Persistent activity in the prefrontal cortex during working memory

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in working memory. Notably, persistent activity in the DLPFC is often observed during the retention interval of delayed response tasks. The code carried by the persistent activity remains unclear, however. We critically evaluate how well recent findings from functional magnetic resonance imaging studies are compatible with current models of the role of the DLFPC in working memory. These new findings suggest that the DLPFC aids in the maintenance of information by directing attention to internal representations of sensory stimuli and motor plans that are stored in more posterior regions.     

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.     

Damage to the retrosplenial cortex produces specific impairments in spatial working memory

Mounting evidence indicates that the retrosplenial cortex (RSP) has a critical role in spatial navigation. The goal of the present study was to characterize the specific nature of spatial memory deficits that are observed following damage to RSP. Rats with RSP lesions or sham lesions were first trained in a working memory task using an 8-arm radial arm maze. Rats were allowed 5 min to visit each arm and retrieve food pellets and a 5-s delay was imposed between arm choices. Consistent with previous research, rats with RSP damage committed more errors than controls. In particular, RSP-lesioned rats committed more errors of omission (failing to visit an arm of the maze), but there were no lesion effects on errors of commission (revisiting an arm). Neither group of rats exhibited a turn bias (i.e., always turning a certain direction when choosing an arm). At the end of the training phase of the experiment, both groups had reached asymptote and committed very few errors. In the subsequent test phase, a longer delay (30-s) was imposed during some sessions. Both control and RSP-lesioned rats continued to make few errors during sessions with the standard 5-s delay, but RSP-lesioned rats were impaired at the 30-s delay and committed more errors of commission, consistent with an increase in taxing spatial working memory.     

Intraseptal administration of bicuculline produces working memory impairments in the rat.

Male Sprague-Dawley rats, trained to perform a delayed-non-match-to-sample eight-arm radial maze task, were implanted with a single cannula aimed at the medial septal nucleus. A within-subjects design was utilized to examine the effects of intraseptal administration of bicuculline (0.5 micrograms) on performance of this task with 1- and 4-h delay intervals imposed between choices four and five. Administration of bicuculline immediately following the first four choices produced an impairment in maze performance at both a 1- and a 4-h delay interval. This treatment also produced an increase in latency per choice. Bicuculline-induced impairments were not observed when administered 2 h following the predelay session (2 h prior to testing). These data support previous observations that pharmacological manipulation of GABAergic activity within the septum modifies working memory processes.     

Repeated checking causes distrust in memory but not in attention and perception

Repeated checking to reduce memory distrust seems to be counterproductive: it increases memory distrust. Obsessive-compulsive (OC) patients tend to be uncertain about other cognitive domains as well, like attention and perception. In an experiment with 70 healthy participants, we tested whether perseverative checking induces distrust not only in memory, but also in attention and perception. Participants were administered a computer task in which they had to activate, deactivate, and check threat-irrelevant stimuli, and rate their confidence in memory, attention, and perception in a pre-test and post-test. In between these tests, the relevant checking group performed 20 checks of the same stimuli used in the pre- and post-test. The irrelevant checking group performed 20 checks of different stimuli. Although memory accuracy improved in both groups, repeated checking reduced confidence in memory, vividness, and detail in the relevant checking group, but not in the irrelevant checking group. A trend was found towards a decline in attentional confidence in the relevant checking group only. Perception was not affected by repetitive checking. A replication study revealed similar results of relevant checking on meta-memory, however, the trend for attentional distrust was not confirmed. The results suggest that perseveration may be domain specific, i.e., only the cognitive processes that are subject to perseveration are affected.     

Hyperstriatal lesions in pigeons disrupt recognition memory at long, but not at short, inter-trial intervals

Two series of experiments investigated short-term visual recognition memory in pigeons following lesions of the hyperstriatal complex; the first series used a choice technique, the second, a single-key go/no go technique. The results of the two series agreed, first, in finding impaired performance in hyperstriatal birds at long but not at short inter-trial intervals, and, second, in obtaining no evidence of differential rates of decay of traces in hyperstriatal and control subjects. A final experiment confirmed that the hyperstriatal birds were, as expected from previous work, impaired on reversals of colour and position discriminations. It is tentatively suggested that deficits following hyperstriatal damage in both recognition and reversal performance may be understood as being the consequence of an increased susceptibility to frustrating events in hyperstriatal subjects.     

