1 Department of Experimental Psychology, Oxford University, Oxford, UK, , 2 School of Psychology, University of Nottingham, Nottingham, UK and , 4 Department of Experimental Psychology, Cambridge University, Cambridge, UK
Alexander Easton, School of Psychology, University of Nottingham, University Park, Nottingham NG7 2RD, UK. Email: ae{at}psychology.nottingham.ac.uk.
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Abstract |
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Introduction |
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One explanation of the effects of this combined lesion is that it interrupts the projections of the cholinergic cells of the basal forebrain to the medial temporal lobe and inferior temporal cortex, as these projections pass through the fornix, amygdala and anterior temporal stem in monkeys (Kitt et al., 1987) and humans (Seldon et al., 1998
). The cholinergic projections to the cortex are widespread while the cortical inputs to the same cells are much more restricted (Mesulam and Mufson, 1984
). This pattern of limited cortical afferents with extensive cortical efferents makes these cholinergic cells an ideal intermediary for cortical modulation of the entire cortical mantle by only a few cortical areas (such as the frontal cortex).
This cortico-cortical modulation via the basal forebrain would support a role for the cholinergic basal forebrain in learning, by allowing the individual's goals (which might be represented in the frontal cortex) to mediate the learning of appropriate stimuli and information. Disruption of the basal forebrain interaction with inferior temporal cortex by crossed unilateral lesions of the medial forebrain bundle and inferior temporal cortex produces learning impairments similar to those seen after section of the anterior temporal stem, amygdala and fornix (Easton and Gaffan, 2000)
In humans, damage to the basal forebrain can result in severe learning problems. Surgical resection of aneurysms of the anterior communicating artery, or their rupture, can produce widespread damage in the region of the basal forebrain and result in a severe amnesia (Damasio et al., 1985; Abe et al., 1998
). The cholinergic cells of the basal forebrain are also among the first to degenerate in Alzheimer's disease (Whitehouse et al., 1982
). Of a large number of transmitter systems assessed in a wide range of brain areas in Alzheimer's patients at postmortem, only the reduction in the cholinergic marker cholineacetyltransferase in the cortex is seen to correlate with the severity of dementia prior to death (Bierer et al., 1995
). In cases of Alzheimer's disease or aneurysm of the anterior communicating artery, however, cell loss is not confined to the cholinergic basal forebrain, so more selective lesions in animals can clarify the importance of the cholinergic basal forebrain in learning.
Recent advances have allowed examination of the specific role of the cholinergic basal forebrain by immunolesioning the cholinergic cells of the basal forebrain alone. The ribosome-inactivating toxin, saporin, can be conjugated to an antibody that recognizes the p75 neurotrophin receptor, and thus can selectively kill the cholinergic cells of the basal forebrain that express the p75 receptor (Wiley et al., 1991). In the marmoset these immunotoxic lesions have produced evidence that the cholinergic system is essential to normal mnemonic performance in the primate (Fine et al., 1997
; Ridley et al., 1999a
,b
; Barefoot et al., 2000
).
In humans there is evidence that patients in the early stages of Alzheimer's disease not only have loss of the cholinergic cells of the basal forebrain, but also have damage to the medial temporal lobe structures including the hippocampus and entorhinal cortex (Frisoni et al., 1999). Therefore, in the present study, the effects of combined lesions of the cholinergic basal forebrain and fornix in one hemisphere and inferior temporal cortex in the opposite hemisphere were tested. A lack of impairment from this combined lesion would indicate that combined damage to both the cholinergic projections to cortex and the hippocampal system is not the cause of the severe amnesia in the monkeys with section of the temporal stem, amygdala and fornix. A severe learning impairment, however, would support the hypothesis that the cholinergic isolation of the inferior temporal cortex and medial temporal lobe (either with or without associated disruption of the hippocampal system) leads to a severe learning impairment.
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Materials and Methods |
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Subjects were nine rhesus monkeys (Macaca mulatta), all female. The animals weighed between 2.2 and 4.1 kg at the start of training. Animals AG formed group ACh+fx while animals H and I formed group Con.
