Towards understanding of the cortical network underlying associative memory

Declarative knowledge and experiences are represented in the association cortex and are recalled by reactivation of the neural representation. Electrophysiological experiments have revealed that associations between semantically linked visual objects are formed in neural representations in the temporal and limbic cortices. Memory traces are created by the reorganization of neural circuits. These regions are reactivated during retrieval and contribute to the contents of a memory. Two different types of retrieval signals are suggested as follows: automatic and active. One flows backward from the medial temporal lobe during the automatic retrieval process, whereas the other is conveyed as a top-down signal from the prefrontal cortex to the temporal cortex during the active retrieval process. By sending the top-down signal, the prefrontal cortex manipulates and organizes to-be-remembered information, devises strategies for retrieval and monitors the outcome. To further understand the neural mechanism of memory, the following two complementary views are needed: how the multiple cortical areas in the brain-wide network interact to orchestrate cognitive functions and how the properties of single neurons and their synaptic connections with neighbouring neurons combine to form local circuits and to exhibit the function of each cortical area. We will discuss some new methodological innovations that tackle these challenges.     

Prefrontal cortex and neural mechanisms of executive function

Executive function is a product of the coordinated operation of multiple neural systems and an essential prerequisite for a variety of cognitive functions. The prefrontal cortex is known to be a key structure for the performance of executive functions. To accomplish the coordinated operations of multiple neural systems, the prefrontal cortex must monitor the activities in other cortical and subcortical structures and control and supervise their operations by sending command signals, which is called top-down signaling. Although neurophysiological and neuroimaging studies have provided evidence that the prefrontal cortex sends top-down signals to the posterior cortices to control information processing, the neural correlate of these top-down signals is not yet known. Through use of the paired association task, it has been demonstrated that top-down signals are used to retrieve specific information stored in long-term memory. Therefore, we used a paired association task to examine the neural correlates of top-down signals in the prefrontal cortex. The preliminary results indicate that 32% of visual neurons exhibit pair-selectivity, which is similar to the characteristics of pair-coding activities in temporal neurons. The latency of visual responses in prefrontal neurons was longer than bottom-up signals but faster than top-down signals in inferior temporal neurons. These results suggest that pair-selective visual responses may be top-down signals that the prefrontal cortex provides to the temporal cortex, although further studies are needed to elucidate the neural correlates of top-down signals and their characteristics to understand the neural mechanism of executive control by the prefrontal cortex.     

Model of Familiarity Discrimination in the Perirhinal Cortex

Much evidence indicates that recognition memory involves two separable processes, recollection and familiarity discrimination, with familiarity discrimination being dependent on the perirhinal cortex of the temporal lobe. Here, we describe a new neural network model designed to mimic the response patterns of perirhinal neurons that signal information concerning the novelty or familiarity of stimuli. The model achieves very fast and accurate familiarity discrimination while employing biologically plausible parameters and Hebbian learning rules. The fact that the activity patterns of the model's simulated neurons are closely similar to those of neurons recorded from the primate perirhinal cortex indicates that this brain region could discriminate familiarity using principles akin to those of the model. If so, the capacity of the model establishes that the perirhinal cortex alone may discriminate the familiarity of many more stimuli than current neural network models indicate could be recalled (recollected) by all the remaining areas of the cerebral cortex. This efficiency and speed of detecting novelty provides an evolutionary advantage, thereby providing a reason for the existence of a familiarity discrimination network in addition to networks used for recollection.     

Consolidation of passive avoidance learning is associated with transient increases of polysialylated neurons in layer II of the rat medial temporal cortex

Within the rat medial temporal lobe, transient modulations of neural cell adhesion molecule (NCAM) polysialylation have been observed to follow spatial learning. These have been attributed to neuroplastic events associated with the processing of information destined for long term memory consolidation. To determine if similar events are associated with avoidance learning, we investigated change in polysialylated cell number in the entorhinal, perirhinal, and piriform cortex, following acquisition of a passive avoidance task in the rat. Direct quantification of polysialylated neurons in layer II of these cortical regions revealed a significant increase in polysialylated cell frequency at 12 h following passive avoidance training. Unlike spatial learning, the increased expression of polysialylated neurons persisted for up to 24-48 h following training. In the more dorsal aspect of the perirhinal/entorhinal cortex, this increase was found to be specific to learning, as it was not observed in animals rendered amnesic with scopolamine. By contrast, change in polysialylated cell frequency in the ventral aspect of the medial temporal lobe was only partially reduced by amnesic doses of scopolamine. The persisting activation of NCAM polysialylation in the more dorsal aspects of the perirhinal and entorhinal cortex is suggested to reflect the need for more extensive synaptic alterations, as compared to those required for the consolidation of spatial learning. Moreover, the neuroplastic modulations observed in the more ventral regions of the entorhinal and perirhinal cortex appear to be a unique aspect of avoidance conditioning that reflects the activation of alternative learning strategies associated with motivational and/or contextual parameters of the task.     

