Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

A comparative review of rodent prefrontal cortex and working memory

The prefrontal cortex is critical to working memory processes. Current theories of prefrontal function are largely based on primate behavioural and electrophysiological data. As molecular genetic techniques advance in mice, so investigations into the rodent prefrontal cortex should expand, such that rodent models of prefrontal function during working memory may be used to study the synaptic and molecular basis of the phenomenon. This review attempts to summarize aspects of published data that pertain to working memory and suggest directions that will allow a coherent comparison of prefrontal function and interaction in monkey, rat and mouse.     

Traveling waves in visual cortex

Electrode recordings and imaging studies have revealed that localized visual stimuli elicit waves of activity that travel across primary visual cortex. Traveling waves are present also during spontaneous activity, but they can be greatly reduced by widespread and intensive visual stimulation. In this Review, we summarize the evidence in favor of these traveling waves. We suggest that their substrate may lie in long-range horizontal connections and that their functional role may involve the integration of information over large regions of space.     

The prefrontal cortex and working memory: physiology and brain imaging

Sustained activity has been recorded in the prefrontal cortex during working memory tasks. First, we compare the anatomical distribution of this activity in humans and monkeys. Then, we show that it reflects many factors, maintenance of the items presented, preparation for the response, transformation of the items during the delay, task rules and task goals. Finally, we point out that sustained activity has also been recorded in other areas, such as the parietal cortex. We suggest that the key to prefrontal cortex lies not in the maintenance of sensory information but in the prospective use of that information for behaviour.     

The role of prefrontal cortex in working memory: examining the contents of consciousness.

Working memory enables us to hold in our ''mind''s eye'' the contents of our conscious awareness, even in the absence of sensory input, by maintaining an active representation of information for a brief period of time. In this review we consider the functional organization of the prefrontal cortex and its role in this cognitive process. First, we present evidence from brain-imaging studies that prefrontal cortex shows sustained activity during the delay period of visual working memory tasks, indicating that this cortex maintains on-line representations of stimuli after they are removed from view. We then present evidence for domain specificity within frontal cortex based on the type of information, with object working memory mediated by more ventral frontal regions and spatial working memory mediated by more dorsal frontal regions. We also propose that a second dimension for domain specificity within prefrontal cortex might exist for object working memory on the basis of the type of representation, with analytic representations maintained preferentially in the left hemisphere and image-based representations maintained preferentially in the right hemisphere. Furthermore, we discuss the possibility that there are prefrontal areas brought into play during the monitoring and manipulation of information in working memory in addition to those engaged during the maintenance of this information. Finally, we consider the relationship of prefrontal areas important for working memory, both to posterior visual processing areas and to prefrontal areas associated with long-term memory.     

Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.     

Integration in working memory: a magnetic stimulation study on the role of left anterior prefrontal cortex

Integration is a fundamental working memory operation, requiring the insertion of information from one task into the execution of another concurrent task. Previous neuroimaging studies have suggested the involvement of left anterior prefrontal cortex (L-aPFC) in relation to working memory integration demands, increasing during presentation of information to be integrated (loading), throughout its maintenance during a secondary task, up to the integration step, and then decreasing afterward (unloading). Here we used short bursts of 5 Hz repetitive Transcranic Magnetic Stimulation (rTMS) to modulate L-aPFC activity and to assess its causal role in integration. During experimental blocks, rTMS was applied (N = 10) over L-aPFC or vertex (control site) at different time-points of a task involving integration of a preloaded digit into a sequence of arithmetical steps, and contrasted with a closely matched task without integration demand (segregation). When rTMS was applied during the loading phase, reaction times during secondary task were faster, without significant changes in error rates. RTMS instead worsened performance when applied during information unloading. In contrast, no effects were observed when rTMS was applied during the other phases of integration, or during the segregation condition. These results confirm the hypothesis that L-aPFC is causally and selectively involved in the integration of information in working memory. They additionally suggest that pre-integration loading and post-integration unloading of information involving this area may be active and resource-consuming processes.     

Modulation of inferotemporal cortex activation during verbal working memory maintenance

Regions of the left inferotemporal cortex are involved in visual word recognition and semantics. We utilized functional magnetic resonance imaging to localize an inferotemporal language area and to demonstrate that this area is involved in the active maintenance of visually presented words in working memory. Maintenance activity in this inferotemporal area showed an effect of memory load for words, but not pseudowords. In the absence of visual input, the selective modulation of this language-related inferotemporal area for the maintenance of words is accompanied by an increased functional connectivity with left prefrontal cortex. These results demonstrate an involvement of inferotemporal cortex in verbal working memory and provide neurophysiological support for the notion that nonphonological language representations can be recruited in the service of verbal working memory. More generally, they suggest that verbal working memory should be conceptualized as the frontally guided, sustained activation of pre-existing cortical language representations.     

Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.     

Encoding strategies dissociate prefrontal activity from working memory demand

It is often proposed that prefrontal cortex is important in organization and control of working memory contents. In some cases, effective reorganization can decrease task difficulty, implying a dissociation between frontal activity and basic memory demand. In a spatial working memory task, we studied the improvement of performance that occurs when materials can be reorganized into higher level groups or chunks. Structured sequences, encouraging reorganization and chunking, were compared with unstructured sequences. Though structured sequences were easier to remember, event-related functional magnetic resonance imaging (fMRI) showed increased activation of lateral frontal cortex, in particular during memory encoding. The results show that, even when memory demand decreases, organization of working memory contents into higher level chunks is associated with increased prefrontal activity.     

Oscillations in the prefrontal cortex: a gateway to memory and attention

We consider the potential role of oscillations in the prefrontal cortex (PFC) in mediating attention, working memory and memory consolidation. Activity in the theta, beta, and gamma bands is related to communication between PFC and different brain areas. While gamma/beta oscillations mediate bottom-up and top-down interactions between PFC and visual cortices, related to attention, theta rhythms are engaged by hippocampal/PFC interplay. These interactions are dynamic, depending on the nature and relevance of the information currently being processed. The profound modifications of the PFC neuronal network associated with changes in oscillatory coherence are controlled by neuromodulators such as dopamine, which thereby allow or prevent the formation of cell assemblies for information encoding and storage.     

Neuronal responses related to long-term recognition memory processes in prefrontal cortex

Much evidence indicates that prefrontal cortex plays an important role in long-term recognition memory processes. Here, we report primate prefrontal neuronal responses carrying information necessary for long-term visual recognition memory. The responses of many neurons signaled stimulus familiarity even when the period over which stimuli had to be remembered extended to 24 hr. Such responses occurred frequently in ventromedial, orbitofrontal, and anterior cingulate but not dorsolateral prefrontal cortex. Prefrontal information processing, as indicated by the response latencies, started after that in inferior temporal cortex and might be related to retrieval processes, as responses were typically larger for familiar than for novel stimuli.     

The role of the prefrontal and parietal cortex in learning and memory in monkeys

Removal of the 7th field of parietal cortex and sulcus principalis of prefrontal cortex did not affect learning processes for images with such properties as spatial frequency, orientation, geometrical form, but worsen learning characteristics in visual differentiation of spatial information making the learning processes unstable, longer and below the 85% level. Removal of sulcus principalis also affects learning of differentiation among various colour stimuli. The short-term memory in these monkeys are also much worse than in intact animals. A scheme of learning involving interacting sensory and cognitive processes controlled by motivation system, is proposed.     

Right prefrontal activity reflects the ability to overcome sleepiness during working memory tasks: a functional near-infrared spectroscopy study

It has been speculated that humans have an inherent ability to overcome sleepiness that counteracts homeostatic sleep pressure. However, it remains unclear which cortical substrate activities are involved in the ability to overcome sleepiness during the execution of cognitive tasks. Here we sought to confirm that this ability to overcome sleepiness in task execution improves performance on cognitive tasks, showing activation of neural substrates in the frontal cortex, by using a modified n-back (2- and 0-back) working memory task and functional near-infrared spectroscopy. The change in alertness was just correlated with performances on the 2-back task. Activity in the right prefrontal cortex changed depending on alertness changes on the 2- and 0-back tasks independently, which indicates that activity in this region clearly reflects the ability to overcome sleepiness; it may contribute to the function of providing sufficient activity to meet the task load demands. This study reveals characteristics of the ability to overcome sleepiness during the n-back working memory task which goes beyond the attention-control function traditionally proposed.     

Behavioral planning in the prefrontal cortex

Recent studies have presented evidence that the prefrontal cortex plays a crucial role in every aspect of the cognitive processes necessary for behavioral planning: processing and integration of perceived or memorized information, associative learning, reward-based behavioral control, behavioral selection/decision-making and behavioral guidance. We propose that the creation of novel information is the means by which the prefrontal cortex operates to achieve executive control over behavioral planning. The prefrontal cortex is the site of operation of nodal points, where neural circuits integrate currently available or memorized information to generate the information that is necessary to perform an action. The prefrontal cortex also regulates the flow of information through multiple nodes to meet behavioral demands.