclear, however, whether or not these functional compartments are organized according to ‘traditional’ borders or along longitudinally oriented bands, as would be predicted based upon previous sections in this chapter.
Recent studies in rats and monkeys using more specific lesioning of the basal forebrain cholinergic neurons indicate that the cholinergic projection neurons may not be required for learning, per se, but rather they may be important for specific aspects of attention.91,92 For example, monkeys with ibotenic acid lesions in the substantia innominata showed enhanced sensitivity to disruptive effects of invalid trials in a visuospatial attention shift paradigm.92 This lesion effect is strikingly similar to deficits of Alzheimer patients on this task.93 Similarly, rats with 192-saporin lesions showed impaired choice accuracy and stimulus discriminability in a visual attention task.94 Using a crossmodal divided attention paradigm, immuonolesions of the cholinergic system increased the response latencies under the condition of modality uncertainty.95 The impairments in two-choice96 or multiple-choice97 reaction time tasks in rodents after blocking the central cholinergic neurotransmission also suggests that the BF is involved in some form of bottom-up attentional processes. Finally, immunolesions in a different part of the basal forebrain98 suggest that pathways via the BF affect top-down attentional processes. More recently, PET neuroimaging studies in a human auditory vigilance test showed rCBF changes in the BF, indicating that this brain region is involved in arousal and/or attentional networks.99
BF stimulation delivered before the presentation of a sensory stimulus (within 200 msec) facilitates the evoked responses in the somatosensory or auditory cortices in anesthetized and awake animals.100-103 This facilitatory cortical effect could also be elicited by local cortical administration of ACh and blocked by muscarinic antagonists102,104 or local application of the immunotoxin 192-saporin.105 BF lesions prevent cortical receptive field reorganization after peripheral deafferentation106,107 and electrical stimulation in the BF elicits change in the representational cortical map.108 PET studies in human subjects during auditory discrimination classical conditioning tasks are in accordance with animal studies of experience-dependent plasticity, showing that rCBF of the auditory cortex positively co-varied with activity in the BF, amygdala and orbitofrontal cortex.109 These results support the notion that the BF cholinergic projection to the cortex is an important factor in learning-induced synaptic plasticity in the cortex.
Based upon clinical, imaging and anatomical studies, several networks are suggested as basic to attentional construction.110-114 The obligatory components of such circuits are posterior thalamocortical areas involved in perceptual categorization and anterior (prefrontal, cingulate) cortical areas involved in working memory and planning for action. Given the significance of the BF in mediating tonic cortical cholinergic activation upon electrical stimulation of the midbrain reticular formation,115-117 it is no surprise to find increased rCBF in basal forebrain areas during attentional tasks. It is possible that BF activation would cause a global enhancement of cortical ACh release and that the observed cortical plasticity is due to synaptic modifications through interaction of specific thalamic, ‘diffuse’ cholinergic and local cortical mechanisms.100,118 However, such a general cholinergic mechanism could hardly explain why only the responses to a specific stimulus are selectively enhanced. The emerging organizational plan of the BF, as described above, implies that BF circuits may participate in modality specific (selective) attention and cortical plasticity. According to this model, the enhancement of a sensory representation in the task-relevant sensory cortical area depends on activation of a specific sensory cortex-prefrontal-BF-sensory cortex re-entrant circuits that mediate the behavioral relevance of the situation.
The schematic diagram of Figure 13 is based on electron microscopic data using the strict criteria of correlating neurochemically identified neurons and synapses as well as assumptions derived from the putative organizational principles of the BF. The following points deserve discussion.
1) Brainstem pathways leading to activation of BF neurons. Unexpected or salient stimuli characteristically results in phasic activation of locus coeruleus units.119 The locus coeruleus, via its input to the BF,65 may send a “warning signal” to the forebrain. Basal forebrain neurons, through their input from the mesopontine tegmentum (Figs. 10-11), may also receive broadly tuned sensory-related information. Considering the conduction velocity of these brainstem axons120, it is likely that BF units may be activated as early as 12-14 msec after delivery of the sensory stimulus.115,121 Given the diffuse distribution of noradrenergic inputs to the BF, one could assume that this input would result in only a slight, global increase of cortical ACh efflux.
2) Information processing in the cortex. Attention effects on single-unit discharges are usually observed well after the initial arrival of the thalamo-cortical sensory afferent volleys. For example, auditory and somatosensory inputs arrive at primary cortex in 10-15 msec, but attention-related modulations occur 40-60 msec or even later.122 From the sensory cortex information flow proceeds via hierarchical and parallel routes123,124 and could eventually reach the prefrontal cortex within 10-15 msec after somatosensory (S1) stimulation (Nunez, personal communication).
