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Riddle DR, editor. Brain Aging: Models, Methods, and Mechanisms. Boca Raton (FL): CRC Press; 2007.

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Brain Aging: Models, Methods, and Mechanisms.

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Chapter 3Neuropsychology of Cognitive Aging in Rodents

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I. OVERVIEW

Advancing chronological age is associated with impairments in cognition in rodents, as it is in other species. The behavioral assessment of cognitive function in rodent models of aging provides a basis for understanding biological factors that contribute to these impairments. Advantages of rodent models of cognitive aging include their relatively brief lifespan relative to primates, the large range of behavioral tasks that have been developed for testing cognitive abilities in rodents, the anatomical homology of many brain structures between rodents and primates, the ability to carry out genetic manipulation in rodents (especially in mice), and the absence of many age-related neurodegenerative conditions observed in humans that complicate the study of phenomena associated with “normal” aging (as opposed to pathology).

Our goals in this chapter are twofold. First, we discuss some measurement and methodological issues surrounding the assessment of cognitive abilities in aged rodents. Some of these issues become especially critical when, as is commonly done in this work, one attempts to draw conclusions about the relationship between cognitive aging and neurobiological changes in the aged brain. Second, we provide a relatively brief and selective review of effects of cognitive aging on some of the major behavioral domains that can be readily assessed in rodents, as well as some neurobiological substrates that have been proposed to underlie some of these impairments.

II. MEASUREMENT AND METHODOLOGICAL ISSUES

A. Measurement and Reliability

With regard to the study of individual differences in cognitive performance in aging rodents, consideration of measurement issues is paramount. For example, in the absence of information about test-retest reliability of behavioral assessments, the use of behavioral scores as a basis for correlation with neurobiological measures is problematic. This is not a trivial problem, with many paradigms complicated by practice and carryover effects between assessments. Indeed, spatial learning in the water maze is one of the most problematic tasks in this regard because learning of new problems in the water maze occurs much more rapidly than initial acquisition. Initial acquisition curves are most commonly used as a basis for correlation with neurobiological parameters and it is not really possible to retest each rodent in the water maze as if they were encountering the problem for the first time. Of course, this also speaks to a neuropsychological issue as well as a measurement issue; initial acquisition of the water maze taps into a number of capacities other than spatial learning, including inhibition of prepotent responding (learning to swim away from the wall of the tank) and possibly attentional and cue-selection processes (learning which cues are stably related to the platform location).

Some solutions to this problem include examining correlations of performance across behavioral tasks that presumably depend on the same neurobiological substrate (e.g., the hippocampus). One of the first studies to employ this approach found that subgroups of rats identified as “impaired” and “unimpaired” based on their acquisition of spatial learning in the water maze honored those subgroup distinctions when tested on the Barnes circular platform task and in recovery from gustatory neophobia, both tasks that depend on the integrity of the hippocampus [1], but did not differ in simple reaction time tested in a separate assessment, despite this task revealing differences between young and aged rats overall. More recently, test-retest reliability of the water maze was demonstrated more directly by training rats in a standard protocol and retesting them several weeks later in a rapid-acquisition protocol in a new maze in a different physical room. Subgroups of “impaired” and “unimpaired” rats identified during initial training also differed in retention performance in a probe trial conducted 30 minutes after the rapid training protocol [2]. Performance in the water maze also correlated with acquisition of a reference memory problem in the radial arm maze, but not with working memory errors measured in the same paradigm [3], again confirming the reliability of the assessment in the water maze.

These considerations are important because reliability of behavioral scores constrains the magnitude of correlations with neurobiological measures. If the coefficient of correlation for two different assessments of a particular cognitive ability is 0.7 and the test-retest reliability of a neurobiological measure is 0.9, then the largest correlation that can be observed between these measures is 0.63, although the “true” population correlation between the measures may be 1.0 [4]. Thus, the use of behavioral scores that have poor reliability for correlational analysis makes the determination of correlations with neurobiological markers problematic. Even if the assessment itself is reliable, it is important to ascertain that the measure is reliably indicating the cognitive ability of interest (e.g., spatial learning). Swim times to the platform in the water maze may be very reliable across different assessments but may also include a component of motor ability, which may also be reliable from a testing standpoint but is not an indicator of the cognitive process of interest.

The relative merits of subdividing aged rats into “impaired” and “unimpaired” subgroups have been commented on previously [5]. In the context of measurement reliability, a binary classification may be more reliable than the absolute value of an individual behavioral score. Conversely, this approach discards a considerable amount of information provided by the absolute score value. It may be the case that a subgrouping approach may be more appropriate if there are concerns about the reliability of absolute scores, although it still would be important to confirm that subgroup classifications are reliable across assessments in some way.

B. Behavioral Testing Issues

Issues of behavioral control and specificity of age-related behavioral impairments are also critical to this area of research. We have already alluded to these concerns in the context of measurement issues. This relates not just to the reliability of a behavioral measure in the context of test-retest reliability, but also in terms of its relationship to the latent cognitive variable of interest. It is fairly obvious (but worth restating) that we cannot measure attention, memory, etc., directly, but rather must infer the integrity of these cognitive domains from performance on behavioral tasks. In a sense, this is the converse of the issue addressed in the section above; it is important to know that tasks that presumably measure the same cognitive ability provide performance measures that correlate with one another, but it is equally important to know that these measures are assessing the cognitive process of interest rather than a general age-related decline in behavioral performance or some other factor, such as sensorimotor ability. Indeed, it has been argued in studies of human cognitive aging that practically all the age-related variance in performance on cognitive tasks can be accounted for by a deficit in perceptual speed [6]. In this view, it would be pointless to discuss how age-related impairments in episodic memory retrieval, for example, are related to particular biological changes, because the age-related differences in performance on episodic retrieval owe to a core deficit in perceptual speed rather than a specific impairment in memory per se.

