The Cholinergic Hypothesis Revisited
Robert Jaffard and Aline Marighetto Identifying Memory Dysfunction
The net effect of an experimentally-induced or "naturally" occurring alteration in learning and memory is generally determined by the type of neurological dysfunction (from focal lesions to gene expression) and/or the nature of the learning task. Accordingly, memory systems are defined as distinct, but interactive, psychological and biological entities that still need specification. Within this framework, a full understanding oflearning and memory covering the cellular/molecular, systemic and behavioural levels can be achieved only by experimental studies in animals. This, in turn, requires "animal models" asserting the structural congruence between sets of causally related neurobiological and behavioural variables. In the first part of this chapter, we examine the "cholinergic hypothesis of memory" formulated in the 80s, and then focus on cognitive ageing, giving an example of a possible alternative to the classical "pro-cholinergic" approach to age-related memory disorders. In doing so, the specific constraints on current animal research in learning and memory will be illustrated.
Acetylcholine and Memory: From a Key Neurotransmitter to the Functional Dynamics of Interactive Processes
The Cholinergic Hypothesis of Memory: Lesion Studies
By the 1960s, psychopharmacological experiments conducted in both animals and humans provided evidence that anticholinergic treatments produced a deficit in learning and memory performance. The hypothesis that these effects arose from the common dependency of a set of memory-related brain regions on acetylcholine was supported by the observations that these regions were rich in cholinergic elements. Investigations into the neuropathology ofAlzheimer's disease finally showed that choline acetyltransferase activity (ChAT) was markedly reduced in brain tissue from these patients, and that this decrease was correlated with a loss of cognitive function. Together, these findings provided the basis for the "cholinergic hypothesis of memory".4 Consequently, considerable effort has gone into investigating the behavioural effects of lesions of basal forebrain cholinergic neurons, targeting either the Nucleus Basalis Magnocellularis (NBM) that provides cholinergic innervation to the entire neocortex and amygdala, or the Medial Septal Nucleus (MS) and Vertical Diagonal Band (VDB) which, via the Fimbria/Fornix (FF), supplies almost the entire cholinergic innervation to the hippocampus.
By the 1990s most authors began to share the view that owing to a lack of specificity, the earlier interpretation of electrolytic or excitotoxic lesion studies in terms of support for the hypothesis that cholinergic neurons subserve learning and memory was generally unfounded.21,33 More recently, immunotoxin IgG saporin, a powerful and selective tool with which to destroy cholinergic neurons, has been used in a number of experiments. Taken together, the results have provided evidence that selective destruction of the NBM cholinergic neurons results in no—or only very mild—deficits in learning and memory as assessed by performance in spatial learning tasks such as the Morris water maze (MWM) in rats,13 or by the delayed non-matching to sample (DNMTS) task in monkeys.63 However, there is now strong evidence that the NBM cortical cholinergic projections support certain aspects of attentional function in both species.54'63
Selective destruction of MS cholinergic neurons has been reported to produce significant, although modest, learning and memory impairments in certain behavioural tasks that are sensitive to hippocampal lesions. Selective depletion of pre-synaptic cholinergic markers in the hippocampal formation induced by injection of 192 IgG saporin into the MS/VDB in rats has been shown to impair working memory both in the radial arm maze (RAM) and in the delayed non-matching to place (DNMTP) tasks using an operant chamber.57'60'65 However, both the selectivity of the hippocampal cholinergic denervation and the delay-dependent effect of these impairments remain controversial. Recently, it has been suggested that extensive lesions of both the hippocampal (MS) and cortical cholinergic pathways (NBM) associated with great memory demands (i.e., remembering more than one simple location) are necessary to produce a delay-dependent deficit in the RAM task.67 Although similar selective cholinergic deafferen-tation seems to result more consistently in delay-dependent impairing effects in the operant DNMTP than in the RAM task,45,60 it is not clear whether these tasks assess the same mnemonic