Evidence concerning how neurons of the perirhinal cortex may effect familiarity discrimination

Many studies indicate that recognition memory involves at least two separable processes, familiarity discrimination and recollection. Aspects of what is known of potential neuronal substrates of familiarity discrimination are reviewed. Lesion studies have established that familiarity discrimination for individual visual stimuli is effected by a system centred on the perirhinal cortex of the temporal lobe. The fundamental change that encodes prior occurrence of such stimuli appears to be a reduction in the response of neurons in anterior inferior temporal (including perirhinal) cortex when a stimulus is repeated. The neuronal responses rapidly signal the presence of a novel stimulus, and are evidence of long-lasting learning after a single exposure. Computational modelling indicates that a neuronal network based on such a change in responsiveness is potentially highly efficient in information theoretic terms. Processes that occur in long-term depression within the perirhinal cortex provide candidate synaptic plastic mechanisms for that underlying the change, but such linkage remains to be experimentally established.     

Against memory systems

The medial temporal lobe is indispensable for normal memory processing in both human and non-human primates, as is shown by the fact that large lesions in it produce a severe impairment in the acquisition of new memories. The widely accepted inference from this observation is that the medial temporal cortex, including the hippocampal, entorhinal and perirhinal cortex, contains a memory system or multiple memory systems, which are specialized for the acquisition and storage of memories. Nevertheless, there are some strong arguments against this idea: medial temporal lesions produce amnesia by disconnecting the entire temporal cortex from neuromodulatory afferents arising in the brainstem and basal forebrain, not by removing cortex; the temporal cortex is essential for perception as well as for memory; and response properties of temporal cortical neurons make it impossible that some kinds of memory trace could be stored in the temporal lobe. All cortex is plastic, and it is possible that the same rules of plasticity apply to all cortical areas; therefore, memory traces are stored in widespread cortical areas rather than in a specialized memory system restricted to the temporal lobe. Among these areas, the prefrontal cortex has an important role in learning and memory, but is best understood as an area with no specialization of function.     

Active maintenance of associative mnemonic signal in monkey inferior temporal cortex

We investigated the contribution of the inferior temporal (IT) cortical neurons to the active maintenance of internal representations. The activity of single neurons in the IT cortex was recorded while the monkeys performed a sequential-type associative memory task in which distractor stimuli interrupted the delay epoch between the cue and target (paired-associate) stimuli. For each neuron, information about each stimulus conveyed by the delay activity was estimated as a coefficient of multiple regression analysis. We found that target information derived from long-term memory (LTM) persisted despite the distractors. By contrast, cue information derived from the visual system was attenuated and frequently replaced by distractor information. These results suggest that LTM-derived information required for upcoming behavior is actively maintained in the IT neurons, whereas visually derived information tends to be updated irrespective of behavioral relevance.     

Neural mechanism of dynamic responses of neurons in inferior temporal cortex in face perception

Understanding the neural mechanisms of object and face recognition is one of the fundamental challenges of visual neuroscience. The neurons in inferior temporal (IT) cortex have been reported to exhibit dynamic responses to face stimuli. However, little is known about how the dynamic properties of IT neurons emerge in the face information processing. To address this issue, we made a model of IT cortex, which performs face perception via an interaction between different IT networks. The model was based on the face information processed by three resolution maps in early visual areas. The network model of IT cortex consists of four kinds of networks, in which the information about a whole face is combined with the information about its face parts and their arrangements. We show here that the learning of face stimuli makes the functional connections between these IT networks, causing a high spike correlation of IT neuron pairs. A dynamic property of subthreshold membrane potential of IT neuron, produced by Hodgkin–Huxley model, enables the coordination of temporal information without changing the firing rate, providing the basis of the mechanism underlying face perception. We show also that the hierarchical processing of face information allows IT cortex to perform a “coarse-to-fine” processing of face information. The results presented here seem to be compatible with experimental data about dynamic properties of IT neurons.     

Cholecystokinin from the entorhinal cortex enables neural plasticity in the auditory cortex

Patients with damage to the medial temporal lobe show deficits in forming new declarative memories but can still recall older memories, suggesting that the medial temporal lobe is necessary for encoding memories in the neocortex. Here, we found that cortical projection neurons in the perirhinal and entorhinal cortices were mostly immunopositive for cholecystokinin (CCK). Local infusion of CCK in the auditory cortex of anesthetized rats induced plastic changes that enabled cortical neurons to potentiate their responses or to start responding to an auditory stimulus that was paired with a tone that robustly triggered action potentials. CCK infusion also enabled auditory neurons to start responding to a light stimulus that was paired with a noise burst. In vivo intracellular recordings in the auditory cortex showed that synaptic strength was potentiated after two pairings of presynaptic and postsynaptic activity in the presence of CCK. Infusion of a CCK_B antagonist in the auditory cortex prevented the formation of a visuo-auditory association in awake rats. Finally, activation of the entorhinal cortex potentiated neuronal responses in the auditory cortex, which was suppressed by infusion of a CCK_B antagonist. Together, these findings suggest that the medial temporal lobe influences neocortical plasticity via CCK-positive cortical projection neurons in the entorhinal cortex.     