Nevertheless, dissociations in performance in cognitive aging have already been identified in aging rodents. One of the first studies to address this issue found that deficits in spatial learning in aging rats were independent of deficits in motor performance, indicating that spatial learning deficits could not be easily explained by noncognitive impairments [7]. As already discussed, age-related changes in reaction time were independent of age-related changes in spatial learning and recovery from gustatory neophobia [1, 8]. Similarly, age-related impairments on a putatively prefrontal cortex-dependent attentional set-shifting task were independent of age-related impairments in spatial learning in the water maze [9]. Taken together, these findings argue against a unitary decline in behavioral performance in aged rats that might explain apparent cognitive impairments by a single factor.

Of course, this does not mean that the behavioral scores themselves are pure measures of the cognitive processes that are of interest. Rats that are poor swimmers may perform poorly in the water maze for reasons that have nothing to do with disruption in spatial learning. It may be possible to use measures of performance in the water maze that are less contaminated by possible motor impairments, for example, bias of search during interpolated probe trials [10, 11]. It is better, however, to show that swimming ability per se either does not differ between young and aged rats or, if it does, that swimming ability is independent of performance on measures of cognitive performance. In this vein, visually cued water maze tasks are commonly included as behavioral controls and given after the conclusion of standard, hidden-platform testing in the water maze. The argument is that if rats perform normally when swimming to a visible platform (requiring no learning about its location), then any deficit in locating a hidden platform, which must be done based on the relationships between distal spatial cues, is not due to some impairment in swimming ability or motivation to escape from the water. Similarly, tests of object recognition memory may show that performance is intact at very brief delays but not at longer ones, indicating that the motivation to explore a novel object is intact, even if memory for whether objects are novel or not is impaired [12]. If in a particular experiment aged rats are impaired, for example, in both spatial and visually cued tasks, this does not necessarily mean that their impairment in the spatial task is due exclusively to some nonmnemonic factor, but it makes it very challenging to absolutely exclude this possibility directly. Indeed, blind young rats can perform very well in the standard hidden-platform water maze task [13]. Nonetheless, the inclusion of such behavioral controls is essential if age-related changes in a particular behavioral measure of performance are to be attributed with relative confidence to a deficit in the cognitive process the task purports to measure, rather than some less specific performance deficit.

C. Neuropsychological Specificity

We already have alluded to the issue of how behavioral tasks are associated with the integrity of particular neural systems. For example, spatial learning in the water maze is heavily identified with the hippocampal system. The question of whether a particular behavioral task is a reliable measure of a cognitive latent variable of interest (e.g., spatial learning) is not quite the same as whether that task is reliably associated with changes in the integrity of function within a particular brain region. That is to say, a particular subpopulation of aged rats could reliably demonstrate impairments on several different tests of spatial learning, but this does not necessarily mean that these impairments owe to neurobiological changes in hippocampal function specifically. For example, impaired performance in the water maze has been associated with damage to the frontal cortex, parietal cortex, and temporal cortex [14–17], although some of these deficits are not always found [18, 19].

Of course, this problem is not unique to the water maze. Many different manipulations can affect multiple-choice serial reaction time performance, a test of attention [20], although the presence of many measures of performance and parametric manipulations of task difficulty in that task allow the dissociation of many different causes of overall impairment in performance. These problems also are not unique to the study of aging. Indeed, they are not dissimilar to core issues in the use of neuropsychological assessment to localize brain damage in humans before the advent of neuroimaging techniques. Sensitivity and specificity are two qualities that are important in behavioral tasks used for neuropsychological assessment. Sensitivity denotes the reliability with which a behavioral deficit is observed after damage to a specific brain region; specificity denotes the extent to which the particular deficit is restricted to a specific locus of brain region. By these criteria, one might say that spatial learning in the water maze is extremely sensitive to hippocampal damage because it is unusual to find instances in which hippocampal damage is documented but spatial learning is normal, but it also is relatively unspecific because impairments in spatial learning in the water maze can be seen in animals that have damage to brain regions other than the hippocampus.

D. Neurobiological Correlations

Just because performance in a behavioral task correlates with a particular neurochemical measure does not imply that changes in that neurochemical marker are responsible for the impairment in performance of the behavioral task. It is again fairly obvious to state that correlation does not imply causation and that observing associations between changes in biological markers and age-related impairments in cognition — some of which we will review in subsequent sections — does not imply that changes in the marker necessarily cause the cognitive impairment. There are, however, some experimental approaches that can be brought to bear on this problem. One is to use an intervention to modify the neurobiological parameter of interest to see if this moderates the cognitive impairment. For example, if low levels of a growth factor are associated with impairment in a particular aspect of memory, that growth factor may be replaced in aged, memory-impaired animals to see if memory is restored. The logic of this approach may not be entirely secure — if aspirin relieves a headache, it does not mean that the headache was caused by an aspirin deficiency — but it does provide data more supportive of causality. It also may be possible to model some neurobiological changes in a young animal to determine if these reproduce the pattern of cognitive impairment in aging. One example of this approach is the study of the role of basal forebrain cholinergic neurons in age-related impairments in spatial learning. Although correlations are observed between cholinergic markers and age-related impairments in spatial learning and memory, removal of hippocampal cholinergic input in young rats did not impair spatial learning in a water maze protocol sensitive to the effects of normal aging [21], nor did it cause aged, unimpaired rats to develop spatial learning impairment [22]. These types of approaches, as well as others, can be used to complement correlational studies done in aged rodents.