functions, as the delays used are generally much shorter in the former (tens of seconds) than in the latter task (minutes or hours). In contrast, infusions of 192 IgG saporin into the MS/VDB or even into both the MS/VDB and NBM failed to impair reference memory in either the MWM task or RAM tasks.6,57,60 These reports indicate that removing cholinergic neurons that project to the hippocampus only produces, if any, mild learning and memory deficits in tasks that otherwise are clearly impaired by less selective MS neurotoxic lesions22 or FF transections.33 It is thus possible that damage to both the cholinergic and GABAergic neurons that project to the hippocampus is necessary to impair hippocampus-dependent learning and memory functions. Recent experiments showing that the previously observed cognitive-enhancing effect of muscarinic drugs targeted to the MS44 may be better accounted for by increased impulse flow in the GABAergic than cholinergic septo-hippocampal pathways68 emphasize the potential functional importance of this GABAergic component. Finally, since selective removal of cholinergic neurons in young rats did not reproduce the learning and memory impairments found in aged rats, and since these aged rats displayed a loss of GABAergic neurons in the septal region,48 it may be that the deterioration of the cholinergic system is not sufficient to produce impairments. However, the fact that the severity of the behavioural impairment seen in aged animals is generally linked to the degree of septo-hippocampal cholinergic deficiency23 suggests that this system is necessary for normal learning and memory function. In this respect, it remains possible that the sensitivity of the tasks that, up to now, have been used to assess the behavioural effects of a selective hippocampal cholinergic hypofunction is not sufficient to detect impairments. For example, it has recently been reported that rats injected with 192 IgG saporin into the MS displayed a significant bias toward the preferential use of an egocentric (versus allocentric) response strategy in the MWM task.35 This would suggest that testing designs based on competing strategies3 might provide a more sensitive tool to assess spatial memory dysfunction than the standard testing designs previously used. This also points to interactions existing between memory systems and to the possible involvement of cholinergic neurons in regulating such interactions.
Cholinergic Alterations Induced by Learning and Memory Testing
Based on the assumption that brain cholinergic neurons play a role in learning and memory, several studies have provided evidence that memory testing is associated with significant changes in pre-synaptic markers of cholinergic well as in alterations in the release of acetylcholine in hippocampal and/or cortical regions.1,29,59 In a series of experiments using mice as subjects,41 we showed that both reference-memory (RM) and working-memory (WM) testing in the RAM induced significant and long-lasting changes in hippocampal cholinergic activity using ex vivo measures of sodium-dependent high affinity choline uptake (SDHACU). Namely, i. Both types of training induced an immediate increase in hippocampal SDHACU as compared to the "quiet" control condition.
ii. In the RM task, this immediate increase in SDHACU was followed by a decrease leading to a long-lasting (24 hours and 9 days) inhibition of this cholinergic marker. This secondary decrease in SDHACU occurred earlier with repetition of training, thereby leading to a shortening of the testing-induced cholinergic activation as RM training progressed.
iii. By contrast, in the WM task, SDHACU was still increased 24 hours after the last session of training.
iv. Finally, the amplitudes of both the immediate increase and subsequent secondary decrease in SDHACU were significantly related to the rate of acquisition and behavioural profile of learning in the RM task. Our set of results was interpreted with the aim of reconciling previous seemingly discordant data on training-induced changes in cholinergic activity. Specifically, our proposal was the following: The enhancement of hippocampal cholinergic transmission during training might facilitate the acquisition of a "relational kind" of information (sustaining WM and spatial mapping in RM), but to the detriment of simple associations (e.g., stimulus-response, or stimulus-reward that may also sustain RM performance). The subsequent post-training decrease and inhibition in cholinergic activity would facilitate the subsequent consolidation of the permanent (invariant) aspects of acquired information (e.g., information to be held in RM).