Surgery
All operations were performed in sterile conditions with barbiturate anaesthesia and with the aid of an operating microscope. When the lesion was complete, overlying tissue was sutured in anatomical layers. Following each surgery, 1018 days were allowed for post-operative recovery before the resumption of training.
Unilateral Lesion of the Cholinergic Cells of the Basal Forebrain with Unilateral Fornix Section (Group ACh+fx)
The first surgery for animals in group ACh+fx was a lesion of the cholinergic cells of the basal forebrain, with unilateral transection of the fornix, in the left hemisphere. The animal was placed in a stereotaxic head holder and a D-shaped bone flap was raised at the midline extending laterally on the side of the lesion. The veins constraining access to the midline were cauterized and the hemispheres separated. The hemisphere was retracted from the falx and the fibres of the corpus callosum were cut using a glass aspirator to reveal the fornix. The fornix was retracted, and tissue dorsal to the anterior commisure removed with a glass aspirator to visualize the anterior commissure. In this exposure of the anterior commisure, the descending column of the fornix was sectioned unilaterally. A Hamilton syringe (1 ml) with a blunt needle was then guided visually onto the surface of the anterior commissure in the midline and the stereotaxic coordinates of this position were measured. The coordinates for the injections were then calculated. There were 54 injections made for one hemisphere, with 22 needle tracks. Each injection was of the immunotoxin ME20.4IgGsaporin (Advanced Targetting Systems, San Diego, CA, USA) which is the ribosome inactivating toxin saporin conjugated to the antibody ME20.4IgG which recognizes the primate (including human) low-affinity neurotrophin receptor protein p75 which exists on the cholinergic cells of the basal forebrain (Maclean et al., 1997). Each injection was at a rate of 1 µl/min, with a total volume of 1 ml per injection site for every animal except animal G that received 2 ml per injection site. At the end of each injection the needle was kept in place for a further minute, and at the end of a needle track for 2 min. The sites of the injections were calculated from a stereotaxic atlas of the macaque brain (Martin and Bowden, 1996
) to include all areas of the basal forebrain that are seen to stain for cholinergic cells with immunohistochemistry using the same ME20.4IgG antibody. The most anterior needle tracks were made first as these were in the region of the anterior perforated substance. Any bleeding or oedema that resulted from damaging any of these small blood vessels could then be spotted and treated during the surgery to minimize the risk to the animal. These small bleeds were reduced by the use of the blunt needled Hamilton syringe.
Unilateral Injection of Saline to Basal Forebrain with Unilateral Fornix Section (Group Con)
The first surgery in animals in group Con were unilateral injections of saline into the left basal forebrain with section of the descending column of the fornix unilaterally on the side of the injections. The procedure was identical to group ACh+fx, but with injections of saline rather than immunotoxin.
Unilateral Ablation of the Inferior Temporal Cortex
All animals received an ablation of the right inferior temporal cortex in a second surgery within 6 weeks of the first surgery. This lesion has been described in detail elsewhere (Easton and Gaffan, 2000, 2001
), and included removal of tissue extending from the fundus of the rhinal sulcus to the fundus of the superior temporal sulcus, including both banks of the anterior part of the occipitotemporal sulcus. The posterior limit of the lesion was just anterior to the inferior occipital sulcus.
Histology
At the conclusion of the behavioural experiment the animals were deeply anaesthetized, then perfused through the heart with saline followed by formolsaline solution. The brains were blocked in the coronal stereotaxic plane posterior to the lunate sulcus, removed from the skull, and allowed to sink in sucroseformalin solution. The brains were cut in 50 mm sections on a freezing microtome. Every fifth section was retained and stained with cresyl violet. Another set of sections were immunostained with antibodies for those cells expressing the p75 neurotrophin receptor, i.e. the same cells as targeted by the immunotoxin used in the experiment, using a procedure previously used in marmosets (Maclean et al., 1997).