3) Origin of late components of the evoked potentials. Selective somatosensory responses can also be observed in the BF 25 msec after S1 stimulation (Nunez, personal communication). BF stimulation provoked bursts in sensory cortex 40-60 msec after the end of the stimulus,51 which is also associated with increased ACh efflux in the appropriate cortical area. Thus, the proposed reentrant circuitry could explain the timeline of attention-related evoked potentials in the sensory cortex and the prefrontal input could amplify computations in a particular sensory area that initially performed the computation, a common observation in human imaging studies during attention tasks.110
4) Topographically organized parallel circuits. Attention in different sensory modalities is characterized by a special pattern of rCBF increase in the prefrontal cortex. Perception of different modalities gave rise to differently located activations in the prefrontal cortex of humans,113 which is compatible with the presence of separate modality-specific sensory areas in the prefrontal cortex of monkeys.125 Partially overlapping sensory areas has also been shown in the rat prefrontal cortex.123 Since different subdivisions of the prefrontal cortex project topographically to the BF,58 this projection via the longitudinally oriented cell bands of the BF could feed back to functionally segregated posterior sensory areas. It is envisaged that if the cell clusters receive prominent prefrontal input, they would be in a powerful position in amplifying selective cortical processing. This more selective cortical activation would be against the low level global cortical activation induced through noradrenergic input to the diffusely located solitary corticopetal cells. It is expected that several cortico-prefrontal-BF-cortical circuits exist and are somewhat similar to the better known parallel forebrain circuits that involve the prefrontal cortex, the basal ganglia and the thalamus.126
Recent anatomical as well as electrophysiological data127,128 contributed substantially to our understanding of the operational features of single cells. However, further investigation of the functions of the basal forebrain as a system requires the appreciation of the precise spatial relation of the different transmitter-specific neurons and their input-output characteristics. We suggest that the working memory and executive (prefrontal, cingulate) cortical areas work in close association with the basal forebrain in funneling towards the respective posterior cortical areas, the ‘energetic factors’ (arousal), and the affective state (amygdala) necessary for coordinating distributed cognitive operations. There are a lot of aspects in the proposed triangular amplification circuit (especially the precise local BF circuitry) that have to be considered hypothetical, but it appears to be consistent with what we know from the neurobiology and psychology of attention and cortical plasticity, respectively, and could serve as a basis for further testing.
FIGURE 1. Composite map illustrating the distribution of cholinergic neurons and their initial (about 150 m ) dendrites. This map was generated from 7 sections stained for choline acetyltransferase using the Neurolucida software package. For better visualization only the outlines and the corpus callosum are indicated. Anterior view. (A) low magnification, (B) enlargement from (A). Note that orientation of the dendrites show systematic shift along the rostro-caudal continuum of cholinergic cells. Abbr. MS/VDB = medial septum/vertical limb of the diagonal band; HDB = horizontal limb of the diagonal band; GP = globus pallidus; ic = internal capsule; SI = substantia innominata. From the unpublished material of J. Somogyi and Záborszky.
FIGURE 2. Scaling of 3-dimensional density distribution of cholinergic cells across species. The total volume in which cholinergic cells are located have been divided both in one rat (upper) (43.5 x 71.8 x 3400 m) and in one monkey (lower picture) (168 x 163 x 750 m) into one hundred equal cubes. Red dots represent cubes that contain at least 1 cholinergic cell (total cell number: rat = 15,777; monkey = 5,736). Asterisks symbolize cubes which contain 3-8 cells in the rat and 6-14 neurons in the monkey. These cubes altogether contain the most dense upper 20% of cells in each animal. The number of such cubes in rat (1,773) is much higher than in monkey (153), suggesting that the cholinergic cells in the unit volume of monkey are arranged in more clusters than in the rat. Distances in the coordinate system are in m. Note the different scaling factor in the two coordinate system. In the monkey (Macaca mulatta) we used an antibody against the low affinity NGF receptor for cholinergic marker, which is colocalized in 90-95% of the cholinergic neurons.
FIGURE 3. Distribution of cholinergic (ChAT), parvalbumin (PV), calretinin (CR) and calbindin (CB) containing neurons in adjacent sections, alternately stained for these four markers. Each dot represents one cell body. The approximate distances of the sections from the bregma are indicated in parentheses: ChAT (-0.82 mm); PV (0.88mm); CR (-0.76 mm) and CB (-0.69 mm).
FIGURE 4. Quantitative comparison of the four markers (ChAT, PV, CR and CB) in different basal forebrain structures. Ordinate indicates cell number counted in both sides in each structure using 48 alternately stained sections. Note the ratio of cholinergic cells to the other three non-cholinergic neurons varies from 1:3-4 (MS-VDB; HDB; VP; IC) to 1:8 (GP, SI-BST). VP = ventral pallidum; IC = internal capsule; BST = bed nuclus of the stria terminalis.
FIGURE 5. Three-dimensional spatial relational distribution of ChAT, PV, CR and CB cells in the basal forebrain. The viewpoint of the model is from below and most of the outlines are removed for clarity. The three sections with their approximate location to the bregma is for orientation. Because the symbols representing the different cell types are not-transparent, in order to appreciate their real position, the four models show four different renderings, placing one type of symbol on the top.
FIGURE 6. Comparative distribution of basal forebrain cells projecting to the prefrontal cortex (PFC), the primary somatosensory cortex (S1) and the auditory cortex (AUD). These maps were generated from 12 sections from three brains using the retrograde tracer Fluoro-Gold deposited in these cortical areas. Only the outlines and the corpus callosum are shown. Lateral view, left is rostral, right is caudal. White dots label the presence of cholinergic neurons, yellow down triangle symbolizes retrograde non-cholinergic cells and the red up triangle marks the location of cholinergic projection neurons. Note that the center of gravity of S1 projection neurons are slightly more rostral than that for auditory projection neurons.
