Researchers trained monkeys to perform two tasks: an object-matching task and a location task.

Accepted taxonomies of memory typically distinguish among different kinds of remembering depending upon the information that must be remembered. A basic dichotomy distinguishes between the retention of factual or experiential information on the one hand, and the retention of habits and motor skills on the other. Factual memory can be further differentiated into working and reference memory. As first described by Werner Honig’s group [1], working memory is required when “different stimuli govern the criterion response on different trials, so that the cue that the animal must remember varies from trial to trial.” Thus, working memory is required for remembering information that varies unpredictably in time and/or in content: it is this type of memory that is decimated in Alzheimer’s disease and other dementias [2]. In contrast, reference memory is used to retain information that remains constant over time (e.g., removing the cup from a baited well provides access to food). The study of working memory processes is generally accomplished using delayed response (DR) tasks and, within the confines of even relatively short test sessions, one can readily assess processes associated with short-term memory using these procedures. In such tasks, one presents a bit of information (a sample) to a subject, withdraws that information, waits for a period of time (recall delay), then presents that same bit of information along with a comparison bit and asks the subject to identify (choose) which bit of information was presented previously. This process is then repeated across a number of trials.

DR tasks using nonhuman primates as surrogates are used primarily to determine the biological underpinnings of human learning and memory processes and their associated mechanisms. The complex brain functions associated with the performance of these tasks can be assessed using a variety of approaches, and the careful monitoring of behavioral outputs provides important experimental advantages. Many of the different types of assessments of memory processes have evolved from studies ranging from those employing neuroanatomical lesions to electrophysiological recordings and, more recently, neuroimaging techniques. Goldman-Rakic et al. have shown the importance of the prefrontal cortex in the performance of DR tasks in nonhuman primates by employing lesions and electrophysiological and neuroimaging techniques [3–6]. Brain lesion experiments in monkeys have also demonstrated the importance of the hippocampus and its relevance to performance in DR tasks [7]. Through the use of lesions, Zola et al. (2000) and Squire (2004) have also demonstrated the importance of the medial temporal lobe in performance of these types of tasks in monkeys [8,9]. Taken together these and other studies have elucidated the importance of the prefrontal cortex in visual-spatial functions, inhibition of behavior (temporal mechanisms), decision making, working memory, problem solving, planning, and organizing. Likewise, the findings that the hippocampal formation (medial temporal lobe) is important in memory consolidation, associative memory formation, declarative memory, and recognition memory stem from these and similar studies. The prefrontal cortex and the hippocampal formation are two brain areas intricately involved in the performance of DR tasks. The understanding of short-term memory and, more specifically, working memory has benefited greatly from this work.

Animal models are essential components of basic science and preclinical research, and their use in behavioral experiments is often more practical than is the use of human subjects. While the most commonly used research animals are rodents, non-human primates are phylogenetically the most similar to humans. Goldman-Rakic et al. have observed that “the organization of the cortical dopamine system is essentially the same in macaque monkey and human and that the nonhuman primate is a suitable animal model for analysis of dopamine function in prefrontal cortex.” [10] Nonhuman primates are excellent models for studying behavior during different periods of development and for use in pharmacological and toxicological studies, and the ethics of using these animals in research has been eloquently addressed [11].

Since DR tasks often use food reinforcement, food restriction is commonly used as a means of increasing motivation and positive behavioral output [12,13]. Caloric intake is usually reduced by about 15%–20% from that of free-feeding animals and can result in many positive effects such as enhanced quality and length of life [14–17]. Studies performed in nonhuman primates are easily relatable to studies conducted in lower species, such as rodents, and in humans [18].

Most of the early DR tasks were conducted using the Wisconsin General Test Apparatus or WGTA (Figure 12.1). In this apparatus a monkey sits in a cage or a restraint chair in front of a tray that contains recessed food wells. The experimenter baits a well with food, covers it, and then lowers a screen to block the experimental tray from the monkey’s view. Subjects can retrieve the food reinforcer after the screen is removed at some later time. This approach, while very productive, is labor intensive and prone to the vagaries of experimenter–subject interactions. More recently, however, automated behavioral systems have become increasing popular. In a typical primate behavioral test system, the subject is either placed in a behavior chamber in which it interacts with a response panel, or a test panel is positioned so that the animal can interact with it; for example, a panel can be temporarily affixed to its home cage during test sessions. The response panels can be outfitted with a variety of manipulanda such as response levers or bars or press-plates on which visual stimuli can be presented. In these configurations, there is generally a food cup or trough into which food reinforcers are delivered when correct responses are made. An example of the behavioral panel used in one such system, in this case the National Center for Toxicological Research (NCTR) Operant Test Battery or OTB [19], is shown in Figure 12.2.