Immunostained sections were taken at the four levels through the injection sites shown in Figure 3. At each level a score was given to the degree of cavitation in the basal forebrain and in the basal ganglia. A score of 0 represented no cavitation, a score of 5 represented complete cavitation. The sum of the scores for the basal forebrain and basal ganglia cavitation was then calculated across all the four section levels and a final cavitation score (out of a maximum of 40) was obtained. This was not a measure of cell loss, or selectivity of the lesion, but was merely a measure of the non-selective damage produced from the cavitation.
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Apparatus
Monkeys were tested in an automated apparatus, receiving small food rewards for correct choices and a large food reward at the end of a session. The apparatus is described in detail elsewhere (Parker and Gaffan, 1998).
Procedure
Figure 1 shows a timeline for group Con and group ACh+fx showing both surgeries and behavioural tests. Before starting on the experiment, all animals were trained to touch the touchscreen. Then, pre-operatively all animals were trained on scene learning. This task is described in detail elsewhere (Gaffan, 1994
), but required the animal to learn the correct object (a small two-dimensional alphanumeric character) of two presented in specific spatial locations on specific unique backgrounds. Animals were presented with eight trials of 20 such problems in any session, and were presented with a new set of 20 problems for every session. Performance was measured as mean errors after the first trial with each problem, over 10 sessions. This scene learning was then retested after unilateral surgery. After the second surgery to add the inferior temporal cortex ablation, the animals were tested again on scene learning, and then post-operatively taught and tested on visual object reward association learning. The visual objectreward association learning task is described in detail elsewhere (Easton and Gaffan, 2001
) but required the animal to learn over several sessions a set of 10 concurrent visual objectreward associations between small alphanumeric objects. Animals learnt three such sets of objects and performance was measured as mean errors to criterion (90% or greater correct responses in a single test session).
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Results |
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Figure 2 shows the intended area removed in the unilateral inferior temporal cortex ablation. The ablation was seen to be as intended in all animals, extending from the fundus of the superior temporal sulcus to the fundus of the rhinal sulcus, and posteriorly including both banks of the anterior part of the occipitotemporal sulcus. The posterior limit of the ablation was just anterior to the inferior occipital sulcus.
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Scene Learning
The animals' proficiency at scene learning was measured by the mean number of errors made in each session (after the initial presentation when the animals' choice of objects was random). These results are shown in Figure 5 along with the average learning curve for each group.
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Both groups were significantly impaired following the second surgery to ablate the contralateral inferior temporal cortex. Planned comparisons within each group, using the pooled error term from a one-way ANOVA of the change in performance between Pre-op and Post-op 2 (Table 1) showed that both groups were impaired [Con: t(7) = 4.31, P < 0.005 one-tailed; ACh+fx: t(7) = 38.3, P < 0.001 one-tailed]. However, the effect of group in the one-way ANOVA showed that group ACh+fx was significantly more impaired than group Con [F(1,7) = 131.7, P < 0.001].
Concurrent Visual ObjectReward Association Learning
Objectreward association learning was measured by the mean total errors to criterion (not counting the first presentation of each problem when performance was necessarily at chance levels) for each of three sets of 10 visual objectreward association problems. These results are shown in Figure 6. A t-test of the performance by animals in each group shows that the animals in group ACh+fx were impaired, relative to those in group Con [t(7) = 2.21, P < 0.05 one-tailed]. The performance of group Con was at a similar level to that of normal animals in this task (Easton and Gaffan, 2001
; Gaffan et al., 2001
).
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A stepwise multiple regression analysis was undertaken to investigate the power of cholinergic cell loss, pre-operative learning proficiency, and cavitation as predictors of post-operative learning proficiency. The predictors are shown in Table 1 as ACh loss, Pre-op and Cavitation, respectively, and the predicted variable is Post-op 2 in Table 1
. The most powerful single predictor was cholinergic cell loss, which as a single predictor was significantly related to post-operative performance [t(5) = 3.291, P = 0.022]. Adding the next most powerful predictor, preoperative performance, as a second predictor produced a model in which both cholinergic cell loss [t(4) = 4.970, P = 0.008] and pre-operative performance [t(4) = 3.071, P = 0.037] were significant predictors of postoperative performance.
