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Choline acetyltransferase and acetylcholinesterase activities in neocortex and hippocampus of squirrel monkey (Saimiri sciureus).

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American Journal of Primatology 11:195-201 (1986)
Choline Acetyltransferase and Acetylcholinesterase
Activities in Neocortex and Hippocampus of Squirrel
Monkey (Saimiri sciureus)
Departments of ‘Pathology, ‘Neurology, and Neuroscience, 3Neuropathology Laboratory,
The Johns Hopkins University School of Medicine, Baltimore, Maryland and 4Department
of Neurobwlogy, Delta Regional Primate Research Center, Tulane Universitr Medical Center.
Couington, Louisiana
The activities of choline acetyltransferase (ChAT) and acetylcholinesterase
(AChE) were measured in five neocortical regions and in the hippocampal
formation of one hemisphere in eight 30-day-old squirrel monkeys. Enzyme
levels in the hippocampal formation (hippocampus, dentate gyrus, and subiculum) were higher than in any neocortical region. Within neocortex,
ChAT activity was highest in superior temporal and precentral regions,
intermediate in prefrontal and postcentral regions, and lowest in occipital
cortex. AChE activity also varied across neocortical regions and correlated
significantly, but imprecisely, with ChAT activity. The activity of overall
neocortical C U T , but not AChE, differed significantly among animals. The
pattern of cholinergic innervation of neocortex in the lissencephalic squirrel
monkey is highly similar to that reported in gyrencephalic Old World
Key words: acetylcholine, nucleus basalis of Meynert, nucleus of the diagonal band of
In primates, neurons of nucleus basalis of Meynert (nbM) and nucleus of the
diagonal band of Broca (dbB) [Mesulam et al, 19831 are the major source of acetylcholinergic innervation of neocortex [Struble et al, in press]. In addition, cholinergic
neurons of the dbB (which extend into the medial septum) and, to a lesser extent,
the nbM provide substantial innervation of the hippocampal formation [Amaral &
Cowan, 1980; Mesulam et al, 19831. Cholinergic transmission is thought to be
important in cognitive processes such as memory [Bartus et al, 19821; hence, dysfunction and death of neurons in the basal forebrain cholinergic system may contribute to the mnemonic and cognitive impairments and to some focal cortical deficits
occurring in Alzheimer’s disease and in Parkinson’s disease [Bowen, 1981; Whitehouse et al, 1982; Arendt et al, 1983; Whitehouse et al, 1983; Perry et al, 1985;
Rogers et al, 1985; Price et al, 19861.
Received January 23,1986;revision accepted April 26,1986.
Address reprint requests to Dr. Lary C. Walker, Neuropathology Laboratory, 509 Pathology Building, The
Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205-2182.
0 1986 Alan R. Liss. Inc.
196 / Walker et a1
In primates, a n imprecise topographical relationship exists between neurons in
the basal forebrain cholinergic system and their cortical targets [Kievit & Kuypers,
1975; Jones et al, 1976; Mesulam et al, 1983; Pearson et al, 1983; Walker et al, 19851.
For example, more posterior nbM neurons tend to innervate caudal regions of cortex,
and rostra1 nbM neurons project primarily to anterior cortex, with significant intermingling of the two neuronal populations [Kievit & Kuypers, 1975; Mesulam et al,
1983; Tigges et al, 1982; Pearson et al, 1983; Tigges et al, 1983; Walker et al, 19851.
In squirrel monkeys (New World monkeys), posteriormost neurons of the nbM form
a prominent “tail” occupying the external lamina of the globus pallidus, and numerous nbM neurons also extend into the internal pallidal lamina. In rhesus monkeys
(Old World monkeys), cells in these laminae are somewhat less common, and, in
Great Apes and humans, they are even rarer [Feremutsch, 1961; Gorry, 1963; Tigges
et al, 1983; Hedreen et al, 1984~1.