FIGURE 7. Parvalbumin-containing cells projecting to the prefrontal cortex. (A) three Fluoro-Gold labeled cells. (B) Two of the retrogradely labeled cells are positive for parvalbumin (arrows). Lower inset shows the location of the photomicrograph (star). CP = caudate putamen; LV = lateral ventricle, ox = optic chiasm; ac = anterior commissure; HDB = horizontal limb of the diagonal band. Scale bar: 50 m.
FIGURE 8. Calbindin-containing neurons projecting to the prefrontal cortex from the anterior amygdaloid area. (A) Fluoro-Gold labeled retrograde cells. Arrows point to a neuron which is also positive for parvalbumin (B). GP = globus pallidus; SI = substantia innominata; sm = stria medullaris. Scale bar: 50 m.
FIGURE 9. Calretinin-containing (CR) neurons projecting to the auditory cortex. (A) Row of retrogradely labeled cells in the narrow zone between the optic tract (ot) and the internal capsule. (B) Two of the CR-containing neurons (arrows) are retrogradely labeled in (A). Lower right inset shows the location of the micrographs. + sign label the same vessel. MD = mediodorsal nucleus of the thalamus; BL = basolateral amygdaloid nucleus; ic = internal capsule. Scale bar: 100 m.
FIGURE 10. Ascending input from the pontine reticular formation to parvalbumin-containing (PV) basal forebrain neuron. (A) PHA-L labeled neurons in the oral part of the pontine reticular nucleus (PnO). Aq = aqueductus cerebri; ll = lateral lemniscus, ml = medial lemniscus; IC = inferior colliculus; mf = medial longitudinal fascicle. (A’) boxed are is shown with higher magnification in (B). Rt = reticular thalamic nucleus; sm = stria medullaris; f = fornix; AHA = anterior hypothalamic area; ox = optic chiasm. (B) Arrow points to a PV cell in the substantia innominata. (C) The PV-containing neuron is enwrapped by PHA-L labeled varicosities. Scale bar: 50 m.
FIGURE 11. Synaptic input from the brainstem to a PV-containing neuron in the ventral pallidum (A: asterisk). (B) Low magnifcation overview of a PV-containing neuron. Arrows point to PHA-L labeled synaptic terminals. (C) high magnification light micrograph of the PV-containing neuron depicted in (B). Arrows point to PAH-L labeled varicosities originating from the injection site in the brainstem (Fig. 10A). (D, E) high magnification electron micrographs of the left and right synaptic boutons from (B). Arrows point to the postsynaptic site. Scale bars: 1 m.
FIGURE 12. Rostro-caudal series of schematic coronal sections depicting the locations of juxtacellularly labeled non-cholinergic basal forebrain neurons that were tested for responses after substantia nigra (SN) or locus coeruleus (LC) stimulation using 2 mA. Cells # 4-8 responded both to SN and LC stimulation, while cells # 1-3 responded only to SN stimulation. Cell #9 did not respond to either stimulation. From the unpublished material of Pang, Tepper and Záborszky.
FIGURE 13. Hypothetical circuitry between prefrontal (PFC) and specific somatosensory (S1) cortical areas via GABAergic local and projection neurons of the basal forebrain. Cholinergic and non-cholinergic neurons in the basal forebrain receive identified synaptic input from the locus coerules (LC, brown), the substantia nigra (SN, green) and the mesopontine tegmentum (PPT, blue). The projection target of these BF neurons was not determined. The innervation territory of GABAergic and cholinergic axons in the PFC and S1 are indicated schematically as non-overlapping black (GABA) and red (cholinergic) columns. The axons of pyramidal cells in the S1 cortex (hyphenated line) innervate a pyramidal neuron in the PFC. IC = inferior colliculus; LP = lateral posterior thalamic n.; ml = medial lemniscus MV = medial vestibular n.; PPT = peduculopontine tegmental n.; SC = superior colliculus; sc = superior cerebellar peduncle; VL = ventrolateral thalamic n.; VPM = ventral posteromedial n.; 7 = facial n. To prepare this drawing we used Fig. 84 from the atlas of Paxinos and Watson.129
1. Heimer, L. & R.D. Wilson. 1975. The subcortical projections of the allocortex; similarities in the neural associations of the hippocampus, the priform cortex and the neocortex. In Golgi Centennial Symposium Proceedings. M. Santini, Ed. :177-193. Raven Press, New York, NY.
2. Heimer, L., R.D. Switzer & G.W. Van Hoesen. 1982. Ventral striatum and ventral pallidum. Components of the motor system? Trends Neurosci. 5: 83-87.
3. Heimer L., G.F. Alheid & L. Zaborszky. 1985. The basal ganglia. In The Rat Nervous System, Vol. 1, Forebrain and Midbrain, G Paxinos, Ed. : 37‑86. Academic Press, Sydney.