III. NEUROPSYCHOLOGY OF AGED RODENTS

A. Spatial Learning

Although a comprehensive review of studies examining spatial learning in aged animals is beyond the scope of this chapter, we will attempt to summarize recent reports in a number of areas relating to spatial cognition in aged subjects.

1. Age-Related Impairments in Spatial Learning

As has already been noted, spatial learning in the water maze is commonly used to assess hippocampal-dependent cognitive function in aged rodents. This is probably because the water maze does not require food or water restriction, which may place differential physiological stress on aged rodents, and because learning in the water maze proceeds rapidly and efficiently. However, it has been noted that aged rats may have exacerbated responses to the stress of submersion in water [23, 24], which may need to be considered in these experiments. These impairments are also seen in other spatial tasks, including the Barnes circular maze [25], which uses escape from bright light in an open field as a motivator, as well as the more standard radial arm maze [26]. Aged mice are also impaired in spatial tasks in the water maze, although measures of performance different than those used in rats may be maximally sensitive to these impairments [27]. In general, spatial learning impairments appear to emerge gradually as chronological age increases. Even 11-month-old Fischer-344 rats are impaired relative to 4-month-old Fischer-344 rats on a demanding measure of spatial memory, the number of platform crossings on probe trials [28].

2. Behavioral Strategies

Barnes and co-workers [29] were the first to report that aged rats were less likely than young rats to use place strategies to solve a simple spatial discrimination in a T-maze in which egocentric (body-turn) and visual cue-guided strategies were also able to support accurate discrimination behavior. Subsequent reports indicated that aged rats used different behavioral strategies in the Morris and T-water mazes, and detection of age-related spatial learning deficits depended on the task used and the strategies employed [30]. In particular, these authors noted that the acquisition of spatial tasks using egocentric strategies was unimpaired in aged rats. Complementary observations were reported by Nicolle et al. [31] in aged mice using a cue-competition paradigm in the water maze. In this task, mice learn to swim to a visible platform in a fixed location. Probe trials are given in which the visible platform is moved to a different location in the maze: mice either swim toward the visible platform in its new location (a cue strategy) or swim toward its previous location first (a place strategy). The prevalence of a cue strategy increased with age, with 23-month-old mice using a cue strategy exclusively. Aged rats were impaired on a number of behavioral assessments in the radial arm water maze, and committed both reference and working memory errors compared to young rats across all days of testing, thus suggesting that aged-rats may have employed nonspatial strategies in learning new platform locations [32].

3. Structural and Anatomical Analyses

Despite overwhelming behavioral and electrophysiological data on hippocampal dysfunction in aging, a clear understanding of the anatomical and structural basis for these cognitive declines is lacking. Cell sizes and numbers do not differ in the subdivisions of entorhinal cortex between young and aged rats despite behavioral differences in the water maze, suggesting that parameters other than neuronal size and number may be relevant for understanding age-related cognitive declines [33]. In a more recent study, this group examined hippocampal cell genesis in its relation to spatial learning and again found that behavioral deficits did not appear to correlate with adult hippocampal neurogenesis [34] (see also Chapter 6). These studies are consistent with reports that total neuron number in the entorhinal, perirhinal, and postrhinal cortices is largely preserved during normal aging. Moreover, individual variability in hippocampal-dependent learning in aged rats does not correlate with neuron number in any area examined [35]. Thus, age-related cognitive decline can occur in the absence of significant neuronal death in any major area of the hippocampal system. In contrast, a significant age-related relationship between deficit in spatial learning and the loss of p75-positive neurons in the basal, but not rostral, forebrain has been reported. Although there was no learning impairment at 6 months of age, fully one-half the rats were impaired at 12 months and 71% displayed deficits at age 26 months [36]. Another study examined basal forebrain cholinergic neurons in young and aged, male and female Fischer 344 rats that had been trained on the Morris water maze [37]. Young rats’ performance was superior to aged rats’ performance, but young male rats were better at finding the precise platform location compared to young females. When examining structural differences, young male and female rats had larger basal forebrain cholinergic neurons compared to the aged groups, but this was largely a function of a difference between aged and young male rats. In no case, however, was there a correlation between neuron size and spatial memory performance. Examination of postsynaptic densities in hippocampal excitatory synapses in aged spatial learning-impaired and unimpaired rats found a significant decrease in postsynaptic density area in aged-impaired compared to aged-unimpaired rats, suggesting that hippocampal synapses might become less efficient in aged-impaired animals, which might manifest as behavioral deficits in cognitive tasks [38].

