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Basal forebrainЧlesioned monkeys are severely impaired in tasks of association and recognition memory.

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Basal Forebrain-T-sioned Monkeys Are
Severely Impaired in Tasks of Association
and-Recognition Memory
Eva Irle, PhD,' and Hans J. Markowitsch, PhDt
Six squirrel monkeys received ibotenic acid-induced lesions targeted to the basal nucleus of Meynert (BNM). Postop
eratively, the monkeys were trained in a broad spectrum of learning tasks and compared to normal and sham-operated
controls. The lesioned monkeys showed severe and enduring learning and memory deficits in a visual reversal task,
several concurrent object discriminations, a delayed nonmatch-to-sample task, and, most outstanding, an angle
threshold discrimination. Although in some of the monkeys the BNM was lesioned only partly with some surrounding
tissue affected as well, the lesion of the BNM appears to be crucial in the large and apparently irreversible learning
deficits of the monkeys. However, final proof for this suggestion is still needed.
Irle E, Markowitsch HJ. Basal forebrain-lesioned monkeys are severely impaired in tasks
of association and recognition memory. Ann Neurol 1987;22:735-743
The increase in the geriatric population is raising dementia to a medical, social, and psychological problem
of high order. At the beginning of the century Alzheimer 13) defined a form of dementia that he associated with certain cortical pathological changes including neuronal degeneration, neuritic plaques, and
neurofibrillary tangles. Since then, it has become evident that many other neuropathological changes contribute to Alzheimer's disease. For instance, the occurrence of neuritic plaques is not limited to the cerebral
cortex, but extends to many subcortical structures C27,
31). Even more important is the fact that notable neuronal degeneration also occurs in the basal nucleus of
Meynert (BNM) in the basal forebrain [ S , 32, 50, 531.
In contrast to some other syndromes, such as the
Wernicke-Korsakoff syndrome, the neuropathological
contributions to the psychological impairments of Alzheimer's disease are not well defined. However, there
are reasons to believe that the basal forebrain degeneration is the critical lesion in the first and most outstanding deficits in patients with Alzheimer's disease,
namely the mnemonic changes. First, degeneration
within the BNM is also observed in Korsakoff s disease
141, and thus, along with some medial diencephalic
damage, may well contribute to the drastic mnemonic
disturbances of patients suffering from this disease.
Second, many observations in patients with ruptures of
anterior communicating artery aneurysms (leading to
profound basal forebrain damage) also suggest a
memory-related role of some basal forebrain structures,
especially the BNM 12, 11, 171. Furthermore, the
assumption of a memory-related role of the basal
forebrain is underlined by anatomical and neuropharmacological evidence. The connectivity patterns of the
BNM include predominantly limbic afferent sources
125, 341 and widespread cortical efferents C24, 351,
which overwhelmingly use acetylcholine for transmission 136, 471. Cholinergic transmission is frequently
assumed to play a major role in cognitive and mnemonic information processing, and pharmacological interventions with cholinergic agonists and antagonists
give support to the hypothesis that Alzheimer's disease
is linked to disorders in cortical cholinergic innervation
C6, 101.
The purpose of this study was to investigate the role
of the BNM in mnemonic and cognitive information
processing using basal forebrain-lesioned squirrel
monkeys. The investigation of a highly developed primate species promised to be a useful model for human
basal forebrain damage, as the basal forebrain cell
groups of human and nonhuman primates share considerable similarities 1491, and as the behavioral outcome in monkeys can be compared to that of humans
with Alzheimer's disease.
From the 'Department of Psychology, University of Heidelberg,
Heidelberg, and the TDepamnent of Psychology, University of
Konstanz, Konstanz, Federal Republic of Germany.
The experiment described in this article was carried out at the University of Konstant.
Received Nov 25, 1986, and in revised form Mar 16, May 19, and
June 23, 1987. Accepted for publicationJune 23, 1987.
Address reprint requests to Dr Irle, Department of Psychology,
University of Heidelberg, Hauptstr. 47-51, D-6900 Heidelberg,
Federal Republic of Germany.
Copyright 0 1987 by the American Neurological Association
735
Methods
Subjects
Fourteen squirrel monkeys (Saimin’ sciureus), aged 2 to 6
years, were used. The control group consisted of 8 animals, 3
of which were sham-operated; 6 monkeys constituted the
experimental group (BF) with lesions of the basal forebrain.