Subsequent pharmacological experiments42 provided evidence that the long-lasting inhibition of hippocampal cholinergic activity subsequent to RM testing could be mediated, at least in part, by glutamatergic receptors located in the lateral septum (LS). Indeed, such receptors would, presumably through GABAergic interneurons, provide an inhibitory input to cholinergic cells in the medial area.27 Therefore, we hypothesized that hippocampo-septal glutamatergic synapses in the LS could be the locus of an "LTP-like" mechanism sustaining the post-RM training inhibition of cholinergic cells, a phenomenon that should not be observed following WM testing. This hypothesis was confirmed. As compared to their controls (i.e., treadmill group), mice trained in the RM task exhibited a progressive and persistent enhancement in hippocampal-LS synaptic neurotransmission as training progressed, whereas an opposite change (i.e., a depression) occurred in mice trained in the WM task.25,34 As previously observed for SDHACU, the magnitude of the RM training-induced enhancement of hippocampal-LS neurotransmission was correlated with discriminative performance. It is highly unlikely that the training-induced LTP- and LTD-like changes of the LS synapses are involved in the storage ofspecific information;61 rather, they might "shape" the hippocampal-septal-hippocampal circuitry in the more appropriate configuration for coping with the requirement of the task. Specifically, the RM training-induced synaptic enhancement ofhippocampal-septal synapses could be involved, through the rapid post-testing decrease in hippocampal acetylcholine release, in the consolidation of the to-be-learned trial-independent information (RM), a process which is not required for the trial-dependent WM performance. As mentioned above, the increase in hippocampal cholinergic activity might be necessary for the short-term maintenance of (a relational kind of) information during both RM acquisition and WM testing, whereas its immediate post-acquisition inhibition might make it possible to consolidate information hold in RM alone. The functionality of these training-induced "biphasic" changes in hippocampal cholinergic activity as well as its above-mentioned putative mechanisms are in fact congruent with data obtained with pharmacological approaches. Namely, it has been shown that increasing or decreasing cholinergic activity by pre-training infusion of drugs in the septal area (i.e., the NMDA receptor blocker AP5 or the GABAergic agonist muscimol, respectively) facilitated the maintenance of information in WM50 and impaired acquisition of spatial RM in the MWM
task.49 Furthermore, using the same experimental design, Nagahara et al49 showed that inducing inhibition of hippocampal cholinergic activity immediately after (rather than prior to) training actually facilitated (rather than impaired) subsequent retention.
Should the Cholinergic Hypothesis Be Re-Examined?
If the participation of the proposed "biphasic" mechanisms of the septo-hippocampal cholinergic neurons is to be confirmed in some forms of memory, many apparent discrepancies within cholinergic-related findings would be resolved, and the importance of the dynamical aspects would have to be taken into account. An example of such discrepancies is that, even though selective cholinergic lesions have, on the whole, failed to reproduce the impairing effect of ageing in the MWM task, it remains that the magnitude of this impairment is significantly correlated with the magnitude of cholinergic loss. It therefore seems that the cholinergic hypothesis of age-related cognitive decline deserves to be re-examined in the context of interactive and dynamical processes at both the neural (structures and circuits) and psychological (forms of memory) levels. It might indeed be that part of such a decline in cognitive abilities is related to alterations in the connective processes that sustain proper recruitment of a set of structures in the brain, as suggested by neuroimaging studies in humans.7,12,47 The fact that in comparison with younger adults, aged animals displayed a different pattern of cholinergic responses to memory training and, in particular, that the long-lasting inhibition of hippocampal cholinergic activity subsequent to RM training was not observed in aged subjects.10,3 is coherent with this view. Thus, if the plastic properties of glutamatergic synapses in the LS are really necessary for adjusting optimally the septo-hippocampal activity both as a function of the stage of memory formation and of the relative contribution of different information processing functions (e.g., "relational" vs. "simple associations"),11 then the observation that aged mice display strong alterations in LS synaptic plasticity24 should not be without consequences on their learning and memory capabilities. In this respect, alterations in LS synaptic plasticity and thus alterations in the capacity of the aged brain to configure the brain circuitry needed for optimal encoding, storage and retrieval of specific information, might be one of the numerous possible causes of the deficits observed at the behavioural level.62
Together, these data provide a potential framework in which to examine the neurobiological basis of cognitive ageing and, in particular, the possible involvement of the septo-hippocampal cholinergic pathway. However, due to the complexity of the system (both in terms of interactions between its components and of its temporal dynamics), it is not clear how it might be possible to correct the dysfunction by pharmacological means that could be used to alleviate age-related cognitive impairments in humans. Up to now, another problem that has not been considered is the validity of animal behavioural models used to assess the cognitive impairments occurring in senescence.46 As an illustration of both issues, it has recently been shown that the enhancing effect of tacrine (an inhibitor of acetylcholinesterase) on spatial navigation performance (MWM task) in aged rats was blocked by non-spatial pre-training.2 Indeed, this suggests either that targeting the cholinergic system of aged subjects is totally inefficient or that the cholinesterase inhibitor improves some major non-cognitive or procedural aspects of the task performance.30,38 The latter possibility might explain why cholinergic agonists have been reported to be ineffective in reversing age-related deficits in tasks that need intensive pre-training (e.g., the DNMTP task).14
From Assessment to Alleviation of Age-Related Memory Impairments in Mice
Although the need for experimental studies of ageing in animals is obvious, the relevance of these studies depends on whether both the specific functions and biological systems targeted for study are appropriate models of human ageing. In this section, we describe how we tackled both issues using C57BL/6 mice as subjects.