4. Signal Transduction

Brightwell and colleagues [39] investigated the effectiveness of signal transduction in aged rats with impaired spatial performance. Individual proteins from the CREB family can function as either enhancers (e.g., CREB1) or repressors (e.g., CREB2) and influence the short-term to long-term memory transitions. Aged animals that were impaired in the Morris water maze were found to have lower levels of CREB1 in the hippocampus compared to both younger animals and aged non-impaired animals, suggesting dysregulation of CREB1 levels may lead to some aspects of spatial learning deficits in aged subjects. Aged rats with impaired spatial memory, compared to young rats, demonstrated increased protein kinase C (PKC)-gamma immunoreactivity in the CA1 region of the hippocampus, but not in the dentate gyrus [40]. Furthermore, this increased PKC-gamma activity in CA1 was significantly correlated with spatial memory deficits. These data are consistent with a report that demonstrated a significant relationship between choice accuracy and PKC-gamma immunogenicity in the hippocampal CA1 region, but not amygdala, of aged animals [41].

5. NMDA Receptors

Adams et al. [42] investigated the association between levels of the NR1 subunit of N-methyl-D-aspartate (NMDA) receptors and performance in the Morris water maze task. Although neither global nor region-specific differences in hippocampal NR1 levels were observed, there was a selective association between individual behavioral performance and NR1 immunofluorescence levels in the CA3 region, suggesting that NMDA abundance in the CA3 region is critical for spatial learning over the lifespan. More recently, Clayton and colleagues [43] used antisense oligonucleotides to knock down the NR2B subunit expression in the hippocampus, suggesting a key role for reduced NR2B expression in aged-related cognitive deficits in older animals. Another way to examine NMDA subunit involvement in learning and memory is by pharmacological manipulation. Suldinac is a nonsteroidal anti-inflammatory drug (NSAID) that is a nonselective cyclooxygenase (COX) inhibitor. Chronic administration of suldinac, but not its non-COX active metabolite, ameliorated age-related decreases in the NR1 and NR2B NMDA receptor subunits and prevented similar age-related increases in the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in the hippocampus. Moreover, suldinac reversed age-related deficits in radial arm maze deficits [44]. In a fashion consistent with these data, others have reported that chronic aspirin (a NSAID) treatment improves spatial learning in both adult and aged rats [45].

6. Hormones and Stress

Although much research suggests that ovarian hormone levels are important in cognition, the effect of manipulating hormone levels in aged animals has been less well explored. Foster and colleagues [46] reported that estradiol did not enhance acquisition of cue and spatial discrimination in the Morris water maze, but the researchers noted a dose by age interaction such that a high dose of estradiol did produce higher retention scores in aged animals. Markham et al. [47] also noted an age and hormone interaction. Ovarian hormone replacement early in life can be detrimental to cognitive performance, whereas ovarian hormone replacement when rats are at least 14 to 16 months old has a beneficial effect on spatial learning. These studies contrast with recent work by Bimonte-Nelson and colleagues [48], who reported that a lack of ovarian hormones over a longer period (e.g., greater than 1.5 months) improved spatial memory in aged female rats. These seemingly contradictory data might be explained not by levels of estradiol, but by lower levels of progesterone being related to the ovarectomized-induced enhancement of spatial learning. This idea was supported by a subsequent study that demonstrated that progesterone supplementation reversed the cognitive enhancement produced in aged ovarectomized rats [49]. Recently, Ziegler and Gallagher [50] attempted to elucidate whether estrogen is critical to spatial learning in middle-aged females that generally have declining ovarian hormone cyclicity. Estradiol was administered in a phasic pattern to simulate normal cyclic behavior, yet estradiol did not have any effect in either young or middle-aged rats, nor on any behavioral measure. The lack of significant effects where others have previously observed cognitive effects of estradiol might be explained by methodological or training differences across laboratories.

Bimonte-Nelson and colleagues [51] also reported on the importance of hormone-related cognitive enhancements in aged male rats by demonstrating that testosterone, which is aromatized to estrogen, improved working memory. In contrast, administration of dihydrotestosterone, which is not aromatized to estrogen, did not attenuate age-related deficits in working memory. Thus, hormone therapy in aged males and females may have beneficial effects on some aspects of cognition when the age of the subjects is taken into consideration.

Bizon et al. [52] examined the function of the hypothalamic-pituitary-adrenal (HPA) axis in young and aged animals. Plasma corticosterone levels in cognitively impaired aged animals were slower to return to baseline following restraint stress compared to both younger rats and cognitively unimpaired aged rats. Analysis of neurobiological data revealed that glucocorticoid receptor mRNA was reduced in the hippocampus and medial prefrontal cortex in aged cognitively impaired rats compared to either young or aged unimpaired groups. Moreover, the decreased mRNA levels in these regions were significantly correlated with impaired performance in the water maze task. In a subsequent study to evaluate the role of neurogenesis in aged animals, Bizon and colleagues demonstrated that nonimpaired aged rats did not demonstrate enhanced hippocampal neurogenesis compared to cognitively impaired aged rats. Thus, aged rats that maintain cognitive function do so while still enduring the same significant reductions in hippocampal neurogenesis that are characteristic of cognitively impaired aged subjects [53]. This contrasts somewhat with a previous study that reported spatial memory performance of aged rats was predictive of hippocampal neurogenesis ([54]; see also Chapter 6).