All monkeys were experimentally naive at the start of the
study.
Operation
All operations were performed aseptically under ketamine
and xylazine anesthesia, which was delivered in low doses (40
mg/kg for ketamine and 1 mg/kg for xylazine) to reduce the
depressive effect on the central nervous system caused by
high intracerebral doses of ibotenic acid. All lesions were
bilateral. The injections with ibotenic acid (Biosearch, Sigma;
dissolved in distilled water) were carried out stereotaxically
in two stages spaced on the average 8.5 days apart. Animals
received altogether 0.22 pmoles (BF l),0.76 pmoles (BF 2),
0.39 pmoles (BF 3), 0.42 pmoles (BF 4), 0.41 pmoles (BF
5), and 0.45 +moles (BF 6) ibotenic acid, divided equally
between the hemispheres.
green cup (discrimination). After reaching 90% correct responses in two consecutive sessions, the reinforcement conditions were reversed and the red cup was reinforced (reversal; same success criterion).
Two identical unpainted metal
cups were used. The cup to the right was always baited until
90% correct responses were achieved in two consecuti.+t
sessions; thereafter, the choice of left cup was always reinforced (reversal).
SPATIAL REVERSAL TASK.
CONCURRENT OBJECT DISCRIMINATION TASK. This task
generally requires the discrimination of several object pairs
concurrently presented. Seven forms with increasing difficulty were applied, beginning with 2 object pairs and ending with 8. Identical junk objects were used for all monkeys;
each single object was used only for one form of the task and
then never appeared in the following tasks. Each object pair
appeared at least 5 times per session. The monkeys were
trained in each form of the task to a success criterion of 85%
correct responses in two consecutive sessions.
DEIAYED NONMATCH-TO-SAMPLE TASK. The monkey was
HistoIogy and Microscopy
After completion of testing, all lesioned monkeys and 4
monkeys in the control group were deeply anesthetized and
perfused transcardially with saline followed by a 1.25%
glutaraldehydell% paraformaldehyde solution in 0.1 M
phosphate buffer. Eight hours before perfusion the animals received an intramuscular injection of diisopropylfluorophosphate (1 mg/kg) dissolved in peanut oil. The
brains were stored for 48 hours in 30% sucrose-phosphatebuffered solution and subsequently cut on a freezing microtome at 80 pm. Every second and third section of the
basal forebrain and every ninth and tenth section of the rest
of the brain was mounted and stained with cresyl violet, or a
procedure was used for the visualization of acetylcholinesterase (AChE) 1331. The loci and extent of the lesions were
examined by light microscopy and by use of a microfilm
reader with reference to the atlases of Emmers and Akert
{13] and Gergen and MacLean 1181. Representative sections
stained for AChE were chosen, and the loci and number of
stained neurons were plotted on corresponding sections of
the atlases. Counts were taken for neuronal loss within the
BNM and a possible neuronal loss within the cerebral cortex
and striatum. Neurons were distinguished from glial cells
according to the criteria given by Peters and associates 1461.
Behavioral Testing
Ten days after the last operation the monkeys were shaped
for training in a modified Wisconsin General Test Apparatus.
For all tasks except the delayed nonmatch-to-sample task, 30
trials constituted one session. For all tasks, the position of
the correct response stimulus varied according to chance
stimulus sequences 1151. Meal worms were given for reinforcement. The monkeys were trained once daily before
they were fed. Tasks were applied in the following order:
VISUAL REVERSAL TASK. The animals were trained with a
green and a red metal cup with identical shape and weight.
At first, the animals were always reinforced for choosing the
shown one object first; it was always baited. Shortly thereafter, the same object was shown in combination with a new
object, and the monkey was trained to recognize the first
object and choose the new one (nonmatch-to-sample). For
each trial, objects were used that the monkey had not seen
for at least one week. A pool of 400 objects was used.
Twenty trials constituted a session, and the monkeys were
trained 3 to 4 times per week. To test delays, the time
elapsing between the presentation of the single object and
the object pair was increased. Delays of 30, 60, and 120
seconds were tested in each of 5 sessions with 10 trials each.