4. Heimer L., G.F. Alheid & L. Zaborszky. 1989. Substantia innominata and basal forebrain. In Neuroscience Year. G Adelman, Ed. : 21-24. Birkhauser, Boston.
5. Heimer L, J. de Olmos, G.F. Alheid & L. Zaborszky. 1991. "Perestroika" in the basal forebrain; Opening the border between Neurology and Psychiatry. Progr. Brain Res. 87: 109-165.
6. Zaborszky L., G.F. Alheid, M.C. Beinfeld, L.E. Eiden, L. Heimer & Palkovits M. 1985. Cholecystokinin innervation of the ventral striatum: A morphological and radioimmunological study. Neuroscience 14: 427‑453.
7. Reil, J.C. 1809. Untersuchungen uber den Bau des grossen Gehirn in Menschen. Arch. Psysiol. (Halle) 9: 136-208.
8. Brauer, K., A. Schober, J.R. Wolff, E. Winkelman, H. Luppa, H.-J. Luth & H. Bottcher. 1991. Morphology of neurons in the rat basal forebrain nuclei: Comparison between NADPH-diaphorase histochemistry and immunohistochemistry of glutamic acid decarboxylase, choline acetyltransferase, somatostatin and parvalbumin. J. Hirnforsch. 32: 1-17.
9. Dinopoulos, A., J.G. Parnavelas, H.B.M. Uylings & C.G. Van Eden. 1988. Morphology of neurons in the basal forebrain nuclei of the rat: a Golgi study. J. Comp. Neurol. 272: 461-474.
10. Gritti, L., L. Mainville, & B.E. Jones. 1993. Codistribution of GABA-with acetylcholine-synthesizing neurons in the basal forebrain of the rat. J. Comp. Neurol. 329: 438-457
11. Walker, L. C., V. E Koliatsos, C. A. Kitt, R.T. Richardson, A. Rokaeus &. D.L. Price. 1989. Peptidergic neurons in the basal forebrain magnocellular complex of the rhesus monkey. J. Comp. Neurol. 280: 272-282.
12. Zaborszky, L., J. Carlsen, H. R. Brashear & L. Heimer. 1986. Cholinergic and GABAergic afferents to the olfactory bulb in the rat with special emphasis on the projection neurons in the nucleus of the horizontal limb of the diagonal band. J. Comp. Neurol. 243: 488-509.
13. Price, D.L., P.J. Whitehouse & R.G Struble. 1986. Cellular pathology in Alzheimer's and Parkinson's diseases. Trends Neurosci. 9: 29-33.
14. Mesulam, M.M., E.J. Mufson, B.H. Wainer, & A.I. Levey. 1983. Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10: 1185-1201.
15. Vogels, O.J.M., C.A.J. Broere, H.J. ter Laak, H.J. ten Donkelaar, R. Nieuwenhuys & B.P.M. Schulte. 1990. Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer’s disease. Neurobiol Aging 11: 3-13.
17. Mesulam, M.M., E.J. Mufson, A.I. Levey & B.H. Wainer. 1983. 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. J. Comp. Neurol. 214: 170-97.
18. Sofroniew, M.V., F. Eckenstein, H. Thoenen & A.C. Cuello. 1982. Topography of choline acetyltransferase-containing neurons in the forebrain of the rat. Neurosci. Lett. 33: 7-12.
19. Armstrong, D.M., C.B. Saper, A.I. Levey, B.H. Wainer & R.D. Terry. 1983. Distribution of cholinergic neurons in the rat brain demonstrated by immunohistochemical localization of choline acetyltransferase. J. Comp. Neurol. 216: 53-68.
20. Rye, D.B., B.H. Wainer, M.-M. Mesulam, E.J. Mufson and C.B. Saper. 1984.Cortical projections arising from the basal forebrain: a study of cholinergic and noncholinergic components combining retrograde tracing and immunohistochemical localization of choline acetyltransferase. Neuroscience 13: 627-643.
21. Woolf, N.J., F. Eckenstein & L.L. Butcher. 1984. Cholinergic systems in the rat brain, I. Projections to the limbic telencephalon. Brain Res. Bull. 13: 751-784.
22. Amaral, D.G. & J. Kurz. 1985. An analysis of the origins of the cholinergic and non-cholinergic septal projections to the hippocampal formation in the rat. J. Comp. Neurol. 240: 37-59.
24. Luiten, P.G.M., R.P.A. Gaykema, J. Traber & D.G. Spencer. 1987. Cortical projection patterns of magnocellular basal nucleus subdivisions as revealed by anterogradely transported Phaseolus vulgaris leucoaagglutinin. Brain Res. 413: 229-250.
25. Gaykema, R.P.A., P.G.M. Luiten, C. Nyakas, & J. Traber. 1990. Cortical projection patterns of the medial septum-diagonal band complex, J. Comp. Neurol. 293: 103-124.
26. Mesulam, M.M., E.J. Mufson & B.H.Wainer. 1986. Three-dimensional representation and cortical projection topography of the nucleus basalis (Ch4) in the macaque: concurrent demonstration of choline acetyltransferase and retrograde transport with a stabilized tetramethylbenzidine method for HRP. Brain Res. 367: 301-308.