Visual memory,the long and the short of it: A review of visual working memory and long-term memory

The majority of research on visual memory has taken a compartmentalized approach, focusing exclusively on memory over shorter or longer durations, that is, visual working memory (VWM) or visual episodic long-term memory (VLTM), respectively. This tutorial provides a review spanning the two areas, with readers in mind who may only be familiar with one or the other. The review is divided into six sections. It starts by distinguishing VWM and VLTM from one another, in terms of how they are generally defined and their relative functions. This is followed by a review of the major theories and methods guiding VLTM and VWM research. The final section is devoted toward identifying points of overlap and distinction across the two literatures to provide a synthesis that will inform future research in both fields. By more intimately relating methods and theories from VWM and VLTM to one another, new advances can be made that may shed light on the kinds of representational content and structure supporting human visual memory.     

Using TD learning to simulate working memory performance in a model of the prefrontal cortex and basal ganglia

Delayed-response tasks (DRTs) have been used to assess working memory (WM) processes in human and nonhuman animals. Experiments have shown that the basal ganglia (BG) and dorsolateral prefrontal cortex (DLPFC) subserve DRT performance. Here, we report the results of simulation studies of a systems-level model of DRT performance. The model was trained using the temporal difference (TD) algorithm and uses an actor-critic architecture. The matrisomes of the BG represent the actor and the striosomes represent the critic. Unlike existing models, we hypothesize that the BG subserve the selection of both motor- and cognitive-related information in these tasks. We also assume that the learning of both processes is based on reward presentation. A novel feature of the model is the incorporation of delay-active neurons in the matrisomes, in addition to DLPFC. Another novel feature of the model is the subdivision of the matrisomal neurons into segregated winner-take-all (WTA) networks consisting of delay- versus transiently-active units.Our simulation model proposes a new neural mechanism to account for the occurrence of perseverative responses in WM tasks in striatal-, as well as in prefrontal damaged subjects. Simulation results also show that the model both accounts for the phenomenon of time shifting of dopamine phasic signals and the effects of partial reinforcement and reward magnitude on WM performance at both behavioral and neural levels. Our simulation results also found that the TD algorithm can subserve learning in delayed-reversal tasks.     

Neural mechanisms of spatial working memory: Contributions of the dorsolateral prefrontal cortex and the thalamic mediodorsal nucleus

The dorsolateral prefrontal cortex (DLPFC) has been known to play an important role in working memory. Neurophysiological studies have revealed that delay period activity observed in the DLPFC is a neural correlate of the temporary storage mechanism for information and that this activity represents either retrospective or prospective information, although the majority represents retrospective information. However, the DLPFC is not the only brain area related to working memory. The analysis of neural activity in the thalamic mediodorsal (MD) nucleus reveals that the MD also participates in working memory. Although similar task-related activities were observed in the MD, the directional bias of these activities and the proportion of presaccadic activity are different between the MD and the DLPFC. These results indicate that, although the MD participates in working memory, the way it participates in this process is different between these two areas, in that the MD participates more in motor control aspects than the DLPFC does.     

Individual differences in delay discounting: relation to intelligence, working memory, and anterior prefrontal cortex

Lower delay discounting (better self-control) is linked to higher intelligence, but the basis of this relation is uncertain. To investigate the potential role of working memory (WM) processes, we assessed delay discounting, intelligence (g), WM (span tasks, 3-back task), and WM-related neural activity (using functional magnetic resonance imaging) in 103 healthy adults. Delay discounting was negatively correlated with g and WM. WM explained no variance in delay discounting beyond that explained by g, which suggests that processes through which WM relates to delay discounting are shared by g. WM-related neural activity in left anterior prefrontal cortex (Brodmann's area 10) covaried with g, r= .26, and delay discounting, r=-.40, and partially mediated the relation between g and delay discounting. Overall, the results suggest that delay discounting is associated with intelligence in part because of processes instantiated in anterior prefrontal cortex, a region known to support the integration of diverse information.     