Thereafter, item lists (3, 5, 10, or 20 items) were trained:
Several single objects were presented one after the other,
and then again in the same order with a new object each
time. The lists with 3, 5, or 10 items were trained in 5
sessions (total, 45, 50, and 50 trials, respectively) and the 20item list was tested 3 times (one time per session).
This task required the discrimination of increasingly similar angles. Two
black 19-mm lines forming an angle were drawn on white
cardboard that was then affixed to a metal disc and glossed
over with an acrylic varnish. For each angle used, 5 identical
stimuli were made to avoid a possible tendency of the monkeys to discriminate them based not on the angle but on
small flaws in the drawings. For the test of any one angle the
5 identical stimuli were randomly used. At the start, the
monkeys were taught to discriminate between 90- and 10degree angles; the 90-degree angle was baited and remained
positive during all successive testing stages. After the animals
had learned this problem, the 10-degree angle was exchanged for a 26-degree angle. Successively, angles of 39,49,
57,64,69, 73, 76,79,81,83,85,87, and 88.5 degrees were
used as comparison stimuli. If a monkey discriminated a
given pair of angles with at least 85% correct responses at
the first two sessions, the discrimination was made more
difficult for the next session. If the monkey failed to discriminate a pair of angles for more than two sessions, the discrimiANGLE THRESHOLD DISCRIMINATION TASK.
736 Annals of Neurology Vol 22 No 6 December 1987
A
B
Fig 1 . (A, B) Representative coronal sections from the brain of
Iesioned monkty 3. Lesioned areas with no neurons lefr are shown
in black. Dots represent I to 5 neurons staining for acetylcholinesterase (AChE).Neurons staining for AChE and not belonging to cell group Ch4 as described by Mesulam and co-zuorkers 1352 are not plotted. Note that neumns staining for AChE
are present at the immediare bor&rs ofthe ksioned areas. Abl =
basokateral amygdula;Ac = central amygkla; AC = anterior
commissure; Am = medial amygdzla; BM = basal nucleus of
Mqynert; CL = claustrum; DB = diagonal band of Broca; GL
= lateral geniculate nucleus; GP = globus pallidus; Hs = supraopttc hypothalamus; NC = caudute nucleus; Pu = putamen; SI = substantia innominata; TO = optic tract.
nation was made easier by using the preceding comparison
angle. Training on the easier version of the task lasted until
the animal reached success criterion on two consecutive sessions. Thereafter, the more difficult comparison angle was
given again. If a monkey repeatedly failed to learn the more
difficult discrimination, training with the easier pair of angles
was interposed 5 times. Testing was ended after the sixth
failure of an animal to solve the more difficult discrimination
step.
Results
Anatomical Findings
LESIONS. The centers of the lesions within the basal
forebrain were very similarly placed in all experimental
animals. However, the extent of the lesions varied substantially: the smallest lesion (BF 1 ) covered 19 m3of
the basal forebrain and the largest (BF 4), 67 mm3. The
other 4 experimental animals showed intermediate lesion sizes (BF 2, 37 mm3; BF 3, 43 mm3; BF 5 , 41
mm3; BF 6, 34 nun3).Figure 1 shows the locus and
total extent of basal forebrain damage in a single brain
(BF 3);
All brains showed marked atrophy of the basal
forebrain. Within the BNM, the intermediate cell
groups (as defined by Mesulam and co-workers [35])
showed the greatest atrophy (the extent of these regions was reduced on the average by 59%; MannWhitney U-test, U = 0, p < 0.001). The lesions covered parts of the basal forebrain ranging from level
A13 to A10 (however, in monkeys BF 2 and BF 4
they reached to level A8.5), thus leaving the posterior
cholinergic cell groups of the BNM intact (see Fig 1).
Generally, the lesions destroyed substantial parts of
the anterior and intermediate substantia innominatal
BNM complex. Figure 2 shows photomicrographs of
the lesion in monkey BF 4. Apparently, fibers of passage (e.g., the anterior commissure) were spared. In
addition to the lesion of the BNM the following structures were variously affected by the lesion: the borders
of the putamen (BF 1, BF 2, BF 5;and BF 6) and the
globus pailidus (BF 2, BF 4, and BF 5), and some parts
of the central (all animals) and medial (BF 1 through 5 )
nucleus of the amygdala. Furthermore, the claustrum
was sllghtly touched by the lesion in monkeys BF 2,
BF 4, and BF 5 ; monkey BF 2 showed a severe
Irle and Markowitsch Basal Forebrain Lesions and Memory
737
Pig 2. Coronal section (stained with cresyl violet) of the Idt basal
forebrain oflesioned monkey 4. The dotted line (a) marks the
lesioned area; scale bar = 1 mm. (b) Magnification of the inset
shown in (a);scale bar = 1 mm. (6) The inset shvwn in (b)
undr high magn$cation, shwing gliosis and the apparent absence of any neurons in this awa; scale bar = 10 pm. am,bI =
barokateral amygdala; am,c = central amygdala; am,m = medial amyg&kz; ca = anterior commissure; cl = claustrum; ins
= insular cortex.