In humans, there is a consensus that declarative/explicit memory appears to be more vulnerable to deterioration in senescence than procedural/implicit memory.56 Cohen8 has identified two cardinal "non-verbal" characteristics of human declarative memory, i.e., its capacity to compare and contrast items in memory and to support the inferential use of memories in novel situations (flexibility). In contrast, procedural memory involves the facilitation of particular routines for which no such explicit comparisons are executed. Following on from the original reports by Eichenbaum et al, 6,17 we developed tasks to determine whether these different processes could be engaged or disengaged in mice simply depending on how the same items were presented (i.e., using a within-subject design). 0,43 The tasks consisted of unambiguous discriminations between arms of opposite valence in a radial-arm maze. As depicted in Figure 1, each experiment (either A or B) was designed in two-stages, with an initial learning phase followed by a test-phase. The only parameter which was varied among the successive stages was the way of presenting arms to mice, i.e., either in pairs (simultaneous discriminations) or one at a time (successive go-no-go discrimination). During the initial learning phase, most of the aged (21-23 months) mice were impaired in learning the simultaneous discriminations (B, stage 1) whereas all the aged subjects acquired the discrimination task as well as the adult (4-5 months) controls in a successive go-no-go design involving the same set of items (A, stage 1). When challenged with modified presentations of familiar items in the test phase, aged mice were impaired if two arms were presented to them simultaneously in a novel pairing, but not if they were presented one at a time, in a successive go-no-go procedure. Thus our results showed that the extent to which ageing could alter the ability to acquire (stage 1) or to use previously acquired spatial discriminations in novel situations (stage 2), strictly depends on the manner the discriminanda were presented to the subject. This set of data supports the conclusion that two forms of memory expression of the same acquired experience can be preferentially triggered through a change in the way discriminanda are presented. Specifically, even though two-choice tasks can be theoretically solved on the basis of elemental associations, it appears that, at least in the present (and other) specific conditions,43 presentation of discriminanda may encourage the use of explicit comparisons thereby requiring relational representations of past experience. In this sense, the dissociation observed in aged mice is reminiscent of the dissociation between implicit and explicit expression of the same piece of previously acquired material in human amnesic subjects.55
In contrast with most data from experiments carried out using the MWM,5 results from the experiments described above did not provide evidence that impaired and unimpaired individuals could be distinguished within the population of aged mice. In fact, in a study conducted in a large population of F-344 rats tested in the MWM from 1.5 to 26 months, not find any evidence among aged rats of a bimodal distribution of performance in the spatial learning versions of the task.