27. Pang, K., J.M. Tepper & L. Zaborszky. 1998. Morphological and electrophysiological characteristics of non-cholinergic basal forebrain neurons. J. Comp. Neurol. 394: 186-204.
28. Lynch, B., D. Orosz & L. Zaborszky. 1996 Basal forebrain corticopetal system: 3-D computer graphic reconstruction. Soc. Neurosci. Abst. 22: 1256.
29. Gritti, I., L. Mainville, M. Mancia & B. Jones. 1997. GABAergic and other noncholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat. J. Comp. Neurol. 383: 163-177.
30. Poobalasingham, S., K. Pang & L. Zaborszky. 1996. Distribution of neurons containing different type of calcium binding proteins in the cholinergic basal forebrain. Soc. Neurosci. Abst. 22: 1255.
31. Kiss, J. Z. Magloczky, J. Somogyi & T. F. Freund. 1997. Distribution of calretinin containing neurons relative to other neurochemically identified cell types in the medial septum of the rat. Neuroscience 78: 399-410.
33. Pearson, R.C.A., K.C. Gatter, P. Brodal & T.P.S. Powelll. 1983. The projection of the basal nucleus of Meynert upon the neocortex in the monkey. Brain Res. 259: 132-136.
34. Nieuwenhuys, R., L.M.G. Geeraedts & J.G. Veening. 1982. The medial forebrain bundle of the rat. I. General information. J. Comp. Neurol. 206: 49-81.
36. Mesulam, M.M., L., Volicer, J.K. Marquis, E.J. Mufson & R.C. Green. 1986. Systematic regional differences in the cholinergic innervation of the primate cerebral cortex: distribution of enzyme activities and some behavioral implications. Ann. Neurol. 19: 144-151.
37. Lysakowski, A., B.H. Wainer, G.C. Bruce & L.B. Hersh. 1988. An atlas of the regional and laminar distribution of choline acetyltransferase immunoreactivity in rat cerebral cortex. Neuroscience 28: 291-336.
38. Houser, C.R., G.D. Crawford, P.M. Salvaterra, & J.E. Vaughn. 1985. Immunocytochemical localization of choline acetyltransferase in rat cerebral cortex: A study of cholinergic neurons and synapses. J. Comp. Neurol. 234: 17-34.
39. Umbriaco, D., K.C. Watkins, L. Descarries, C. Cozzari & B.K. Hartman. 1994. Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: An electron microscopic study in serial sections. J. Comp. Neurol. 348: 351-373.
40. Mrzljak, L., M. Pappy, C. Leranth & P.S. Goldman-Rakic. 1995. Cholinergic synaptic circuitry in the macaque prefrontal cortex. J. Comp. Neurol. 357: 603-617.
41. Smiley, J.F. Morrell, F. & M.M. Mesulam. 1997. Cholinergic synapses in human cerebral cortex: An ultrastructural study in serial sections. Exp. Neurol. 144: 361-368.
42. Beaulieu, C. & P. Somogyi. 1991. Enrichment of cholinergic synaptic terminals on GABAergic neurons and coexistence of immunoreactive GABA and choline acetyltransferase in the same synaptic terminals in the striate cortex of the cat. J. Comp. Neurol. 304: 666-680.
43. Xiang, Z., Huguenard, J.R. & D.A. Prince. 1998. Cholinergic switching within neocortical inhibitory networks. Science 281: 985-988.
44. McCormick, D.A. 1993. Action of acetylcholine in the cerebral cortex and thalamus and implications for function. Progr. Brain Res. 98: 303-308.
46. Lewandowski, M.H., C.M. Muller & W. Singer. 1993. Reticular facilitation of cat visual cortical responses is mediated by nicotinic and muscarinic cholinergic mechanisms. Exp. Brain Res. 96: 1-7.
47. Muller, C.M., M.H. Lewandowski & W. Singer. 1993. Structures mediating cholinergic reticular facilitation of cortical responses in the cat: effects of lesions in immunocytochemically characterized projections. Exp. Brain Res. 96: 8-18.
48. Munk, M.H.J., P.R. Roelsema, P. Konig, A.K. Engel & W. Singer. 1996. Role of reticular activation in the modulation of intracortical synchronization. Science 272: 271-274.
49. Sillito, A.M. 1993. The cholinergic modulatory system: an evaluation of its functional roles. Progr. Brain Res. 98: 371-378.
50. Freund, T.F. & Gulyas, A.I. 1991. GABAergic interneurons containing calbindin D28k or somatostatin are major targets of GABAergic basal forebrain afferents in the rat neocortex. J. Comp. Neurol. 314: 187-199.
51. Jimenez-Capdeville, M.E., R.W. Dykes & A.A. Myasnikov. 1997. Differential control of cortical activity by the basal forebrain in rats: a role for both cholinergic and inhibitory influences. J. Comp. Neurol. 381: :53-67.
52. Jones, E.G., H. Burton, C.B. Saper & L. Swanson. 1976. Midbrain, diencephalic and cortical relationships of the basal nucleus of Meynert and associated structures in primates. J. Comp. Neurol. 167: 385-420.