neuronal loss and gliosis over all parts of the striatum.
Given the great distance between the degenerating
areas and the center of the lesion, these alterations are
considered to be secondary degenerative changes. The
extent of lesioned tissue for each lesion locus and
animal is shown in Table 1.
AChE. Only distinctly
AChE-stained neurons were analyzed. The lesioned
targets within the basal forebrain were virtually free
of neurons containing AChE. However, AChE-rich
neurons could be observed in the immediate vicinity
of the lesions, thus suggesting that ibotenic acid does
not lead to widespread and distant damage of cholinergic neurons. Figure 3, with a section stained for AChE,
shows the lesioned areas and their immediate surroundings in monkey BF 2.
The number of neurons staining for AChE within
the BNM directly depended on the amount of spared
tissue. Animals with large lesions (see Table l), such as
monkeys BF 4 and BF 6, showed weak labeling as
NEURONS STAINING FOR
compared with the other animals. The density of
AChE-staining neurons within spared tissue was comparable to the staining in similar loci of control animals. Monkey BF 1, with marked degeneration within
the whole striatum, nevertheless had a normal number
of striatal AChE-rich neurons, suggesting that cholinergic neurons are less susceptible to degeneration than
neurons using a different transmitter.
Neuronal counts were taken
from the regions given in Table 2. Basically, the cortical counts revealed no differences between experimental and control animals in the neuronal density of any
cortical region (Mann-Whitney U-test; all p > 0.05). In
addition, the density of isocortical neurons situated in
layers 213 or 4 to 6 did not differ between control and
experimental monkeys. The number of neurons in
homotopical regions of the hemispheres were equal
for both groups.
Neuronal counts of the BNM revealed highly
significant differences for the anterior, intermediate
ventral and dorsal, and posterior cholinergic cell
groups (all U = 0, p < 0.001). Despite the partial
spread of degeneration from the lesioned loci to
striatal structures in some basal forebrain-lesioned animals, all striatal neuronal counts (taken from distant
tissue) showed virtually normal densities. The results
suggest that ibotenic acid does not lead to distant lesion effects and that lesioning of cholinergic basal
NEURONAL COUNTS.
738 Annals of Neurology Vol 22 No 6 December 1987
Table I . Behavioral Pe~ormanceand Extent of Lesion in Each MonRey
Errors to Success Criterion
No.
Angle
Volume of Lesion (%)
DNMS DNMS Threshold
Visual
Spatial
COD Taskb
Task'
DiscrimiGlobus Central
Medial
ClausReversal Reversal Task" (Delays) (Lists) nation
BNMd Putamen Pallidus Amygdala Amygdala trum
BF 1
BF 2
BF 3
BF 4
BF 5
BF 6
205
563
15gf
160
113'
118
Monkey
-
Median 159.5
NC 1
NC2
NC 3
NC4
NC 5
sc 1
sc 2
sc 3
98
149
87
136
152
106
110
100
Median 108
67
60
83
159
123
68
75.5
19
57
126
44
115
65
43
26
50.5
284
294
322
167
335
134
54
61
35
55
67
64
75
86
57
76
91
68
243'
187'
320'
287'
430
304
289
58
75.5
295.5
178
173
166
152
145
181
133
124
35
28
44
19
63
40
55
81
30
82
...
68
69
58
118
...
...
...
28
18
56
45
58
43
159
28
55
63
24
41
59
83
48
74
0
30
0
0
0
1
0
50
0
6
3
0
10
21
64
88
76
13
15
83
58
40
24
0
0
5
0
2
8
0
Brrors in all seven forms applied.
bErrors in 150 trials.