Recently, a touch-screen-based system, the CANTAB (Cambridge Neuropsychological Test Automated Battery) system was developed for the assessment of cognitive deficits in humans with neurodegenerative diseases or brain damage. It is now being used by some laboratories to test nonhuman primates [20,21]. The battery consists of computerized tests of memory, attention, and executive function, one of which is a delayed matching-to-sample (DMTS) task for the assessment of working memory. The CANTAB apparatus, like all of the other systems discussed here, is nonverbal in nature, making it language independent and largely culture-free. CANTAB performance has been standardized in an elderly human population and validated in neurosurgical patients and in patients with basal ganglia disorders, Alzheimer’s disease, depression, and schizophrenia.

As mentioned earlier, DR tasks have historically been performed using the WGTA. Initially, in full view of the subject, the experimenter baits one of two or three reinforcer wells with food, covers all food wells with identical items (e.g., cardboard plaques), then lowers an opaque screen to block the experimental tray from the monkey’s view. After a delay period the screen is lifted, allowing the monkey to recall from memory and choose the baited food well. This DR task measures mnemonic processes associated with working memory [22,23]. Reinforcers are randomly distributed between the food wells over a number of trials (e.g., 30) that make up a daily test session. During the initial training phase, delays are held constant at short values and are gradually increased according to a stepwise procedure as animals demonstrate mastery of the task [24]. DR task performance has been used to examine the involvement of specific neurotransmitters with aspects of working memory. For example, it has been shown that guanfacine, a norepinephrine agonist, improves performance in young adult rhesus monkeys [25], suggesting that the norepinephrine system is important in the modulation of working memory.

There are several variations of delayed alternation tasks, for example, delayed spatial alternation and delayed object alternation (nonspatial). For both of these tasks, the trials are temporally related to one another: a correct response is dependent upon the previous response. The delayed spatial alternation task is a two-choice task in which the monkey has to alternately displace a left or right plaque to retrieve a reward, i.e., if the right food well was baited on one trial, then the left food well will be baited on the next trial. This task is typically used with a delay or recall duration of at least 5 sec. The delayed object alternation task is also a two-choice task in which the monkey needs to correctly select an object that alternates between trials. Levy et al. [26] have reported that delayed spatial alternation tasks increase neural metabolic activity, as measured by local cerebral glucose utilization, in the head of the caudate nucleus where efferents from the dorsolateral prefrontal cortex project most densely. Performance of a delayed object alternation task increase neural metabolic activity in the body of the caudate nucleus, which is innervated by the temporal cortex. These findings show that spatial and nonspatial cognitive operations are subserved by distinct cortico-striatal circuits.

For DMTS tasks, as with other DR tasks, each trial begins with the presentation of a sample stimulus. As used in the NCTR OTB, this involves illumination of the center one of three horizontally aligned press-plate manipulanda (Figure 12.2) with one of seven white-on-black geometric shapes. Subjects make an observing response to the initial shape (sample stimulus) by pushing the illuminated plate, after which it is immediately extinguished. Following an interval (recall delay) that varies randomly (from 2 to 32 sec, for example), all three press-plates are illuminated, each with a different stimulus shape, but one of which matches the sample stimulus. A choice response to the plate matching the sample stimulus results in food reinforcer delivery. Incorrect choices are followed by a 10-sec timeout, then initiation of a new trial. As indicated by lesion studies [27], this task [28] and other DMTS procedures are thought to depend upon the prefrontal and inferior temporal cortices. Damage to the higher visual area inferior temporal cortex interferes with the performance of the task for visual stimuli [27], while lesions of the prefrontal cortex still allow successful completion of the task but only for short recall delay periods [29].

The use of distractors in DMTS tasks has been employed to increase task difficulty (for review, see [30]). Distractors are thought to inhibit the subject’s ability to sustain attention and serve to impair working memory. Distractors are usually either auditory or visual stimuli presented during the delay or recall interval to distract the monkey from relevant test stimuli. It is believed that the presentation of distractors during the delay or recall interval, a time during which selective attention and rehearsing are thought to be important, disrupts the cognitive processes subserving working memory.