Assessing Similarities of Memory Impairments in Senescent and Hippocampal Lesioned Subjects
Within a neuropsychological framework, the cognitive decline in non-demented aged individuals grossly parallels that observed in medial temporal lobe amnesia9 and is thought to originate mainly in deficient hippocampal processing. In this view (i) aged mice should display alterations in hippocampal functioning when confronted with problems in the RAM tasks described above, and (ii) hippocampal damage in adult mice should result in the same selective deficit as that seen in aged mice. When confronted with selected RAM problems in which they were able to perform at the same (above-chance) level as adults, aged animals indeed displayed an overall reduction of the testing-induced increase in the expression of the immediate early gene cFos (for review, see Greenwood et al, this book) in the whole septo-hippocampal system (SHS). Importantly, this diminished activation was accompanied by a loss of correlation between Fos activity levels in the connected sub-regions of the SHS.69 Ibotenate hippocampal
Figure 1. Two-stage paradigms of RAM discrimination tasks (adapted from ref. 40). Each mouse was separately assigned six adjacent arms. Out of these, three served as positive (baited) arms and the remaining three served as negative (not baited ) arms. Design A: In stage 1, the six arms were always presented one at a time using a go-no-go discrimination procedure (in each trial, the door to only one arm was open). Go-no-go discrimination was indexed by a ratio between the median latency to enter negative arms and positive arms. Each mouse was trained until reaching a predetermined criterion of go-no-go discrimination and then transferred to stage 2. Mice failing to reach the criterion within 360 trials were dropped from further testing. The discrimination problems presented in stage 2 were between the same arms as in stage 1: the reward contingency of the discriminanda remained unchanged, but their presentation was modified. The six arms were now grouped into, and presented as, three adjacent pairs A, B and C. In each trial, the mouse was confronted with access to two adjacent arms with opposing valence and allowed to visit only one of them. Accuracy was measured by percentage correct, i.e., choice of the positive arm within a pair. Design B: In stage 1, the six arms were grouped into the three pairs A, B and C (exactly as design A, stage 2) . A mouse was considered to reach criterion performance when its choice accuracy was above 75% correct for two consecutive sessions and then transferred to stage 2. Again mice failing to reach the acquisition criterion within 360 trials were rejected. In stage 2, the presentation of the arms only was modified. Two choice arms of opposing reward valence, each taken from a different discrimination problem featured in stage 1, were presented either one at a time or simultaneously as members of a novel pairing. These corresponded to "go" or "no-go" trials and "recombined" two-choice discrimination, respectively.
lesions in adult mice nicely reproduced the selective behavioural impairment previously observed in aged mice.19 Namely, hippocampus-lesioned mice performed as intact mice in learning the location of reward versus non-reward when arms were presented one at a time (see Figure 1, A stage 1). However, as aged mice, they were unable to translate this knowledge into an efficient approach to the rewarded arm in the two-choice (simultaneous) discrimination (i.e., A stage 2).
The selective deficit seen in both aged mice and hippocampal-lesioned mice in the RAM tasks described above is unlikely to be due to confounding (non-specific) changes (affect, motivation, perception or motor control), as all the basic requirements of the task were largely identical in the successive stages. In contrast, in-depth analysis of the performance of rats in the MWM38 has revealed significant relationships between non-cognitive and or non-mnemonic factors (e.g., swim speed, thigmotaxia, performance in the cued platform version of the task) and measures of cognitive functions (i.e., swim distances in the spatial learning versions). This suggests that swim distances in the MWM may be affected by non-specific factors.31 Moreover, it is unlikely that presenting arms one at a time (see A, stage 1 in Figure 1) in the RAM task is easier than presenting them by pairs (i.e., B, stage 1), as the speed of acquisition of adult mice was very similar in both situations. This is also an important point since it has been suggested that since the visible platform task in the MWM is easier to solve than the hidden platform task, this experimental design may be biased towards false specificity.26 Whatever the case, two (multiple)-stage testing designs1 such as the RAM tasks seem to provide a valuable tool for dissociating impaired from unimpaired forms of memory expression and, as we have shown, to support the hypothesis that the selective cognitive deficit of senescent mice stems from hippocampal dysfunction.
The anomalous performance seen in both aged mice and hippocampal-lesioned mice resembles the deficit observed in rats with fornix lesions in the studies of Eichenbaum et al16,17 on odour-guided discrimination tasks. It has been proposed that in both animals and humans, this deficit may stem from alterations in forming relations between separately experienced cues (i.e., relational representation),15,36 a process that would critically depend on the functional integrity of the hippocampus here conceived of as an associator of discontiguous (spatial and/ or temporal) items.64 It is therefore conceivable that one basic dysfunction underlying learning and memory impairments in senescence is the difficulty in prolonging neural activity subserving the representation of a cue.53 Such a dysfunction may account for age-related impairments observed in a variety of tasks such as Pavlovian conditioning in the trace paradigm,58 delayed response or delayed recognition tasks,14 and in tasks that require the encoding and storage of relationships between discontiguously perceived cues or events to guide performance (i.e., contextual information, cognitive maps).