'Errors in 205 trials.
dAs defined by Mesulam and co-workers [ 3 5 } as cholinergic cell group Ch4.
'Failed to reach success criterion.
'Failed to reach success criterion in the visual reversal task; the given value represents the number of errors in an easier object reversal task.
COD = Concurrent object discrimination; DNMS = delayed nonmatch-to-sample; BNM = basal nucleus of Meynert; BF = basal forebrain lesion; N C
= normal control; SC = sham-operated control.
forebrain neurons does not inevitably lead to a reduction in the number of cortical neurons.
Behavioral Findings
After the first operation all animals required more
time to recover from the anesthesia than after the second. After the first operation, the abilities to sit, walk,
and swallow were not fully regained until 48 hours
postoperatively. A further 3 days was required until
hypothermia, aphagia, and motor (especially gait) abnormalities were reversed. The second operation did
not evoke any similar symptoms. Shaping the animals
for the behavioral tests began 10 days after the second
operation, and quickly, within 6 to 15 days, led to the
start of the testing period. Training of all behavioral
tasks took an average of 12 to 18 months. A free
period of 10 to 2 0 days was interposed between the
different tasks. The behavioral performance in different tasks is given for each monkey in Table 1.
The initial visual discrimination was mastered within 300 trials by only 4 of the 6
lesioned monkeys. The 2 monkeys that failed (BF 3
and BF 5) were relegated to an easier object reversal
VISUAL REVERSAL TASK.
task, which they learned with few errors. Monkey BF
2, which also had considerable difficulty in solving the
visual discrimination task, was injected with physostigmine (0.05 mglkg intramuscularly) 30 minutes before
training for 6 days and immediately improved its learning performance to success criterion levels during this
time. The performance levels (errors to success criterion) in the visual reversal task differed significantly
between control and lesioned groups (Mann-Whitney
U-test; U = 5, p < 0.01).
SPATIAL REVERSAL TASK. The performance of the
lesioned monkeys in this simple task was sllghtly inferior to that of the control monkeys and differed only
insignificantly for both discrimination and reversal (U
= 10,p > 0.05).
All
animals reached success criterion in this task; however,
the lesioned monkeys were highly impaired in performing the more difficult forms of the task. The overall performance (for all testing stages) differed significantly between lesioned and control monkeys (U = 9,
p < 0.05). Some lesioned monkeys (BF 4 and BF 6)
CONCURRENT OBJECT DISCRIMINATION TASK.
Irle and Markowitsch Basal Forebrain Lesions and Memory
739
Table 2. Neuronal Counts
Basal
ForebrainLesioned
Control
Group
Group
(mean SD) (mean SD)
*
*
Region
~~~~
Basal nucleus of Meynert"
Ch4 am
Ch4 al
Ch4 iv
Ch4 id
Ch4 p
Striatumb
Caudate nucleus
Globus pallidus
Putamen
Isocortexb
Orbitofrontal cortex
Temporal pole
Cingular cortex
Insular cortex
Area 4
Area 7
Allocortexb
Parahippocampal cortex
Area 28
Subicular cortex
Hippocampal field CA1
23
8
19
27
17
48 f 16
74 f 16'
66 t 17'
38 2 15'
78 2 27'
201 f 19
152 4
162 2 24
203 2 35
192 4
195 2 38
229 2 26
195 41
177 5 19
231 ? 24
141 f 32
234 ? 20
244 =k 25
203 14
188 t 20
260 r 40
170 5 49
235 2 83
224 f
187 2
952
132 2
253 5 71
179 5 30
97 r 20
123 +- 31
51 &
97f
103 5
147 5
125
*
*
*
17
14
2
16
"Number of neurons belonging to the cell group as defined by
Mesulam and associates [35}; neurons counted on coronal sections
(80 km). Ch4 am, al, iv, id, p = anterior, intermediate ventral and
dorsal, and posterior cholinergic cell group.
bNumber of neurons/mm2/80 pm.
'Significantly different from control group (p < 0.001).
Fig 3. Coronal section (stainedfor acetylcholinesterase{AChE))
ofthe basal forebrain of lesioned monkey 2. (a) The dotted lines
mark the lesioned areas; scale bar = 1 mm. (b) Magnz5cation of
the inset shown in (a),showing the presence of neurons staining
for AChE in the immediate vicinity of a lesioned area; scale bar
= 1 mm. ca = anterior commissure; co = optic chasm; gp =
globus pallidus; pu = putamen.