In a creative study, Gatewood and co-workers [55] examined the effect of motherhood on age-related deficits in a food-reinforced spatial learning task by comparing age-matched nulliparous, primiparous, and multiparous females (0, 1, and 2 pregnancies and lactations, respectively) at ages from 6 to 24 months. Primiparous and multiparous females demonstrated significantly accelerated acquisition and showed decreased memory decline up to 24 months of age when compared to the nulliparous subjects. Furthermore, amyloid precursor protein, a marker of neurodegeneration, was decreased in the CA1 and dentate gyrus regions of the hippocampus in multiparous females compared to nulliparous and primiparous females. Moreover, the level of amyloid precursor protein was inversely related to spatial learning performance, suggesting that natural reproductive related hormone levels and postpartum experiences may decrease vulnerability for age-related cognitive decline in females. The role of maternal behaviors was indirectly assessed by Lehmann and colleagues [56], who examined the effects of maternal separation and handling on long-term cognitive outcome. Rats that had been handled extensively early in life were observed to have superior spatial cognition, a decreased stress response, and no decrease in hippocampal neuronal counts when compared to those rats that were either not handled or underwent early maternal separation [56].

7. Plasticity and Cognition

Aging has been documented to be related to specific impairments in learning and memory, many of which are associated with selective damage to the amygdala and hippocampal regions that are important in long-term potentiation (LTP) and long-term depression (LTD) [for review, see 57]. Almaguer and colleagues [58] compared aged rats that were cognitively impaired to both young rats and aged, nonimpaired rats and noted that stimulation of the perforant path produced reduced LTP in the aged impaired rats, whereas aged rats that were nonimpaired were comparable to young animals. Barnes et al. [59] demonstrated that aged, spatially impaired rats had a higher threshold for LTP induction compared to middle-aged and younger controls, suggesting that the fewer perforant path synaptic contacts in aged, spatially impaired rats require greater depolarization and convergence before any modifications of synaptic strength can be produced. Schulz and co-workers [60] attempted to find behavioral and neurobiological correlates with aged rats that were divided into superior and inferior learners and then examined in a battery of behavioral assessments. In aged superior rats, levels of LTP in CA1 correlated with hippocampal mediated tasks (e.g., spatial preference learning and water maze escape). Unfortunately, there were no significant correlations observed in the aged inferior learning group, which may suggest an effect of overall impairment or other yet unknown factors. Subsequently, Schulz and colleagues [61] probed striatal parameters for associations with age-related cognitive decline. Superior and inferior learners were again compared and individual differences in the different behaviors of the aged rats were accounted for by variability in some striatal parameters for both superior (e.g., LTP) and inferior (e.g., NR2 subunit expression) rats [61].

Rosenzweig et al. [62] attempted to examine the flexibility of hippocampal spatial mapping in an elegant methodology by monitoring rats that were attending to a spatial reference that was in conflict with another frame of reference. When adult and aged rats attempted to find an unmarked goal, aged rats were impaired in their ability to find the unmarked goal and in their ability to realign the hippocampal map based on the changing contextual information. Wilson and colleagues [63] observed spatial performance of young and aged rats in the Morris water maze and then examined firing patterns of hippocampal place cells when animals were in familiar and novel environments, in an attempt to better understand how spatial representations distinguish familiar and altered environments. One consistent pattern to emerge from the data was that the (in)ability of the hippocampus to encode subtle differences in contextual environmental information may represent a major component of memory deficits [63]. Subsequently, Wilson and colleagues [64] expanded on this model and better characterized the ability of the hippocampal place cells to form new representation but also noted the delay in some spatial representations being anchored to external cues and landmarks. Taken in sum with previous work by Wilson’s colleagues and others [62], these descriptions and observation help converge seemingly divergent data into a more comprehensive model of hippocampal function and aging.

8. Treatment: Diet and Exercise

Research has demonstrated that vegetables and fruit that are high in antioxidant activity can have beneficial cognitive effects (see Chapter 15). Andres-Lacueva and colleagues [65] reported that aged rats fed a diet rich in blueberries had better water maze performance than those on a control diet, and behavioral performance was associated with brain levels of several blueberry-derived anthocyanins isolated in cortical tissue. This work is in agreement with the previous report by Casadesus et al. [66], who assessed changes in hippocampal plasticity parameters (e.g., neurogenesis; extracellular kinase activation; levels of insulin growth factor-1, IGF-1) in aged animals that were supplemented with a blueberry-rich diet. Parameters of hippocampal plasticity were enhanced in supplemented animals and cell proliferation, extraceullular receptor kinase activation, and IGF-1 levels all correlated with improved spatial task performance, suggesting that hippocampal plasticity may contribute to enhanced learning and memory measures observed in aged animals on a blueberry-rich diet. Many have also explored the role of exercise-induced cognitive enhancement. Albeck and colleagues [67] found that aged rats that exercised for 7 weeks performed significantly better in the water maze than controls, an improvement that reflected cognitive improvement because the groups did not differ in swim speed.