Perceptual expertise enhances the resolution but not the number of representations in working memory

Despite its central role in cognition, capacity in visual working memory is restricted to about three or four items. Curby and Gauthier (2007) examined whether perceptual expertise can help to overcome this limit by enabling more efficient coding of visual information. In line with this, they observed higher capacity estimates for upright than for inverted faces, suggesting that perceptual expertise enhances visual working memory. In the present work, we examined whether the improved capacity estimates for upright faces indicates an increased number of "slots" in working memory, or improved resolution within the existing slots. Our results suggest that perceptual expertise enhances the resolution but not the number of representations that can be held in working memory. These results clarify the effects of perceptual expertise in working memory and support recent suggestions that number and resolution represent distinct facets of working memory ability.     

Blockade of IP3-mediated SK channel signaling in the rat medial prefrontal cortex improves spatial working memory

Planning and directing thought and behavior require the working memory (WM) functions of prefrontal cortex. WM is compromised by stress, which activates phosphatidylinositol (PI)-mediated IP3-PKC intracellular signaling. PKC overactivation impairs WM operations and in vitro studies indicate that IP3 receptor (IP3R)-evoked calcium release results in SK channel-dependent hyperpolarization of prefrontal neurons. However, the effects of IP3R signaling on prefrontal function have not been investigated. The present findings demonstrate that blockade of IP3R or SK channels in the prefrontal cortex enhances WM performance in rats, suggesting that both arms of the PI cascade influence prefrontal cognitive function.     

The amygdala is involved in the modulation of long-term memory, but not in working or short-term memory

Rats with cannulae implanted in the junction between the central and the basolateral nuclei of the amygdala were trained in one-trial step-down inhibitory avoidance and tested at 3 s for working memory (WM) or 1.5 or 24 h later for short-term memory (STM) and long-term memory (LTM), respectively. Several drugs were infused 6 min prior to training in the animals in which WM was measured or 0 min posttraining in those in which STM and LTM were measured: the glutamate receptor antagonists CNQX (0.5 microg) and AP5 (5.0 microg), the indirect GABA A receptor antagonist picrotoxin (0.08 microg), the cholinergic muscarinic receptor blocker scopolamine (2. 0 microg), norepinephrine (0.3 microg), the protein kinase C inhibitor staurosporin (1.0 microg), or the calcium/calmodulin dependent protein kinase II inhibitor Kn-62 (3.5 ng). None of the drugs had any effect on either WM or STM. All had, as previously shown, strong effects on LTM: picrotoxin and norepinephrine enhanced it, and CNQX, AP5, scopolamine, Kn-62, and staurosporin inhibited it. The results do not support the idea that memory of this task is formed in the amygdala; they indicate that the amygdala is not involved in WM or STM processing and support the idea that the amygdala modulates LTM storage processes carried out elsewhere.     

The medial prefrontal cortex and memory of cue location in the rat

We developed a single-trial cue-location memory task in which rats experienced an auditory cue while exploring an environment. They then recalled and avoided the sound origination point after the cue was paired with shock in a separate context. Subjects with medial prefrontal cortical (mPFC) lesions made no such avoidance response, but both lesioned and control subjects avoided the cue itself when presented at test. A follow up assessment revealed no spatial learning impairment in either group. These findings suggest that the rodent mPFC is required for incidental learning or recollection of the location at which a discrete cue occurred, but is not required for cue recognition or for allocentric spatial memory.     

Decision making in the short and long run: Repeated gambles and rationality

Experimental evidence indicates that decision makers who reject a single play of a gamble may accept repeated plays of that gamble. The rationality of this pattern of preference has been investigated beginning with Samuelson's colleague (SC) who gained notoriety in a well‐known paper. SC's pattern of preference is commonly viewed as a behavioural anomaly. Researchers from branches of psychology and economics have analysed the choice and, despite much debate, there remains considerable confusion. An axiomatic analysis of SC's choice has been used to motivate experimental studies in several disciplines. This paper identifies the axiomatic violation as that of an assumed rather than a normative condition. Therefore, contrary to popular belief, SC's choice is consistent with expected utility theory.     