1.0
$
I
1
CG
90-
a
g
a
BO70-
L
60L-
$
showed increasing behavioral improvement over time,
leading to unimpaired learning even in the difficult
stages of this task. However, these recoveries seemed
to be task dependent, as the animals relapsed in the
following testing conditions.
DELAYEDNONMATCH-TO-SAMPLETASK. The acquisition of the basic task was significantly impaired in the
lesioned monkeys (U = 5, p < 0.05). In addition, the
testing of delays and of lists of items showed large
deficits in the lesioned monkeys (Fig 4 ) (delays: U =
5.5, p < 0.05; lists: U = 8, p < 0.05).
Training in this task revealed the most outstanding deficits
of lesioned monkeys: they acquired the initial discrimi-
ANGLE THRESHOLD DISCRIMINATION TASK.
740 Annals of Neurology
50-
I
I
l
l
30" 60" 120"
delays
I
,
3
5 10 20
Items
,
,
Fig 4. Performance in the aUayed nonmatch-to-sampletask. The
medians of comct responses (percent)aw shown as circles (CG,
control group) or squares (BF, basal forebrain-lesioned group).
nation (10 versus 90 degrees) only slowly and when
the task became increasingly difficult, 4 monkeys failed
at angles of 76,85, or 88.5 degrees. The learning curve
for all animals during the different stages of the task is
shown in Figure 5. The overall performance revealed
highly significant differences between control and
lesioned monkeys (U = 0, p < 0.001).
Vol 22 No 6 December 1987
11-
1098-
k.76s
54-
32f1
9 0 ’ ~ s . 10’
I
f
I
I
I
I
I
26” 39’ 49’ 57’ 64’ 69’ 73’
!
!
76O 79’
I
81‘
I
,
,
,
83’ 85’ 87’ 88.5’
angles
Fig 5 . Performance in the angle threshold discrimination task.
The medians of training sessions to criterion are shown as circles
(CG, control group) or squares (BF, basal forebrain-lesioned
group); ranges are indicated by vertical linef. Each star marks
the failure of 1 monkey at a given stage of task dgficulty. As the
training was finished at this point for the respective animal, the
performance in the next step of testing refers on& to the remaining monkqs of the group. Note that only 3 basal forebrainlesioned monkeys reached the&nal test stage and that only 2 of
them succeeded within the 10 sessions allmed.
Anatomical-Bebauioral Interrelations
Despite the great variation in lesion sizes of individual
monkeys (see Table l ) , no correlations were found
between the behavioral performance of any task tested
and the absolute lesion extent or the degree of damage
in the BNM (Spearman rank coefficients;allp > 0.05).
In fact, the 2 monkeys with the largest lesions of the
BNM (BF 4 and BF 6) had the best overall behavioral
performance of all lesioned monkeys.
Discussion
Monkeys with subtotal lesions of the BNM show substantial impairments in a variety of learning and memory tasks and do not recover within 12 to 18 months.
Even small lesions of the BNM, destroying less than
50% of the tissue, lead to severe and enduring learning and memory deficits.
Although incidental lesioning of other basal telencephalic structures (see Table 1) may account for the
anatomical-behavioral relationships, we nevertheless
consider that our overall results justify attributing a
memory-related role to the BNM. The lesioned monkeys were impaired in learning new associations between stimuli and reinforcement values as well as in
the pure recognition of stimuli seen shortly before.
Testing for delays and item lists in the delayed nonmatch-to-sample task (see Fig 4 ) showed that the
lesioned monkeys, once they had acquired the non-
match-to-sample rule, were nevertheless unable to
memorize an item for a longer time. This represents a
pure memory defect, which is also observable in patients with Alzheimer’s and Korsakoff s diseases 11,
23, 39, 441, in a patient with bilateral hippocampal
lesions 1521, and in monkey models of temporal and
diencephalic amnesia 137, 541.
Recently, investigations carried out in rats lesioned
with kainic or ibotenic acid have all found that lesioning the BNM leads to substantial impairments in spatial learning tasks, including T-maze alternation 120,
481, spatial discrimination and reversal learning 112,
20, 21, 281, radial arm maze learning 112, 20, 21, 411,
and passive avoidance learning r21, 28, 381. On the
other hand, active avoidance learning may be facilitated or remains unimpaired in rats t21, 281.