9. Treatment: Drug

Compounds having activity at the nicotinic acetylcholine (nACh) receptor have been identified as having potential therapeutic benefits in aged populations. SIB-1553A is a novel nACh ligand that has subtype selectivity for alpha2-beta4 subunits. Administration of SIB-1553A was reported to be effective in enhancing T- and water-maze performance in aged rats [68]. Manipulations of other cholinergic receptor subtypes have also been found to have a positive effect on some types of learning in aged animals. Lazaris and colleagues [69] examined the effects of bilateral injections of methoctramine into the dorsolateral striatum of cognitively impaired aged female rats. The selective muscarinic M2 cholinergic antagonist improved procedural working memory, but was without effect on spatial memory. In contrast, a recent study by Rowe and colleagues [70] reported that the selective M2 antagonist, BIBN-99, significantly improved spatial learning and memory in aged animals during testing and the enhanced performance was observed to persist for up to 24 days post drug administration.

The noradrenergic system has also been suggested to play an important role in enhanced learning in aged animals. Chopin and colleagues [71] demonstrated that the selective alpha(2) antagonist dexefaroxan attenuated age-related memory deficits in 24-month-old rats, as well as reversing cognitive impairments induced by nucleus basalis magnocellular lesions. Recently, Ramos et al. [72] examined the effects of the beta-1 adrenergic antagonists in aged animals and found that the mixed beta-1/beta-2 antagonist propanolol had no effect on spatial memory but that the selective beta-1 ligand betaxolol produced dose-dependent enhancement of spatial cognition in aged subjects. Thus, the use of more selective beta-adrenergic compounds warrants further investigation.

The use of monoamine oxidase inhibitors has also been investigated. Kiray and colleagues [73] examined the effects of deprenyl, an irreversible monoamine oxidase B inhibitor, on spatial memory in aged rats. Initially, the effects of deprenyl were examined in combination with estradiol on aged female rat cognition and a synergistic effect between deprenyl and estradiol was observed. Subsequently, the actions of deprenyl were examined in aged male rats. Spatial learning in males, like females, was enhanced by deprenyl administration [74]. Other examination of antidepressant treatment has revealed that chronic treatment with the tricyclic antidepressant amitriptyline from middle age on prevents normal age-related deficits in water maze learning. Administration of amitriptyline also decreases plasma corticosterone levels, suggesting altered anxiety and stress-related behaviors [75].

The identification of effective cognitive enhancing compounds continues to be an unmet need. Hernandez and colleagues [76] examined the effects of two acetyl-cholinesterase inhibitors, galantamine and donepezil, on spatial learning. Both galantamine and donepezil dose-dependently enhanced cognitive performance while modestly increasing choline acetyltransferase activity in the basal forebrain and hippocampus. In a similar fashion, Aura and Riekkinen [77] demonstrated that the acetylcholinesterase inhibitor tetrahydroaninoacridine and the NMDA allosteric modulator D-cycloserine both enhanced spatial navigation. However, if aged rats were pretrained on the task, then any drug-enhanced effect on behavior was eliminated. Moreover, pretraining did not reverse age-related deficits; thus, compounds with apparent cognitive-enhancing capabilities may function by enhancing procedural aspects of learning in aged animals. Thus, while a number of compounds have been suggested to have demonstrated effectiveness in reversing age-related deficits, procedural and methodological issues are important considerations.

Administration of the 5-HT(6) receptor antagonist SB-271046 improved acquisition and consolidation in a water maze task in aged rats. Treatment with SB-271046 improved swim strategy, escape latencies, and task recall, suggesting that the drug may enhance cognitive processes as well as ameliorate age-related cognitive deficits observed in older animals [78]. In addition, Froestl et al. [79] examined the effects of the novel GABA(B) receptor antagonist SGS742. Chronic administration of SGS742 was reported to upregulate GABA(B) receptors in the frontal cortex of rats and produce cognitive enhancing effects in aged rats in both radial and water maze tasks.

B. Fear Conditioning

Although the spatial water maze has been frequently used as a common measure of hippocampus-dependent learning, other animal paradigms have attempted to contribute to and expand our understanding of the role of the hippocampus in learning and memory. Fear conditioning is a hippocampally mediated form of associative learning that requires an animal to associate a conditioned stimulus (CS) and a fear-producing unconditioned shock stimulus (US). For delay conditioning, the foot shock immediately follows the tone, whereas in trace conditioning, the tone and shock are often separated by a short interval (15 to 20 seconds) and then the retention of this learning is tested a discrete time late (e.g., 24 hours).

1. Age-Related Impairment in Fear Conditioning

Blank and colleagues [80] first reported data suggesting that the trace fear conditioning procedure was sensitive to the effects of aging. By examining behavioral freezing in mice, they demonstrated that aged mice were impaired when compared to their younger controls. McEchron et al. [81] continued in this vein when they examined the effects of trace fear conditioning in aged rats. Both freezing and heart rate were sensitive measures for detecting age-related changes in trace fear conditioning. Although aged animals were not impaired at short durations of delay, they were significantly impaired in the 20-second long trace fear conditioning when compared to their younger control subjects. These data are in agreement with the recent work of Villarreal et al. [82], who demonstrated that aged rats were impaired in trace, but not delay, fear conditioning. The differences between these two tasks is the imposed delay between the tone and shock. These data, when taken in sum, suggest that aged animals are not impaired in the sensory-motor abilities to perform the task, but rather display a deficit that is characteristic of compromised hippocampal functioning and processing.