53. Mesulam, M.M. and Mufson, E.J., 1984, Neural inputs into the nucleus basalis of the substantia innominata (Ch4) in the rhesus monkey, Brain, 107:253-274.
54. Russchen, F.T. D.G. Amaral & J.L. Price. 1985. The afferent connections of the substantia innominata in the monkey, Macaca fascicularis, J. Comp. Neurol. 242: 1-27.
55. Irle, E. H. & J. Markowitsch. 1986. Afferent connections of the substantia innominata/basal nucleus of Meynert in carnivores and primates, J. Hirnforsch. 27: 343-367.
56. Grove, E.A., V.B. Domesick & W.J.H. Nauta. 1986. Light microscopic evidence of striatal input to intrapallidal neurons of cholinergic cell group Ch4 in the rat: a study employing the anterograde tracer Phaseolus vulgaris leucoagglutinin (PHA‑L). Brain Res. 367: 379‑384.
57. Semba K., Reiner P. B., McGeer E. G. and Fibiger H. C. (1988) Brainstem afferents to the magnocellular basal forebrain studied by axonal transport, immunohistochemistry, and electrophysiology in the rat. J. Comp. Neurol 267: 433-453.
58. Sesack S. R., A. Y. Deutch, R. H. Roth & B. S. Bunney. l989. Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: An anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 290: 213-242.
59. Jones B. E & A.C. Cuello. 1989. Afferents to the basal forebrain cholinergic cell area from the pontomesencephalic-catecholamine, serotonin, and acetylcholine-neurons. Neuroscience 31: 37-61.
60. Hurley K. M., H. Herbert, M.M. Moga & C.B. Saper. 1991. Efferent projections of the infralimbic cortex of the rat. J. comp. Neurol. 308: 249-276.
61. Zaborszky L., C. Leranth C. & L. Heimer. 1984. Ultrastructural evidence of amydalofugal axons terminating on cholinergic cells of the rostral forebrain. Neurosci. Lett. 52: 219-225.
62. Zaborszky L. & W. E Cullinan. 1989. Hypothalamic axons terminate on forebrain cholinergic neurons: An ultrastructural double‑labeling study using PHA‑L tracing and ChAT immunochemistry. Brain Res. 479: 177‑184.
63. Cullinan W. E. and Zaborszky L. (l991) Organization of ascending hypothalamic projections to the rostral forebrain with special reference to the innervation of cholinergic projection neurons. J. Comp. Neurol. 306: 631-667.
64. Zaborszky L. & W.E Cullinan. 1992. Projections from the nucleus accumbens to cholinergic neurons of the ventral pallidum: a correlated light and electron microscopic double-immunolabeling study in rat. Brain Res. 570: 92-101.
65. Zaborszky, L., W.E. Cullinan & V.N. Luine. 1993. Catecholaminergic-cholinergic interaction in the basal forebrain. Prog. Brain Res. 98: 31-49.
66. Zaborszky L. & W. E Cullinan. 1996. Direct catecholaminergic-cholinergic interactions in the basal forebrain. I. Dopamine-b-hydroxylase- and tyrosine hydroxylase input to cholinergic neurons. J. Comp. Neurol. 374: 535-554.
67. Gaykema, R.P.A. & L. Zaborszky. 1996. Direct catecholaminergic-cholinergic interactions in the basal forebrain: II. Substantia nigra and ventral tegmental area projections to cholinergic neurons. J. Comp. Neurol. 374: 555-577.
68. Rodrigo, J., P. Fernandez, M.L. Bentura, J.M. de Velasco, J. Serrano, O. Uttenthal & R. Martinez-Murillo. 1998. Distribution of catecholaminergic afferent fibres in the rat globus pallidus and their relations with cholinergic neurons. J. Chem. Neuroanat. 15: 1-20.
69. Henderson, Z. 1997. The projection from the striatum to the nucleus basalis in the rat: An electron microscopic study. Neuroscience 78: 943-955.
70. Zaborszky L., Heimer L., Eckenstein F. and Leranth C. (1986) GABAergic input to cholinergic forebrain neurons: An ultrastructural study using retrograde tracing of HRP and double immunolabeling. J. Comp. Neurol. 250: 282-295.
71. Chang, H.T., Penny, G.R. & S.T. Kitai. 1987. Enkephalinergic-cholinergic interaction in the rat globus pallidus: a pre-embedding double-labeling immunocytochemistry study. Brain Res. 426: 197-203.
72. Martinez-Murillo, R. Blasco, I. Alavrez, F.J. Villalba, R. Solano, M.L. Montero-Caballero & J. Rodrigo. 1988. Distribution of enkephalin-immunoreactive nerve fibers and terminals in the region of the nucleus basalis magnocellularis of the rat: a light and electron microscopic study. J. Neurocytol. 17: 361-376.
74. Bolam, J.P., C.A. Ingham, P.N. Izzo, A.I. Levey, D.B. Rye, A.D. Smith & B.H. Wainer.1986. Substance P-containing terminals in synaptic contact with cholinergic neurons in the neostriatum and basal forebrain; a double immunocytochemical study in the rat. Brain Res. 397: 279-289.
