The delayed response task has been used extensively to investigate the cellular bases of working memory processes (see Goldman-Rakic 1987, 1990, 1995 for reviews). In the classic delayed response task, monkeys observed an experimenter bait one of two covered food wells. An opaque screen was then lowered to block the monkey’s view of the covered food wells. After a delay, the screen was raised and the monkey must choose the previously baited well to obtain the reward. More recently, an oculomotor delayed response task has been used to assess working memory. In this task,
a monkey is placed in front of a video screen and must initially fixate on a center dot of light. During the cue phase, a light is flashed in one of 8 spatial locations on the screen that are equidistant from the center fixation light. The fixation and cue light are then extinguished for a few seconds in the
delay period. During the response phase which follows the delay, the
monkey is required to perform a saccade to the spatial location on the screen where the light was flashed. Since the cue light was extinguished, the saccade must be directed based on mnemonic information. In rats, a similar task has been used (Orlov et al., 1988; Bateuv et al., 1990), but a light was flashed above a food well to the right or left of the rat. After a delay of 5sec, the rat was allowed to visit the previously lighted food well. Approximately 54% of PFC neurons responded preferentially during the delay while the firing of 85% was correlated with the response (Orlov et al., 1988; Bateuv et al., 1990). These processes have been studied much more extensively in the primate dorsolateral PFC. Neurons in the primate PFC increase in activity during the cue, delay, and response phases of the original (Kubota and Niki, 1971; Fuster and Alexander, 1971; Fuster, 1973) and the oculomotor delayed response tasks (Funahashi et al., 1989). Most attention has been paid to the delay-active neurons in the PFC as the activity of these neurons may underlie the ability to retain information transiently (Goldman-Rakic, 1990, 1995). There are a number of findings that suggest that the activity of these neurons represents an active neural trace of previously encountered external stimuli.
First, delay-period activity is not observed on ‘mock’ trials, when the monkey does not observe a food well being baited (Fuster 1984, 1991). Second, delay-active neurons have ‘memory fields’ in that individual neurons fire during the delay period of the task, only if a cue was presented previously in a specific spatial location (Funahashi et al., 1989; Goldman- Rakic, 1990). Third, if the activity of these neurons decreases throughout the delay, the animal is highly likely to make an error (Niki and Watanabe, 1979; Funahashi and Kubota, 1994; Funahashi et al., 1989). Fourth, these neurons show sustained firing during the delay even if the animal is required to make a response in the opposite location from the initial cue, indicating that the activity is related to the memory of the previously presented stimuli and not the mechanics of the response itself (Funahashi et al., 1993). Finally, activity during the delay increases or decreases uniformly as the delay interval increases or decreases (Kojima and Goldman, 1982). These finding suggest that indeed neurons in the dorsolateral PFC seem to transiently and actively encode information about previously presented stimuli. While having this type of activity is a requirement for a working memory system, it does not imply that the short-term retention of information is the primary
function of the PFC. Rather, information must be held transiently if it is to be manipulated and used to guide action.
The PFC is not unique in its ability to exhibit delay period activity. Delay- active neurons are also found in other areas of the brain such as the parietal and inferotemporal cortex and hippocampus (Watanabe and Niki, 1985; Koch and Fuster, 1989; Fuster, 1990), suggesting that copies of recently presented task-relevant stimuli are distributed. This may explain why PFC lesions alone do not impair short-term memory. However these brain areas interact during the performance of delayed tasks since PFC cooling disrupts delay-period activity in the inferotemporal cortex (Fuster et al., 1985), while cooling of the parietal cortex or inferotemporal cortex disrupt task related activity in PFC neurons (Fuster et al., 1985; Quintana et al., 1989; Chafee and Goldman-Rakic, 1998, 2000). Miller and Desimone (1994) and Miller et al. (1996) have pointed out key differences between activity in PFC and inferotemporal or parietal neurons. The activity of PFC neurons is less stimulus dependent but exhibits greater ‘match-non-match’ effects on delayed matching and nonmatching to sample tasks, again suggesting that PFC neurons are more involved in the manipulation of information in memory. In addition, PFC neurons exhibit progressive increases in activity during the delay period. The progressive increase in activity of PFC neurons during the delay has been termed “climbing activity” and is related to the probability of making a correct forthcoming response (Quintana and Fuster, 1992). The climbing activity in the PFC may be related to the prospective memory of the upcoming response. Response-correlated activity in PFC neurons is also observed on simple non-delayed tasks without a memory component, such as Go/No Go tasks (Watanabe, 1986a,b). Furthermore, on more complex conditional tasks, the activity of motor-set units can precede that of delay-active neurons in well trained animals. In such tasks, the color of a cue light instructs experienced monkeys where to direct their response following a delay. The activity of motor set neurons often begins to increase as soon as the light cue is presented, presumably because information about the direction of a forthcoming response is given completely by the color of the cue light (Fuster, 1991). Thus, on both working memory tasks and conditional memory tasks, the discharge of the motor-set units in the PFC may predict the direction of the impending motor response. Thus, there is a subclass of PFC neurons that encode impending actions based on memory.