2. Neurobiological Associations

Gale and colleagues [83] examined the neurobiological role of the basolateral amygdala in maintaining stable memories of fear. Animals that had received lesions of the basolateral amygdala after fear conditioning displayed robust freezing deficits compared to sham controls. Moreover, these deficits were observed independent to the training-to-lesion interval. Indeed, rats with lesions showed robust deficits during both recent (1 day) and distant (16 months) memory tests. Thus it would appear that the basolateral amygdale might be important for encoding and storage function of emotionally and/or fear-related conditioning. The role of amount of contextual information within an environment on emotional memory was reported by Doyere and colleagues [84]; and in an interesting finding they reported that performance task deficits in aged animals were restricted to particular procedures that employed poor cues within the environment. When aged rats were tested in a more cue-rich environment, task performance improved, suggesting that aged animals may be able to employ different or enhanced learning strategies under different environmental conditions.

Monti et al. [85] took a different approach when exploring conditioned fear in aged rats. They examined whether changes in the functional state of proteins that were known to be involved with hippocampal learning could be associated with age-related decline in hippocampal-mediated behaviors in aged rats. These authors found that aged-related impairments in freezing were causally associated with a dysregulation in CREB activation, and specifically to the increased phosphorylation in aged rats after learning.

A similar approach was investigated by Kasckow and colleagues [86]. Noting that aging in rodents was accompanied by age-related changes in the immune system, they sought to identify relevant changes in the hypothalamic-pituitary-adrenal (HPA) axis. Despite finding decreased ACTH and corticosterone release following dexamethasone administration in aged-animals, testing revealed no significant associations between HPA-related data and the decreased freezing times observed in aged animals relative to middle- or younger-aged animals. The authors noted that any decrease in pituitary-related functions might be overcome by an associated increase in adrenal-related activity in aged animals.

A neuroimmune approach of age-related cognitive decline was investigated by Barrientos et al. [87]. They reported that peripheral injection of Escherichia coli produced both anterograde and retrograde amnesia in 24-month-old rats, but not in younger animals. Indeed, aging alone did not produce significant impairments in freezing time, nor in water maze acquisition time, but the immune challenge did produce decreased accuracy in swimming following a longer delay, suggesting a deficit in long-term memory consolidation. Moreover, immune challenge produced marked increased levels of the pro-inflammatory cytokine, interleukin 1-beta (IL-1-beta) in the hippocampus that is associated with aged-related memory impairments. Combined with the immune challenge observations, these data suggest that aged animals may be vulnerable to cognitive impairments produced by immune challenge, and that the behavioral effects of the immune challenge were observed for an extended duration following challenge.

3. Modulating Changes in Fear Conditioning

Attempts to identify effective pharmacological agents to combat cognitive decline in aged populations is a continuing goal. Gould and Feiro [88] explored context and cued fear conditioning to see if galantamine, an acetylcholinesterase (AChE) inhibitor and nicotinic acetylcholine receptor allosteric modulator, would prove effective in reducing impairments. Aged C57BL/6 mice were not impaired in the acquisition of auditory cued or contextual fear conditioning, and were not impaired in the retention of contextual fear conditioned memories. However, mice were significantly impaired in the retention of auditory fear cued conditioned memories. Moreover, galantamine significantly improved the age-related deficits in the retention of cued fear conditioning. Feiro and Gould [89] also examined the interactive effects of nicotinic and muscarinic receptor antagonists. Administration of the muscarinic receptor antagonist scopolamine uniformly disrupted contextual fear conditioning across all ages, and younger animals were more sensitive to the disruptive effect of scopolamine in auditory cued fear conditioning than were aged rats. In contrast, the nicotinic receptor antagonist mecamylamine had no effect on contextual or auditory-cued conditioned fear in young or old animals. Examination of combined drug administration of subthreshold doses disrupted fear conditioning in younger animals, but not in aged animals, suggesting that cholinergic involvement in conditioned fear is differentially affected by age.

The involvement of nicotinic receptors in fear conditioning was further examined by Caldarone and colleagues [90], who investigated mice lacking the beta-2 subunit of the nicotinic receptor. The absence of the beta-2 subunit in young animals had no effect on contextual or tone-conditioned fear, but aged knockout males were impaired in freezing to both context and tone-conditioned fears compared to wildtype controls. These findings are consistent with previous reports that nicotinic acetylcholine receptors that lack the beta-2 subunit are not critical for normal performance in a fear conditioning task, but are likely involved in the maintenance and preservation of neuronal functioning during the aging process.

Another pathway that may have a role in age-related cognitive decline is that of oxidative stress. Quinn and colleagues [91] examined the effects of a diet high in the antioxidant alphalipoic acid in Tg2576 mice, a transgenic model of the cerebral amyloidosis associated with Alzheimer’s disease. Aged mice that received the antioxidant-enhanced diet for 6 months demonstrated improved performance in context fear conditioning and in Morris water maze performance compared to the normal-diet controls. Although beta-amyloid levels remained unchanged, these data suggest that chronic dietary manipulation can improve some aspects of learning and memory in aged populations.

In a similar fashion, chronic administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported to have neuroprotective effects in aging. Administration of the nonselective cyclooxygenase (COX) inhibitor sulindac for 2 months produced significant improvement in Fischer-344 rats in contextual fear conditioning [44]. Interestingly, administration of the COX inhibitor also decreased the age-related decline of N-methyl-D-aspartate receptor subunits (NR1, NR2B) that are typically associated with age-related memory decreases. In addition, COX inhibitor administration also prevented the age-related increases in the proinflammatory cytokine, interleukin 1-beta (IL-1-beta) in the hippocampus, supporting the inflammation hypothesis of aging and suggesting therapeutic value of NSAID administration in aged populations.