Alleviating the Selective Age-Related Memory Deficit
Most of the pharmacological strategies traditionally used to improve age-related cognitive decline are designed to restore the deficiency of neurotransmission of one (e.g., cholinergic) or several (e.g., cholinergic and serotoninergic) specific types. Alternatively, other compounds (e.g., Nerve Growth Factor) are used to improve the "general health" of neurons and thus to maintain their normal cellular functions as they age. Recently, experiments were carried out to determine whether normalising a broad profile of brain gene expression in aged mice to pre-senescent (adult) levels would improve their associated cognitive deficits. The rationale was the following. First, it has been reported in mice that ageing is associated with a reduction (20-30 %) in the levels of mRNA for brain retinoid acid nuclear receptors (i.e., RAR and RXR) and in particular that this age-related reduction is susceptible to reversal by acute systemic administration of retinoic it is now well established that these nuclear receptors regulate the expression of a number of genes coding for neural proteins involved in synaptic plasticity (e.g., neurogranin, NMDA receptors, synaptophysin etc.), for cholinergic-specific proteins, and for neurotrophic factors (for references, see ref. 20). All of
Stage I Stage 2
(successive go-nogo discrimination) (simultaneous discrimination)
acquisition Inst two sessions
Daily session number
Figure 2. Behavioural data from ref. 20. Four groups of mice (i.e., adult mice treated with vehicle, aged mice treated with vehicle, aged mice treated with RA and aged mice treated with RA and the antagonist of retinoid nuclear receptors, CD3106) were trained in our RAM discrimination tasks (design A as described in figure 1). Learning curves in stage 1 (successive go-no-go discriminations) were identical among the four groups. Each group of mice reached about the same mean level of no-go/go latency ratio in the last two sessions of stage 1. Conversely, between-groups differences emerged in stage 2 when the same arms were combined into three pairs. While aged mice treated either with vehicle or a mixture of RA and CD3106 behaved as if they were naive, failing to transfer their acquired preference into the choice of the positive arm within a pair, aged mice treated with RA displayed nearly the same above chance level of accuracy as seen in adult controls.
these constitute a potential therapeutic target for attenuating cognitive deterioration. Using the RAM tasks we20 showed that restoring the brain (and hippocampal) levels of retinoid receptors and the expression of certain specific associated target genes [in particular, that of the Ca2+-sensitive calmodulin-binding protein neurogranin (RC3)] by administration of RA specifically alleviates the selective deficit of aged mice (see Fig. 2). Conversely, decreasing brain levels of brain retinoid receptors (and expression of RC3) by 20-30 % in adult mice using a vitamin A deprived diet was demonstrated to produce the same selective cognitive deficit as seen in aged mice.70 Given that retinoid receptors play a major role in the foetal development of the nervous system, these findings are, in a sense, in line with the general principle that "the signals transduced by cells during growth and physiologic activity are the same as those that become overloaded during pathological events and ageing".39
We have shown in this chapter that processes more complex than that suggested by the hypothesis linking age-related memory loss to cholinergic deficiency have to be considered. First of all, we have underlined the need to optimise the development of animal behavioural models providing closer analogy with -and greater sensitivity and selectivity to- the cognitive deficits known to date to accompany human senescence. Second, we have emphasised the need to recognise that ageing cannot be reduced to a neurobiological dysfunction at a single locus, but rather that it involves a set of dysfunctions, including compensatory changes whose functional relevance lies at the system-property level. In this respect, it must be noted that both observations are not inherent to ageing studies, as they concern all research investigating the problem of relating brain function to memory. Returning to the ageing issue, we tentatively propose that rather than compensating a single identified dysfunctional target, a better strategy would be to attempt to globally re-establish cellular homeostasis. Although the strategy of using RA administration seems efficient (see Figure 2), we are at present unable to pinpoint the protein product(s) of the retained-activated target genes that are responsible for the observed improvement in cognitive function in senescent animals. Yet it has long been a dream of neurobiologists to reduce complex cognitive function to a simple molecular device (but see ref. 3 and 52), as well as to equate cognition (a psychological construct) with measures of behavioural performance assessed by training and testing techniques currently in vogue.28 As already widely remarked, no one has ever measured learning and memory. They can only be inferred from careful behavioural analysis specifying what, how, and why, and not simply by stating that "something" has been learned. Such are the prerequisites for thoughtful integration of the neurobiological level with the behavioural level.
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