Prefrontal cortex and the mediation of proactive interference in working memory

Mediating proactive interference (PI), the deleterious effect of antecedent information on current memory representations, is believed to be a key function of prefrontal cortex (PFC). Item-specific PI results when an invalid probe matches a memorandum from the preceding trial; item-nonspecific PI is produced by the accumulation of no-longer-relevant items from previous trials. We tested the hypothesis that these two types of PI are mediated by common PFC-based processes with an fMRI study of a delayed-recognition task designed to produce both types of PI. Our results indicated that the fMRI correlates of both effects were restricted both to Brodmann’s area 45 in the left hemisphere and to the memory probe epoch of the trial. These results suggest that a unification of the literatures and approaches that have independently studied these phenomena might offer a fruitful new perspective from which to study the relations between working memory, executive control, and the PFC.     

A male advantage for spatial and object but not verbal working memory using the n-back task

Sex-related differences have been reported for performance and neural substrates on some working memory measures that carry a high cognitive load, including the popular n-back neuroimaging paradigm. Despite some evidence of a sex effect on the task, the influence of sex on performance represents a potential confound in neuroimaging research. The present study investigated sex-related differences in verbal, spatial, and common object versions of the high cognitive load "n-back" working memory task. Eighteen male and 18 female undergraduates completed all 3 versions of the task. A mixed ANOVA, with Sex (male and female) as the between-subjects factor and Condition (verbal, spatial, and object) as the within-subjects repeated measure revealed that males were significantly more accurate than females on the spatial and object versions of the n-back task and performed equivalently to females on the verbal version of the task. Although the expected female advantage for verbal working memory was not found using this effortful n-back task, these results support a male advantage for high cognitive load spatial and object working memory. Future research should take into account the influence of sex on performance of the n-back task, and examine sex-related differences in working memory using other paradigms.     

Rho-associated kinase in the gustatory cortex is involved in conditioned taste aversion memory formation but not in memory retrieval or relearning

Rho-associated kinase (ROCK) is intimately involved in cortical neuronal morphogenesis. The present study explores the roles of ROCK in conditioned taste aversion (CTA) memory formation in gustatory cortex (GC) in adult rat. Microinjection of the ROCK inhibitor Y-27632 into the GC 30 min before CTA training or 10 min after the conditioned stimulus (CS) impaired long-term CTA memory (LTM) formation. ROCK inhibitor had no effect on taste aversion when injected before the first LTM test day and did not alter taste aversion on subsequent test days. Microinjection of ROCK inhibitor into GC 30 min before preexposure to the taste CS had no effect on latent inhibition of CTA learning suggesting that ROCK is involved in CS-US association rather than taste learning per se. Cumulatively, these results show that ROCK is needed for normal CTA memory formation but not retrieval, relearning or incidental taste learning.     

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.     

A comparison of the effects of fimbria-fornix, hippocampal, or entorhinal cortex lesions on spatial reference and working memory in rats: short versus long postsurgical recovery period.

Using a radial maze task and different postoperative recovery periods, this experiment assessed and compared the reference and working memory performances of adult Long-Evans male rats subjected to entorhinal cortex, fimbria-fornix, and hippocampus lesions. Sham-operated rats were used as controls. In order to see whether the duration of the postsurgical recovery period would influence acquisition of the complex radial maze task, training began 1 month following surgery (Delay 1) for half the rats in each group, while for the other half training was started 6.5 months following surgery (Delay 2). The results indicated that at both recovery periods the entorhinal cortex lesions failed to affect either working or reference memory in the spatial task. Conversely, both fimbria-fornix and hippocampus lesions impaired both reference and working memory. While the reference memory deficit was generally similar in both fimbria-fornix and hippocampal lesion groups, analysis of the results for working memory indicated that at the longer delay rats with fimbria-fornix lesions were still impaired but in animals that had the hippocampus removed, working memory did not differ from that of controls. These results suggest that there was some recovery in those rats with hippocampal lesions (e.g., on the working memory task) but both hippocampal and fimbria-fornix animals were still impaired compared to controls when training was delayed 6.5 months following the operations.