These procedures are conceptually similar to DMTS paradigms, however, in delayed non-matching-to-sample (DNMTS) tasks, the subject is required to choose the stimulus that does not match the test (sample) stimulus that was presented before the recall delay. This task has been used extensively in monkeys to identify the brain regions involved in recognizing previously presented stimuli [8,31]. In a typical DNMTS task, the subject is presented with a trial-unique (unfamiliar) sample stimulus followed by a recall delay during which the sample is removed from sight, and then presentation of the sample and a novel stimulus item. Choosing the novel stimulus is reinforced as the correct response. It is thought that monkeys learn to perform DNMTS tasks much more rapidly than they learn to perform DMTS tasks because of their natural tendency to preferentially attend to novel stimuli, in this case, the non-matching stimulus. Lesion studies in monkeys have revealed a number of interconnected areas involved in the encoding, retention, and retrieval of stimulus representations within DNMTS trials. This memory circuit consists principally of the ventromedial and ventrolateral prefrontal cortices, rhinal (entorhinal and perirhinal) cortex, thalamus, and the inferotemporal cortex [31–34]. The hippocampus, located in the medial temporal cortex, might also be a component of this circuit, but its precise role is currently the subject of debate [8,31]. Recent findings have suggested that an intact hippocampal formation is critical for acquisition of DNMTS task performance, and specifically for the delay component [35].

Trial-unique stimuli are stimuli that do not appear in more than one trial during a test session or during many test sessions (i.e., they are unfamiliar). Repetitive stimuli, on the other hand, may repeat in multiple trials during a given test session. Tasks that employ trial-unique stimuli activate the medial temporal lobe more than tasks that employ repetitive stimuli [36]. This suggests a stronger role for the medial temporal lobe in working memory for complex, novel, trial-unique stimuli, relative to working memory for familiar stimuli. However, repetitive stimuli tasks activate the prefrontal and parietal cortices more than tasks that employ trial-unique stimuli [36]. This suggests that the prefrontal and parietal cortices play a stronger role in working memory for familiar stimuli. These differences are thought to reflect the engagement of medial temporal lobe regions in tasks that require the formation and maintenance of new short-term representations; whereas the prefrontal cortex is preferentially engaged when prior representations already exist in the brain but must be selectively updated and monitored to avoid interference effects [36].

The analyses of data obtained using the working memory tasks described here sometimes vary between laboratories, but, generally, common endpoints are used. Idealized data for typical DR tasks are shown in Figure 12.3, where response accuracy is plotted on the ordinate, and length of recall delay is plotted on the abscissa. Typical data from normal subjects might be represented by line A, where it can be seen that at zero—or very short—delays recall accuracies are very high. The point where these data intercept the y axis is thought to be related to the ability of subjects to attend to the task, discriminate the stimuli, and encode the information relevant to problem solution. Thus, if aspects of attention, discriminability, or encoding are degraded, accuracy at zero or very short delays will decrease. The slope of this line indicates the normal rate of short-term/working memory decay. Line B represents data showing a decrease in initial attention and/or encoding, with a normal rate of forgetting; similar observations have been noted after the administration of the hallucinogen lysergic acid diethylamide (LSD) (see also Figure 12.7) [37]. The data in line C represent a circumstance under which the initial level of attention and/or encoding is no different from that of the normal condition (line A), but under which the rate of forgetting has been increased (slope is steeper). This kind of effect can be seen after surgical ablations of the hippocampus and amygdala (Figure 12.4) [8], after treatment with certain drugs, such as tetrahydrocannabinol (THC) [38], and when distractors are used [39]. Line D represents data showing a decrease in both initial attention and/or encoding and an increase in the rate of forgetting. These data examples are relevant to DR tasks whether or not they have time limitations (predetermined session lengths), and whether or not they include the measurement of response speed (latencies). By setting maximum session lengths and measuring response speed, however, several additional important metrics of task performance can be had.

The typical measure used by our lab for DNMTS and DMTS tasks is the percent task completed (PTC) measure. This measure is a function of both response accuracy and speed, so changes in either of those measures can affect the PTC. Conceivably, an experimental treatment (drug or toxicant exposure, brain lesion, other stressor, etc.) could increase response rate while decreasing accuracy and, thus, have no effect on PTC. Conversely, response rate could be decreased and accuracy increased, again resulting in no effect on PTC. Practically speaking, these effect combinations have not been seen in our lab. Typically, if a treatment has an effect, it will manifest in the PTC metric, alerting one to look further for more information as to the specific nature of the effect. Thus, overall accuracy (collapsed across all recall delays) and overall response latencies (both observing and choice) are examined next. Since latencies are inverses of response rates, they provide metrics of speed of responding. Observing response latency is defined as the time elapsed before the subject initiates a trial by responding to or “observing” the initial sample stimulus. Choice response latency is defined as the time to respond to a choice stimulus following the presentation of choices. Choice response latency can be determined for each recall delay, whereas observing response latency is generally independent of recall delay.