Cavitation was not significantly related to post-operative performance, either when added to the model with cholinergic loss as the single predictor [t(4) < 1] or when added to the model with both cholinergic loss and pre-operative learning as the two predictors [t(3) < 1]. The results of the stepwise regression analysis show, therefore, that cholinergic cell loss, and not cavitation, predicts post-operative performance.
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Discussion |
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Relationship of Cholinergic Cell Loss and Post-operative Learning
The possibility needs to be considered that a generalized (but unilateral) cell loss in the basal forebrain following the injections of immunotoxin may be responsible for the impairment, rather than a loss of the cholinergic cells in particular. Cavitation of tissue did occur in some animals in group ACh+fx, and we did not measure the loss of transmitter systems other than acetylcholine in any animal. However, the toxin used here has previously been shown to produce selective loss of acetylcholine in rhesus monkeys (Mrzljak et al., 1998), and produces significant learning impairments in marmosets without any cavitation of tissue (Fine et al., 1997
; Ridley et al., 1999a
,b
; Barefoot et al., 2000
). The impairment in marmosets is both sensitive to exacerbation by the cholinergic antagonist scopolamine (Fine et al., 1997
) and to amelioration by the cholinergic agonist pilocarpine (Ridley et al., 1999b
). What can be concluded from the current experiment is that a lesion of the basal forebrain using an immunotoxin, shown in other studies to be specific for cholinergic cells, produces a severe learning impairment in rhesus monkeys.
The design of the present experiment, using a large number of monkeys and a range of doses of immunotoxin in group ACh+fx, allowed a regression analysis to determine the relationship between post-operative learning and both the loss of cholinergic cells in the basal forebrain and generalized tissue damage in the form of cavitation in these animals. The results clearly show that general cavitation of tissue does not predict the post-operative learning impairment in group ACh+fx, while the loss of cholinergic cells does. This is strong evidence in support of a cholinergic explanation of the data. It is also apparent that some animals did not have any, or only had small amounts, of cavitation of tissue, but they were still severely impaired at new learning (e.g. animal A). Of interest is the observation that neither of the two animals in group Con showed any cavitation following injections of the same volume of saline. This may suggest that cavitation is a risk of near complete cholinergic depletion throughout the basal forebrain in the macaque monkey.
Effects of Fornix Section
All animals in group ACh+fx had a unilateral section of the fornix on the side of the immunotoxic lesion. The current experiment does not allow us to examine the role of the fornix section specifically in these animals. However, previous work has shown that the cholinergic projections to both inferior temporal cortex and medial temporal lobe must be lesioned to produce a severe and persistent learning impairment in the monkey (Ridley et al., 1999a,b
). It is possible, however, that the fornix section in the current experiment serves not only to isolate the hippocampal system from its cholinergic afferents, but actually has an additional and additive effect to the immunotoxic lesion.
Lesions in the hippocampalanterior thalamic circuit produce impairments in scene learning comparable to those seen in group Con (Gaffan and Parker, 1996; Parker and Gaffan, 1997a
,b
). Group Con had a unilateral fornix section crossed with a lesion of the inferior temporal cortex that has previously been shown to produce a similarly sized impairment (Gaffan and Parker, 1996
). However, the impairment seen in group ACh+fx is much more severe than that seen in animals with interruption of this hippocampalanterior thalamic circuit alone. This indicates that the cholinergic cell loss in the basal forebrain is having an effect independent of, and possibly in addition to, the interruption of cholinergic projections to the hippocampus. Patients with Alzheimer's disease show pathology that includes not only degeneration of cells in the cholinergic basal forebrain, but also of pathology in the medial temporal lobe. This explanation would also provide an explanation for the smaller effect of excitotoxic lesions of the basal forebrain in monkeys (Aigner et al., 1991
; Voytko et al., 1994
) compared with those of the more selective immunotoxic lesions in the current experiment. If the hippocampalanterior thalamic circuit must be damaged in addition to the cholinergic basal forebrain, then an additional fornix lesion in these earlier studies would have produced a more severe learning impairment.