The postulation of a procedural memory system
which, unlike others, is assumed to be unaffected in
patients with Alzheimer’s disease 1141 and in those
with the classical global amnesic syndrome 1457 (as
well as in corresponding monkey models 1291) may in
fact not hold for the lesioned monkeys of the present
investigation. Procedural mnemonic information processing means skill-like learning (e.g., mirror-reading
or playing a piano), and testing for this processing has
been assumed principally under animal discrimination
tasks. However, our monkeys did not do well in the
discrimination tasks, and their performance correlated
well principally with task difficulty; spatial discrimination was impaired least and angle threshold discrimination was impaired most. Moreover, studies of patients
with Alzheimer’s disease reveal strikingly similar impairments when “monkey discrimination tasks” are applied [231, thus suggesting that perceptual forms of
procedural memory are also lost in those with Alzheimer’s disease.
The lesioned monkeys in this study displayed substantial reversal deficits, which surpassed their discrimination deficits by about 160%. Thus, lesioned
monkeys may suffer from an interruption of responseinhibitory or response-controlling mechanisms, which
prevents the animals from changing an adopted response strategy. A disinhibition of response-controlling pathways is frequently claimed to account for
the effects of hippocampal damage (e.g. 126, 301), and
a similar deficit is also described for patients with Korsakoff‘s disease: these subjects seem to suffer from an
enhanced susceptibility to interfering stimuli 191, and
the result of this can also be interpreted as an inability
to “forget” a wrong (but formerly correct) response
strategy. Our lesioned monkeys demonstrated a behavior corresponding to that of monkeys and humans
with hippocampal or diencephalic lesions, and the
same may be said of human patients with Alzheimer’s
disease. There is ample evidence now that persons
with Alzheimer’s disease are not simply incapable of
Irle and Markowitsch: Basal Forebrain Lesions and Memory
741
storing information, but they also have great difficulty
coping with interfering stimuli and withholding falsepositive or perseverating responses {S, 16, 19, 22, 40,
431.
Aside from the basal forebrain’s memory-related
role, its participation in sensory and attentional processes (which are also affected in Alzheimer’s disease
{42, 511) should be kept in mind. Solving the angle
threshold discrimination task depends on sensory and
attentional functions as well. The task was first applied
by Blake and co-workers 171 in monkeys with inferotemporal or lateral striate lesions. Monkeys with
inferotemporal lesions were substantially impaired
only in the initial pattern discrimination, and monkeys
with striate lesions only in the following discrimination
thresholds. The monkeys in our study were impaired
at all testing stages, and 4 monkeys failed to solve the
most difficult discrimination thresholds (see Fig 5).
Blake and associates interpreted their findings as revealing a learning deficit due to inattention to visual
details (for monkeys with inferotemporal lesions) or to
a loss of the visual system’s most finely tuned pattern
detectors and thus to a loss of visual acuity (for monkeys with striate lesions). Put in this way, our data give
the impression that lesioning the basal forebrain also
leads to a secondary cortical inadequacy, which results
in attentional and sensory deficits. However, we stress
the subtle nature of the sensory deficits measured
here, which most probably did not affect performance
on the other learning tasks using junk objects as
stimuli. We tested 8 human subjects with normal visual acuity under the same circumstances as the monkeys and found that only 2 subjects solved the most
difficult test stage (88.5 versus 90 degree angles), and
that the other 6 subjects only succeeded up to the 87degree angle.
The results of this study show that lesions of the
BNM (including some adjacent tissue) widely affect
learning and memory functions of monkeys. This is
especially evident in the lasting impairment on a large
number of behavioral tests. Their deficits may be
viewed as similar to those of patients with Alzheimer’s
disease in the early to middle stages of the disease
process. Furthermore, the anatomical-behavioral relationships provided by the two-stage ibotenate lesions
may provide a more adequate model of progressive
neurodegenerative diseases, such as Alzheimer’s, than
does an acute one-stage lesion.
It is a pleasure to acknowledge the help of Christina Schlatterer and
Katharina Deisinger in training the animals. We also thank David
E~~~
for
of the histological analyses and for
improving our Enghsh. Supported by grant Ma 79515 from the
Deutsche Forschungsgemeinschaft.
742 Annals of Neurology
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