An increase or decrease in overall accuracy is indicative of short-term or working memory effects, particularly if this effect is seen in the absence of any effect on response latencies. This effect can manifest during a particular delay interval and may or may not be delay dependent. Delay-dependent effects would be those that change as a function of recall delay. For example, a treatment may have no effect on response accuracy at short delays (no or little effect on attention and/or encoding), but have significant effects on accuracy at the longer delays (increased rate of forgetting or distractibility; see also hypothetical line C in Figure 12.3).

An increase or decrease in observing response latency following a pharmacological challenge or other experimental manipulation can be indicative of effects on reaction time (psychomotor speed), motivation, and/or motoric capabilities. An increase or decrease in overall choice response latency can be indicative of an effect on attention, reaction time, motivation, or motoric capabilities. If a treatment effect on choice response latency increases with increasing length of recall delay, then that effect is likely related to attentional processes/distractibility. This stems from the fact that there is increasing opportunity for distraction with increasing recall delay.

There is a wide range of applications for which DR tasks are useful. Many studies have investigated the effects of pharmacological challenges on DR tasks in the developing monkey (for review, see [40]). Other studies have observed the effects of brain lesions [41], environmental factors [42,43], and human diseases such as Alzheimer’s disease and attention deficit hyperactivity disorder (ADHD) [44–46].

Old monkeys can sometimes serve as good models for age-related cognitive decline and Alzheimer’s disease because they show impaired performance in the DMTS task as compared with younger monkeys [47]. Some of the earliest findings of drug effects on DMTS task performance demonstrated the importance of the nor-epinephrine system in performance of DR tasks. Jackson and Buccafusco [48] showed that the norepinephrine agonist, clonidine, when administered to either young or aged monkeys, resulted in a significant improvement across all trials in DMTS task performance. Similarly, Franowicz and Arnsten [25] reported that guanfacine, another norepinephrine agonist, improved DR task performance in young adult rhesus monkeys.

The function of the acetylcholine system has, however, remained the focus of memory and Alzheimer’s disease research because of its suspected role in learning and memory processes and in the etiology of Alzheimer’s disease. Applicably, a study by Decker et al. [49] showed that administration of ABT-089 (a nicotinic acetylcholine receptor agonist) to aged monkeys produced a robust improvement in DMTS accuracy at all delay intervals. This effect was not age-specific because task improvement was also seen in younger adult monkeys. Similarly, Prendergast et al. [50] reported improvement in accuracy in a delayed recall task in both aged and younger adult monkeys after administration of the nicotinic receptor agonist, ABT-418. Additionally, Jackson et al. [51] found that the acetylcholinesterase inhibitor, velnacrine, improved DMTS performance in aged monkeys. These findings, relevant to the study and treatment of Alzheimer’s disease, clearly demonstrate the importance of the acetylcholine system in working memory processes and age-associated memory decline.

Monkey subjects have also been used to evaluate aspects of attention and focus using DR tasks. ADHD patients exhibit difficulties in sustaining focus/attention. Therefore, the DMTS task has been modified to include a component in which distractors (flashing sample and choice stimuli) are presented during the recall delay intervals. Distractors inhibit the subject’s ability to sustain attention and impair working memory during DR tasks. Prendergast et al. [52] found that nicotine, ABT-089, and ABT-418 (all acetylcholine agonists) attenuated the effects of distractors in the DMTS task by preventing distractor-induced declines in recall accuracy in adult monkeys. Other potentially beneficial drugs derive from a class of serotonin (5-HT) receptor antagonists. Terry et al. [53] reported that the 5-HT3 receptor antagonist RS56812 enhances DMTS accuracy in monkeys at long recall delays. This compound presumably acts through 5-HT3 receptors on acetylcholine axon terminals where 5-HT receptor inactivation is thought to lead to increases in acetylcholine release. Additionally, Terry et al. [54] found that the 5-HT4 receptor antagonist RS17017 enhances DMTS accuracy in both young and old macaque monkeys. These findings suggest the potential development of new treatments for ADHD and other memory disorders that would be alternatives to the psychostimulant medications currently in common use.