In light of these anatomical differences in the nbM in representatives of different primate families (Cebidae, Cercopithecidae, Pongidae, and Hominidae), we believe it important to ask whether there are corresponding disparities in patterns of
cortical cholinergic innervation by basal forebrain neurons in New World and Old
World primates. One means of assessing cholinergic input to cortex is to measure
the activity of cortical ChAT, the enzyme that synthesizes acetylcholine and is a
specific marker for cholinergic neurons. Studies of ChAT levels in baboons (Pupio)
[Nakamura et al, 19761 and cynomolgus macaques (Mucucu fascicularis) [Lehmann
et al, 19841 suggest that the density of cholinergic innervation may differ among
heterogeneous cortical regions of gyrencephalic Old World primates. However, studies of cholinergic enzymes in cortices of lissencephalic New World monkeys have not
yet systematically addressed the issue of variability among cortical areas. Furthermore, only Nakamura et a1 [1976] measured both ChAT and AChE in the same
cortical regions of a primate. AChE, associated with cholinergic as well as some
noncholinergic elements [Silver, 1974; Butcher et al, 1975; Mesulam & Dichter,
1981;Delfs et al, 19831, is a consistent but nonspecific marker for cholinergic systems
[Levey et al, 19831. Therefore, in the study reported here, we measured the activities
of ChAT and AChE in the neocortices and hippocampi of squirrel monkeys and
compared our data to information derived from studies of Old World primates,
including macaques [Lehmann et al, 19841, baboons [Nakamura et al, 19761, and
humans [Davies, 1979; Rossor et al, 19821.
The subjects of this study were eight 30-day-old squirrel monkeys (Sairniri
sciureus), which served as controls in a study of prenatal radiation effects on postnatal development [Kaack et al, 19801; four monkeys were of Bolivian origin (males),
and four were Guyanan (three males, one female). In each animal, the activities of
AChE and ChAT were measured in five regions of neocortex and in a midlevel
segment of the hippocampal formation (hippocampus, dentate gyrus, and subiculum)
(Fig. 1) from the right hemisphere. In neocortical samples, efforts were made to
exclude subcortical white matter. ChAT activity was measured by the method of
Fonnum [Fonnum, 19751, and AChE activity was determined in the same tissue
homogenate according to Ellman et a1 [1961].
The activities of ChAT and AChE were higher in the hippocampal formation
than in any neocortical region (Fig. 1). In the neocortex, ChAT activity was greatest
in the superior temporal and precentral regions: intermediate activity was demonstrable in postcentral and prefrontal regions; occipital cortex showed the lowest level
Cholinergic Enzymes in Monkey Cortex / 197
Fig. 1. Schematic drawing of loci of neocortical and hippocampal samples from right hemisphere of
squirrel monkey, together with mean levels of ChAT (solid bars) and AChE (dotted bars) activities in eight
squirrel monkeys. In addition, standard deviations are indicated. Abbreviations: O/Occ, occipital cortex;
T/Temp, temporal cortex; Polpost C, postcentral cortex; F’i-Pre C, precentral cortex; F/Fron, frontal cortex;
WHipp, hippocampal formation; LS, lateral sulcus (Sylvian Fissure).
of C U T activity (Fig. 1.) Differences in ChAT activity across cortical subdivisions
were statistically significant (analysis of variance, F = 19.4 p < 0.01). In addition,
levels of AChE activity differed significantly across cortical regions (F = 23.6, p <
0.01) and generally covaried with C U T levels (Pearson’s r = 0.54, p < 0.01; Fig. 1).
However, the ratio of AChE to ChAT in precentral and occipital regions was relatively low, while in frontal cortex the ratio was relatively high. When values for
cortical cholinergic enzymes were pooled for each monkey (Fig. 21, interindividual
differences in cortical ChAT were significant when tested with a repeated measures
(subjects x cortical areas) analysis of variance (F = 3.82; p < 0.01); AChE levels did
not differ significantly among animals (F = 1.38; p > 0.05). The four monkeys of
Guyanan origin did not differ significantly from Bolivian monkeys in either overall
ChAT or AChE activity in cortex, although the sample was too small to compare the
two phenotypes definitively.
These results indicate that individual squirrel monkeys differ in mean ChAT
activity in neocortex, as has been found in cynomolgus, or long-tailed macaques
(Macaca fmciculuris) [Lehmann et al, 19841, and that levels of ChAT activity in
squirrel monkeys (lissencephalic New World primates) vary across cortical regions
in a manner similar to that in gyrencephalic Old World primates [Nakamura et al,
1976; Lehmann et al, 19841. ChAT values in normal human cortex also vary regionally [Davies, 1979; Rossor et al, 19821, and, despite some discrepancies, this variation
is generally comparable to the pattern in other primates. The regional heterogeneity
of ChAT activity may reflect differences in the magnitude of neocortical innervation
by cholinergic neurons in the basal forebrain of primates. Thus, although basal
198 I Walker et a1
Fig. 2. Pooled levels of ChAT (solid bars) and AChE (dotted bars) activities including standard deviations,
across five regions of neocortex in eight 30-day-old squirrel monkeys. ChAT levels, but not AChE levels,
varied significantly among individuals.
forebrain cholinergic neurons are distributed somewhat differently in divergent
primate species [Feremutsch, 1961; Gorry, 1963; Tigges et al, 19831, the pattern of
regional cortical cholinergic innervation in New World monkeys, Old World monkeys, and humans appears to be quite similar.