Increased levels of IL-1-beta are implicated in impaired cognitive performance and in the decline of synaptic plasticity in the hippocampus. However, IL-1-beta is an inactive precursor that is cleaved into its active and mature form by caspase-1. Thus, one way to target this system might be to interfere with the production of the active form of IL-1-beta. Gemma and colleagues [92] used a selective caspase-1 inhibitor to reduce levels of IL-1-beta for one month. Aged control rats had impaired memory for the training context compared to younger animals, but chronic inhibition of caspase-1 activity attenuated this age-related memory impairment. When examined, hippocampal levels of IL-1-beta in aged animals approached levels of younger control subjects.

C. Classical Conditioning

The effects of age on conditioned responses using an eyeblink conditioning paradigm have not been examined in great depth. Weiss and Thompson [93] reported that middle-aged and older rats (18 and 30 months old) were significantly impaired in the ability to form conditioned responses when compared to younger rats (3 and 12 months of age). The lack of deficits in evoking a blink response supported the notion of a deficit in associative conditioning. Subsequent work explored strain differences in aged rat performance, building upon the observation that while aged Fischer-344 rats demonstrate significant impairment in forming conditioned responses, even younger Fischer-344 animals perform submaximally. Examination of the F1 generation of a hybrid cross (Fischer-344 × Brown Norway) revealed that hybrid rats aged 9 to 24 months learned conditioned responses quickly. Aged (36-month-old) F1 hybrid subjects were significantly impaired across all training days, but performed at a significantly greater level than aged Fischer-344 rats [94]. These data suggest that strain differences can be significant, and that the relatively poor performance of younger Fischer rats may be indicative of neurobiological deficits that impair ability in conditioned eyeblink paradigms. Vogel and colleagues [95] examined the development of age-related cognitive impairments in C57BL/6 mice. Measures with a more cerebellar component (e.g., eyeblink-conditioning, rotorod) were shown to be sensitive to age-related changes earlier than other tasks. Specifically, animals 9 to 18 months old demonstrated deficits in conditioned responses compared to younger 4-month-old animals. In a similar fashion, 4-month-old animals performed significantly better than 12- to 18-month-old animals in the latency to fall during the rotorod procedure. In contrast, aged mice were not impaired by the hippocampally dependent Morris water maze task when compared to younger animals.

D. Attention and Executive Function

The effects of aging on performance in attention-related tasks have been somewhat limited by the number of rodent models that assess frontal cognition. Muir et al. [96] demonstrated age-related changes in attentional functioning in 7- vs. 13- to 14-month-old rats in the 5-choice serial reaction time task by manipulating the attentional loading of the task. Subsequently, as animals aged, the difference between younger (10 to 11 months old) and aged (23 to 24 months old) performance became greater, such that significant differences in performance could be observed in baseline measures without any manipulations of the attentional load of the task. This was similar to results reported by Grottick and Higgins [97], who found that aged (24 months old) rats were impaired in 5-CSRTT performance compared to younger (12 months old) subjects. Increasing the difficulty of the task impaired the performance of younger rats, producing comparable performance to older rats. Likewise, decreasing the task difficulty for older subjects produced performance comparable to younger animals.

There have been a few recent studies of executive function in aged rodents. Barense and colleagues [9] examined cognitive decline in aged Long-Evans rats in an attentional set-shifting task. Older rats (27 to 28 months old) were significantly impaired in performance compared to younger (4 months old) subjects across all tasks measured, which included reversal learning and attentional shifts. However, significant impairment was only observed in extradimensional shift (EDS) learning, which required rats to change the dimension of the compound stimulus they were using to solve the discrimination — for example, rats using odor to solve the discriminations had to start using digging medium instead. In addition, impaired performance on EDS was uncorrelated with performance in the Morris water maze, suggesting that age-related declines in frontal- and hippocampal-mediated functions are dissociable. More recently, similar age-related impairments in frontal function have been found in Sprague-Dawley rats. Rodefer and Nguyen [98] demonstrated that older rats demonstrated consistent impairment in discrimination learning but, in a fashion similar to Barense and colleagues, only found significant impairment in EDS learning. Impaired reversal learning in aged rats has also been reported in an automated olfactory discrimination paradigm [99]; perhaps the increased difficulty of discrimination learning in this setting reveals impairments that are not reliable when reversal learning is tested in the set-shifting task.

IV. SUMMARY

Impairments in multiple behavioral domains are observed in aged rodents and a wide variety of neurobiological parameters have been investigated in conjunction with these impairments. These paradigms also provide a setting in which to test possible pharmacological and environmental manipulations that may be able to ameliorate age-related cognitive decline. Careful behavioral design and the use of multiple measures of performance [100] will enhance the ability of experiments in aged rodents to tell us about the biological substrates of cognitive impairment in human brain aging, and will increase the applicability of these models for preclinical development and testing of agents that may be effective cognitive enhancers.

ACKNOWLEDGMENTS

Preparation of this chapter was supported in part by the Wellcome Trust (MGB).

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