In addition to the cholinergic agonists and serotonin antagonists that enhance performance on DR tasks, there are, not unexpectedly, also a host of drugs that degrade such behavior in nonhuman primates. Schulze et al. [55,56] investigated the acute affects of delta-9-THC (the active ingredient in marijuana smoke) and marijuana smoke itself in rhesus monkeys as measured by performance in the NCTR OTB. The results for the DMTS task showed that THC decreased both the number of reinforcers earned and the percent task completed, primarily by increasing the time it took subjects to begin each trial (increased mean observing response latencies). Marijuana smoke administration, at exposure levels that produced plasma THC levels similar to those seen in humans after marijuana smoke exposure, also significantly increased response latencies (increased time to initiate trials and to make recall choices). Similarly, this lab reported that diazepam, a gamma-amino butyric acid (GABA) agonist, significantly decreased DMTS task accuracy in rhesus monkeys across several different time delays [56]. Additionally, the μ opiate receptor agonist, morphine, significantly decreased the number of reinforcers earned and percent task completed and increased response latencies, while having little effect on recall accuracy [57]. Finally, the psychostimulant amphetamine, while having no effects on DMTS task performance at low doses, significantly decreased percent task completed, increased observing response latencies, and decreased accuracy at the longer recall delays [58].

In this section representative nonhuman primate data for all of the tasks described in this chapter are briefly discussed. Figure 12.5A and B show data for a DR task in which performance has been enhanced: overall accuracy (Figure 12.5A) was increased and rate of forgetting (Figure 12.5B) was decreased following pretreatment with bextaxol, a β-1 adrenergic receptor antagonist [59]. These data reveal a role of the adrenergic system in DR performance. Figure 12.6 shows representative data for monkey performance in a delayed alternation task [60], showing an impairment in recall accuracy after the administration of the anxiogenic drug FG 7142 (a β-carboline, GABAA receptor partial inverse agonist), and the amelioration of that effect by pretreatment with three different dopamine receptor antagonists (haloperidol, SCH23390, and clozapine). Additionally, a benzodiazepine receptor antagonist was administered along with FG 7142 to illustrate the GABA agonist’s receptor specificity. These data demonstrate the involvement of the GABA and dopamine systems in the performance of delayed alternation tasks.

Figure 12.7 shows a decrease in delayed matching-to-sample task accuracy following treatment with LSD, a serotonin receptor partial agonist [37]. These data illustrate how this compound preferentially affects discriminability, encoding, or attention, while not affecting rate of memory decay. Additionally, a recent report has demonstrated an enhanced performance accuracy in the DMTS task following treatment with a serotonin receptor antagonist [61]. In that report, the length of recall delays were adjusted subject to attain similar levels of performance accuracy for all subjects: (1) a least difficult zero delay (85%–100% accuracy), (2) a short delay (75%–84% accuracy), (3) a medium delay (65%–74% accuracy), and (4) a long delay representing chance performance (55%–64% accuracy). Figure 12.8A shows representative data of drug-enhanced DMTS task accuracy in young monkeys at a medium-difficulty recall delay. This increase in accuracy resulted from treatment with EMD 281014, a serotonin 2A receptor antagonist [61]. Figure 12.8B shows data for this same compound where it is shown to improve delayed matching performance in aged rhesus monkeys at both medium- and long-recall delays [61]. Figure 12.9 shows data from animals performing a DNMTS task using the CANTAB system. Here a decrease in accuracy of task performance was clear following treatment with the muscarinic cholinergic receptor antagonist scopolamine [62]. Figure 12.10, on the other hand, demonstrates that the cholinesterase inhibitor physostigmine can enhance accuracy of DNMTS task performance [63]. These examples of representative data serve to show how different drugs from a variety of pharmacological classes can either degrade or enhance performance in different DR tasks. These data also suggest that numerous neurotransmitter systems are involved in performance of DR tasks.

DR tasks fulfill many of the criteria needed to measure short-term or working memory. There are, however, some aspects of these paradigms that pose problems if not considered. First, in tasks employing few response locations, subjects frequently develop a position bias, which is evidenced by a majority of their choice responses being restricted to one of the locations, for example, to either the right or left response position in a two-choice paradigm. As a result, on approximately 50% of all trials the subject’s response to the right-hand location can result in a correct response and reinforcement [64]. In addition, even when such biases are not observed under control conditions, they can be seen following drug administration, making interpretation of dose-response curves and drug effects difficult [65]. DR tasks can also suffer from the occurrence of prominent ceiling and/or floor effects. If the task is not challenging enough, response accuracies even at long delays can be very high, making detection of treatment-induced increases in memory impossible. This problem can usually be overcome by lengthening the delays and/or increasing the complexity of the stimuli so that discrimination between sample and choice stimuli becomes more difficult. Conversely, if the task is too difficult, a floor effect can be apparent, in which case delays can be shortened or the difficulty of the discrimination can be made less demanding.

In summary, DR tasks in nonhuman primates are very useful for assessing and elucidating the biological underpinnings of working memory that are relevant to humans. The clinical relevance of these types of tasks is further supported by the observation that DMTS performance in humans correlates significantly with IQ [66]. By inference, then, use of these tasks in animals would seem to provide direct access to important aspects of animal intelligence.

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