75. Martinez-Murillo, R., R.M. Villalba & J. Rodrigo. 1990. Immunocytochemical localization of cholinergic terminals in the region of the nucleus basalis magnocellularis of the rat: a correlated light and electron microscopic study. Neuroscience 36: 361-376.
76. Csillik, B., P. Rakic, & E. Knyihar-Csillik. 1998. Peptidergic innervation and the nicotinic acetylcholine receptor in the primate basal nucleus. Eur. J. Neurosci. 10: 573-585.
77. Smiley, J.F. & M.-M. Mesulam. 1998. Cholinergic neurons of the nucleus basalis of Meynert receive cholinergic, catecholaminergic and GABAergic synapses: An electron microscopic investigation in the monkey. Neuroscience 88: 241- 254.
78. Zaborszky, L., R.P. Gaykema, D.J. Swanson & W.E. Cullinan. 1997. Cortical input to the basal forebrain. Neuroscience 79: 1051-1078.
79. Gaykema, R.P.A. & L. Zaborszky. 1997. Parvalbumin-containing neurons in the basal forebrain receive direct input from the substantia nigra-ventral tegmental area. Brain Res. 478: 375-381.
80. Zaborszky L, Cullinan W.E. & A. Braun. 1991. Afferents to basal forebrain cholinergic projection neurons: An update In Basal Forebrain: Anatomy to Function. Napier T. C., P.W. Kaliwas & I. Hanin, Eds. : 43-100. Plenum Press, New York, NY.
81. Zaborszky, L. 1992. Synaptic organization of basal forebrain cholinergic projection neurons. In Neurotransmitter Interactions and Cognitive Functions. E.D. Levin, M. Decker & L. Butcher, Eds. : 27-65. Birkhauser, Boston.
82. Benzing, W.C., J.H. Kordower & E. J. Mufson. 1993. Galanin immunoreactivity within the primate basal forebrain: evolutionary change between monkeys and apes. J. Comp. Neurol. 336: 31-39.
84. Ding, Y.Q., R. Shigemoto, M. Takada, H. Ohishi, S. Nakanishi & N. Mizuno. 1996. Localization of the neuromedin K receptor (NK3) in the central nervous system of the rat. J. Comp. Neurol. 364: 290-310.
86. Planas, B., P.E. Kolb, M.A. Raskind & M.A. Miller. 1995. Vasopressin and galanin mRNAs coexist in the nucleus of the horizontal diagonal band: A novel site of vasopressin gene expression. J. Comp. Neurol. 361: 48-56.
87. Rance, N.E., W.S. Young III & N.T. McMullen. 1994. Topography of neurons expressing luteinizing hormone-releasing hormone gene transcripts in the human hypothalamus and basal forebrain. J. Comp. Neurol. 339: 573-586.
88. Sobreviela, T., S. Jaffar & E.J. Mufson. 1998. Tyrosine kinase A, galanin and nitric oxide synthase within basal forebrain neurons in the rat. Neuroscience 87: 447-461.
89. Sugaya, K. & M. McKinney. 1994. Nitric oxide synthase gene expression in cholinergic neurons in the rat brain examined by combined immunocytochemistry and in situ hybridization histochemistry. Molecular Brain Res. 23: 111-125.
90. Everitt, B.J. & T.W. Robbins. 1997. Central cholinergic systems and cognition. Annu. Rev. Psychol. 48: 649-684.
91. Dunnett, S.B., B.J. Everitt & T.W. Robbins. 1991. The basal forebrain-cortical cholinergic system: interpreting the functional consequences of excitotoxic lesions. Trends Neurosci. 14: 494-501.
92. Voytko, M.L., D.S. Olton, R.T. Richardson, L.K. Gorman, J.R. Tobin & D.L. Price. 1994. Basal forebrain lesions in monkeys disrupt attention but not learning and memory. J. Neurosci. 14: 167-186.
93. Parasuraman, R., P.M. Greenwood, J.V. Haxby & C.L. Grady. 1992. Visuospatial attention in dementia of the Alzheimer type. Brain. 115: 711-733.
94. Stoehr, J.D. S.L. Mobley, D. Roice, R. Brooks, L.M. Baker, R.G. Wiley & G.L. Wenk. 1997. The effects of selective cholinergic basal forebrain lesions and aging upon expectancy in the rat. Neurobiol. Learning & Memory 67: 214-227.
95. Turchi, J. & M. Sarter. 1997. Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on crossmodal divided attention in rats. Cogn. Brain Res. 6: 147-158.
96. Pang, K., M.J. Williams, H. Egeth & D.S. Olton. 1993. Nucleus basalis magnocellularis and attention: effects of muscimol infusions. Behav. Neurosci. 107: 1031-1038.
97. Muir J.L., B.J. Everitt & T.W. Robbins. 1994. AMPA-induced excitotoxic lesions of the basal forebrain: A significant role for the cortical cholinergic system in attentional function. J. Neurosci. 14: 2313-2326.