AChE levels covary significantly with ChAT levels in cortex of squirrel monkey,
but the correlation is imprecise. This finding is consistent with a study of baboon
neocortex in which both ChAT and AChE were measured [Nakamura et al, 19761,
except that the ratio of AChE to C U T in frontal cortex was lower in adult baboons
than in our 30-day-old squirrel monkeys. This could reflect differences in such
variables as species or sampled cytoarchitectonic areas. The lack of perfect correspondence between ChAT and AChE activities among cortical regions probably
results from the variable contribution of noncholinergic systems to the total pool of
AChE [Butcher et al, 1975; Mesulam and Dichter, 1981; Delfs et al, 19831. Histochemical analysis of AChE-positive [Hedreen et al, 198461 and ChAT-immunoreactive fibers in heterogeneous cortical areas will help to resolve this issue.
The functional implications of quantitative differences in cholinergic markers
in primate cortex are not yet clear. Levels of ChAT and AChE activities in all
neocortical areas studied are lower than those in the hippocampal formation, an
allocortical structure involved in memory processing [Olton et al, 1979; Mishkin et
al, 19821. In primates, the principal source of hippocampal ChAT is the dbB [Mesulam et al, 19831, the cells of which extend into the medial septum, while the major
source of neocortical ChAT is the nbM [Struble et al, in press]. Unilateral lesions of
the nbM reduce cortical cholinergic markers ipsilaterally in macaques [Struble et
al, in press], and bilateral lesions of medial septum, dbB, and nbM cause impairments in visual recognition memory [Aigner et al, 19841. Moreover, some behavioral
abnormalities in aged nonhuman primates [Davis, 1978, Bartus et al, 1982; Presty
et al, 19841 may be related to the presence of neocortical senile plaques [Struble et
al, 19851, some neurites of which are derived from neurons of the basal forebrain
cholinergic system [Struble et al, 1982,1984; Kitt et al, 19841. Finally, neurons
located in this basal forebrain cholinergic complex are affected in several human
neurological diseases associated with impairments in memory and cognition, including Alzheimer’s disease [Bowen et al, 1976; Davies & Maloney, 1976; Rossor et al,
1982; Whitehouse et al, 1982; Arendt et al, 1983; Price et al, 19861, Parkinson’s
disease [Ruberg et al, 1982; Arendt et al, 1983; Whitehouse et al, 1983; Perry et al,
Cholinergic Enzymes in Monkey Cortex / 199
1985; Price et al, 19861, and Down’s syndrome [Mann et al, 1984; Casanova et al,
19851. Similarities in cortical cholinergic innervation between squirrel monkeys and
other primates indicate that the squirrel monkey may be a useful model for functional and anatomical studies of the basal forebrain cholinergic system as it relates
to neurological disorders in humans.
1. Levels of ChAT and AChE varied significantly across five heterogeneous
regions of neocortex in the lissencephalic New World squirrel monkey, and the
pattern of variation was similar to that observed in gyrencephalic Old World
2. There was a significant, but imprecise, positive correlation between ChAT
and AChE levels across five regions of neocortex.
3. The hippocampal formation (hippocampus, dentate gyrus, and subiculum) had
higher levels of ChAT and AChE than did any neocortical area studied.
4. Individual squirrel monkeys differed significantly in levels of neocortical
ChAT when values were pooled across five regions. Interindividual differences in
neocortical AChE levels were not significant.
We gratefully acknowledge helpful discussions with Drs. Robert G . Struble and
Cheryl A. Kitt, as well as the assistance in statistical analyses provided by Dr.
Margaret L. Walker. Ms. Carla Jordon assisted in preparation of the manuscript.
This research was supported by grants from the US. Public Health Service (NIH
HD 09942, RR 00164, NS 07179, and NS 20471) and a gift from the Claster Family.
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neocortex, hippocampus, monkey, saimiri, acetylcholinesterase, choline, squirrel, acetyltransferase, activities, sciureus
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