If a response is guided by information that pertains to future actions not yet completed (i.e. to remember what needs to be done), it is said to be coded prospectively; if it is based on a comparison to stimuli/actions that have already been encountered (i.e. to remember what has already been done), then it is coded retrospectively (Cook et al., 1985). Clearly, motor set units are coding the prospective response, but many of the delay activity
neurons encode memory prospectively as well. Rainer et al. (1999) used a type of conditional task that assessed prospective coding, the delayed paired associate task, and compared it to a simple delayed match to sample task. In the delayed paired associate task, three sets of sample and test stimuli were paired. Two sample stimuli and two test stimuli were similar in appearance. One sample was presented, and following a delay, a test stimulus was presented that may or may not have been previously paired with the sample stimulus. If the previously paired test stimulus appeared after a delay, the animal had to release a level to obtain reward. Reaction times were similar whether the test and sample stimuli were the same (delayed match to sample task) or for test stimuli predicted by a previously paired sample stimulus (delayed paired associate task). Moreover, errors occurred more frequently for similar looking test stimuli as opposed to similar looking sample stimuli. This suggested that the performance of the animals was dependent upon the anticipation of the forthcoming stimulus based on the memory of previous sample-test stimuli pairings, and is therefore indicative of a prospective code. Likewise, a number of neurons exhibited increased firing throughout the delay for a given test stimulus regardless of which sample stimuli preceded it. This increased activity for the forthcoming target occurred prior to the presentation of the test stimulus and was selective for certain forthcoming test stimuli, indicating that the neurons were encoding the anticipated test stimulus. These data provide evidence that neurons in the PFC are capable of encoding the prospective memory of a forthcoming stimulus.
There is also evidence for distinctly retrospective coding by delay active neurons in the PFC (e.g. Rainer et al., 1999; Fuster, 2000; Constantinidis et al., 2001). Yet as noted above, this activity is not unique to the PFC, and the integrity of the PFC is not necessary for short-term memory. Rather, this retrospective coding may only be necessary to hold information long enough so that it can be used to guide responding. Or as Fuster (1990, 1991, 1995) has proposed, mnemonic information encoded by delay-active cells may be communicated to response-active PFC neurons to ensure that a forthcoming response is directed to the correct location. In this way, the retrospective coding by PFC neurons may simply be required to maintain information in memory long enough to manipulate it and use it to guide the appropriate action.
If the delay period is very brief, the online maintenance and manipulation of information occur simultaneously and therefore cannot easily be dissociated. Yet even at short delays, Rainer et al. (1999) showed that activity of PFC neurons shifted from encoding the sample stimulus to anticipation of the test stimulus. If PFC neurons were primarily encoding the manipulation of information in memory, one would predict that at very
delays, too long to maintain information actively, “delay-period” activity should begin to occur near the time of the response because it is at this point where information is manipulated and used to guide action. As a test of this hypothesis in rats, transient inactivation of the rat PFC by lidocaine impaired response phase performance on a delayed working memory radial arm maze task, only if given prior to the response phase and not prior to the sample phase or during the delay (Seamans et al. 1995). However, given the differences in the activity in rat and primate PFC neurons during working memory tasks (see Pratt and Mizumori, 2001), similar experiments with longer delays are required in experiments using primates.
The idea that the role of the PFC is in the manipulation of information in memory rather than its simple storage, removes a temporal component to working memory. Accordingly, dorsolateral PFC lesions do not produce delay-dependent deficits on working memory tasks (Petrides, 2000b). Yet some definitions of working memory emphasize the temporal nature of working memory. Working memory has been defined as memory for trial unique information, while reference memory was related to the memory of trial invariant stimuli (Olton et al., 1979). However, most tasks involving working memory and the prefrontal cortex require the implementation of trial invariant information such as the implementation of learned rules required to solve the task. While this type of information may be viewed as reference memory, it is related more to the abstract procedural rules rather than specific information such as the invariant location of food. A variety of lesion studies highlight the important role of the PFC in the application and use of abstract rules and the firing of delay-active neurons varies when different task rules are implemented (Milner, 1963; Passingham, 1993; Verin et al., 1993; Seamans et al., 1995; Wise et al., 1996; White and Wise, 1999; Wallis et al., 2001).
Collectively, it seems that the PFC provides much more than a short-term memory store. It maintains, monitors, and compares items in memory based on context dependent, abstract rules. In this way, the function of the PFC may be best described not as working memory but rather as “working with memory”.