98. Baxter, G.M & M. Gallagher. 1997. Cognitive effects of selective loss of basal forebrain cholinergic neurons: Implications for cholinergic therapies of Alzheimer’s disease. In Pharmacological Treatment of Alzheimer’s Disease: Molecular and Neurobiological Foundations. Brioni & M.W. Decker, Eds. : 87-103. Wiley-Liss, Inc. New York, NY.
99. Paus, T., R.J. Zatorre, N. Hofle, Z. Caramanos, J. Gotman, M. Petrides & A.C. Evans. 1997. Time-related changes in neural systems underlying attention and arousal during the performance of an auditory vigilance task. J. Cogn. Neurosci 9: 392-408.
100. Bakin, J. S. & N. W. Weinberger. 1996. Induction of a physiological memory in the cerebral cortex by stimulation of the nucleus basalis. Proc. Natl. Acad. Sci. USA. 93: 11219-11224.
101. Edeline, J.-M., B. Hars, et al. 1994. Transient and prolonged facilitation of tone-evoked responses induced by basal forebrain stimulations in the rat auditory cortex. Exp. Brain Res. 97: 373-386.
102. Metherate, R. & J.H. Ashe. 1991. Basal forebrain stimulation modifies auditory cortex responsiveness by an action at muscarinic receptors. Brain Res. 559: 163-167.
103. Tremblay, N., R. A. Warren &. R.W. Dykes. 1990. Electrophysiological studies of acetylcholine and the role of the basal forebrain in the somatosensory cortex of the cat. II. Cortical neurons excited by somatic stimuli. J. Neurophysiol. 64: 1212-1222.
104. Maalouf, M., A.A. Miasnikov & R.W. Dykes. 1998. Blockade of cholinergic receptors in rat barrel cortex prevents long-term changes in the evoked potential during sensory preconditioning. J. Neurophysiol. 80: 529-545.
105. Sachdev, R.N.S., S.M. Lu, R.G. Wiley & F.F. Ebner. 1998. Role of the basal forebrain cholinergic projection in somatosensory cortical plasticity. J. Neurophysiol. 79: 3216-3228.
106. Baskerville, K. A., J. B. Schweitzer & P. Herron. 1997. Effects of cholinergic depletion on experience-dependent plasticity in the cortex of the rat. Neuroscience 80: 1159-1169.
109. Morris, J.S., K.J. Friston & R.J. Dolan. 1998. Experience-dependent modulation of tonotopic neural responses in human auditor cortex. Proc. R. Soc. Lond. B. 265: 649-657.
111. LaBerge, D. 1995. Attentional Processing. Harvard University Press, Cambridge, MA, p. 262.
112. Heilman, K.H., R.T. Watson & E. Valenstein. 1993. Neglect and related disorders. In Clinical Neuropsychology. K.M. Heilman & E. Valenstein, Eds, : 279-336. Oxford University Press, New York, NY.
113. Roland, PE. 1994. Brain Activation. Wiley-Liss, New York, pp. 589.
114. Mesulam M-M. 1990. Large-scale neurocognitive networks and distributed processing for attention, language, and memory. Ann. Neurol 28: 597-613.
117. Steriade, M. E.G. Jones & D.A. McCormick. 1997. Thalamus. Vol. 1. Organization and Function. Elsevier, Amsterdam.
118. Sarter, M. & J.P. Bruno. 1997. Cognitive functions of cortical acetylcholine: toward a unifying hypothesis. Brain Res. Rev. 23: 28-46.
119. Aston-Jones, G., J. Rajkowski, P. Kubiak & T. Alexinsky. 1994. Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. J. Neurosci. 14: 4467-4480.
120. Faiers, A.A. & G.J. Mogenson. 1976. Electrophysiological identification of neurons in locus coeruleus. Expl. Neurol. 53: 254-266.
123. Van Eden, C. G., V. A. F. Lamme & H.B.M. Uylings. 1991. Heterotopic cortical afferents to the medial prefrontal cortex in the rat. A combined retrograde and anterograde tracer study. Eur. J. Neurosci. 4: 77-97
124. Felleman, D.J. & D.C. Van Essen. 1991. Distributed hierarchical processing in the primate cerebral cortex. Cerebral Cortex 1: 1-47.
126. Alexander G. E. and Crutcher M. D. (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 13: 266-271.
128. Alonso, A.1999. Intrinsic electroresponsiveness of basal forebrain cholinergic and non-cholinergic neurons. In Handbook of Behavioral State Control. R. Lydic & A.A. Baghdoyan, Eds. : 297-309. CRC Press, Boca Raton, FL.
129. Paxinos, G. & C. Watson. 1998. The Rat Brain in Stereotaxic Coordinates. Academic Press, San Diego, CA.
a This research was supported by NIH Grant No. NS23945. Special thanks are due to Mr. Derek Buhl, Mrs. E. Rommer, Mr. S. Poobalasingham and Mr. B. Lynch for expert technical assistance.
b Address correspondence to Laszlo Zaborszky, M.D., Ph.D., Center for Molecular and Behavioral Neuroscience, Rutgers Univeristy, 197 University Ave., Newark, NJ 07102.
g For visualizing cholinergic neurons in rats, we used an antibody against choline acetyltransferase.61