Role of the Basal Forebrain in Attention or Memory?
Previous studies in rats (Dunnett et al., 1991; Baxter et al., 1995
, 1997
) and primates (Voytko et al., 1994
) have suggested that the basal forebrain is involved in the performance of attentional tasks. This issue is not directly tested in our monkeys, although in the scene task, where correct and incorrect responses are made to small objects in a complex background, animals that were severely impaired at the task did not increase the number of inappropriate responses (i.e. responses to something other than one of the two foreground objects). This indicates that they were attending normally to the objects, and not reacting to the touchscreen in an inattentive and inappropriate manner.
The Learning Impairment Is Not Due to an Agnosia
It is extremely unlikely that the crossed unilateral lesions in this study produce their impairment through a visual agnosia, i.e. simply by reducing the general activity of inferior temporal cortex by removing the cholinergic afferents to it. Although monkeys were impaired on both of the tasks reported here, as discussed above, animals performing the scene task did not increase the number of inappropriate responses made postoperatively. This implies that the animals were able to identify and accurately respond to the small alphanumeric characters against the complex visual background. Further support against an agnosic explanation comes from monkeys that have received bilateral lesions of the fornix, amygdala and anterior temporal stem (Gaffan et al., 2001). These animals had a large lesion that was not specific to any single transmitter system or fibre pathway. However, one effect of this surgery was to isolate the medial temporal lobes and inferior temporal cortex from their cholinergic afferents, which project through these three main pathways (Kitt et al., 1987
; Seldon et al., 1998
). All these animals exhibited a severe anterograde amnesia. One animal from this group was tested on its retention of 100 visual discrimination problems taught preoperatively. This animal reached a 90% criterion in only three trials with each problem, despite being severely impaired at learning just 10 new problems. A similar dissociation between new learning impairments and normal retention of pre-operatively taught material can also be seen in monkeys where the modulation of the basal forebrain by the midbrain is disrupted by lesion of the medial forebrain bundle (Easton and Gaffan, 2000
). This implies that the medial temporal lobe and inferior temporal cortex can be completely isolated from their cholinergic afferents without the monkey becoming visually agnosic. This contrasts sharply with the effects of direct damage to the inferior temporal cortex (Gaffan et al., 1986
).
A Cholinergic Explanation of Medial Temporal Lobe Amnesia
The results support the hypothesis, outlined in the introduction, that monkeys with section of the fornix, amygdala and anterior temporal stem show a severe anterograde amnesia which is a result of isolating the inferior temporal cortex and medial temporal lobe from their cholinergic afferents. However, the present experiment is unable to dissociate between the fornix section being necessary in addition to a cholinergic deafferentation of the cortex, or as simply isolating the medial temporal lobe from its cholinergic afferents. Section of the fornix, amygdala and anterior temporal stem models the surgical damage that results in severe amnesia in humans following medial temporal lobe surgery (Horel, 1978; Gaffan et al., 2001
). Medial temporal lobe surgery generally involves removal of, or damage to, the amygdala and anterior temporal stem white matter, which are sectioned in the study of Gaffan et al. In these patients, the hippocampus is also damaged, which is modelled by bilateral section of the fornix in the monkeys of Gaffan et al. In contrast to the model of medial temporal lobe amnesia, the loss of cholinergic cells in the basal forebrain in the present study parallels the pathology observed in patients with severe memory deficits in Alzheimer's disease (Whitehouse et al., 1982
; Bierer et al., 1995
). We put forward the hypothesis, therefore, that memory loss in both Alzheimer's disease and following medial temporal lobe surgery is a result of the same underlying isolation of the inferior temporal cortex and medial temporal lobes from their cholinergic afferents, possibly in addition to an interruption of the hippocampalanterior thalamic circuit.
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Footnotes |
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Acknowledgments |
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References |
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