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.
LEGEND
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