Shaping of object representations in the human medial temporal lobe based on temporal regularities

Regularities are gradually represented in cortex after extensive experience [1], and yet they can influence behavior after minimal exposure [2, 3]. What kind of representations support such rapid statistical learning? The medial temporal lobe (MTL) can represent information from even a single experience [4], making it a good candidate system for assisting in initial learning about regularities. We combined anatomical segmentation of the MTL, high-resolution fMRI, and multivariate pattern analysis to identify representations of objects in cortical and hippocampal areas of human MTL, assessing how these representations were shaped by exposure to regularities. Subjects viewed a continuous visual stream containing hidden temporal relationships-pairs of objects that reliably appeared nearby in time. We compared the pattern of blood oxygen level-dependent activity evoked by each object before and after this exposure, and found that perirhinal cortex, parahippocampal cortex, subiculum, CA1, and CA2/CA3/dentate gyrus (CA2/3/DG) encoded regularities by increasing the representational similarity of their constituent objects. Most regions exhibited bidirectional associative shaping, whereas CA2/3/DG represented regularities in a forward-looking predictive manner. These findings suggest that object representations in MTL come to mirror the temporal structure of the environment, supporting rapid and incidental statistical learning.     

Recognition memory: what are the roles of the perirhinal cortex and hippocampus?

The hallmark of medial temporal lobe amnesia is a loss of episodic memory such that patients fail to remember new events that are set in an autobiographical context (an episode). A further symptom is a loss of recognition memory. The relationship between these two features has recently become contentious. Here, we focus on the central issue in this dispute--the relative contributions of the hippocampus and the perirhinal cortex to recognition memory. A resolution is vital not only for uncovering the neural substrates of these key aspects of memory, but also for understanding the processes disrupted in medial temporal lobe amnesia and the validity of animal models of this syndrome.     

Expression of long-term depression underlies visual recognition memory

The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.     

Cholinergic neurotransmission is essential for perirhinal cortical plasticity and recognition memory

We establish the importance of cholinergic neurotransmission to both recognition memory and plasticity within the perirhinal cortex of the temporal lobe. The muscarinic receptor antagonist scopolamine impaired the preferential exploration of novel over familiar objects, disrupted the normal reduced activation of perirhinal neurones to familiar compared to novel pictures, and blocked production of long-term depression (LTD) but not long-term potentiation (LTP) of synaptic transmission in perirhinal slices. The consistency of these effects across the behavioral, systems, and cellular levels of analysis provides strong evidence for the involvement of cholinergic mechanisms in synaptic plastic processes within perirhinal cortex that are necessary for recognition memory.     

Multisynaptic Inputs from the Medial Temporal Lobe to V4 in Macaques

Retrograde transsynaptic transport of rabies virus was employed to undertake the top-down projections from the medial temporal lobe (MTL) to visual area V4 of the occipitotemporal visual pathway in Japanese monkeys (Macaca fuscata). On day 3 after rabies injections into V4, neuronal labeling was observed prominently in the temporal lobe areas that have direct connections with V4, including area TF of the parahippocampal cortex. Furthermore, conspicuous neuron labeling appeared disynaptically in area TH of the parahippocampal cortex, and areas 35 and 36 of the perirhinal cortex. The labeled neurons were located predominantly in deep layers. On day 4 after the rabies injections, labeled neurons were found in the hippocampal formation, along with massive labeling in the parahippocampal and perirhinal cortices. In the hippocampal formation, the densest neuron labeling was seen in layer 5 of the entorhinal cortex, and a small but certain number of neurons were labeled in other regions, such as the subicular complex and CA1 and CA3 of the hippocampus proper. The present results indicate that V4 receives major input from the hippocampus proper via the entorhinal cortex, as well as “short-cut” pathways that bypass the entorhinal cortex. These multisynaptic pathways may define an anatomical basis for hippocampal-cortical interactions involving lower visual areas. The multisynaptic input from the MTL to V4 is likely to provide mnemonic information about object recognition that is accomplished through the occipitotemporal pathway.     

Item, context and relational episodic encoding in humans

Recent functional imaging work supports the view that item and relational memory depend upon distinct encoding operations within the medial temporal lobe. Specifically, emerging findings demonstrate that the level of engagement of perirhinal cortex predicts later memory for individual items, whereas the level of hippocampal processing correlates with later relational memory, or recovery of additional episodic details. Furthermore, recent functional magnetic resonance imaging evidence in humans suggests that medial temporal lobe cortical input structures, the perirhinal and posterior parahippocampal cortices, differentially participate in the encoding of objects and their context, providing domain-specific input to the hippocampus. Taken together, these data help to construct a working model of how distinct medial temporal lobe structures participate in episodic memory formation with domain-general relational binding mechanisms supported by the hippocampus and provide emerging evidence for domain-specificity within the perirhinal and parahippocampal cortices.     

Conserved fMRI and LFP signals during new associative learning in the human and macaque monkey medial temporal lobe

We measured local field potential (LFP) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in the medial temporal lobes of monkeys and humans, respectively, as they performed the same conditional motor associative learning task. Parallel analyses were used to examine both data sets. Despite significantly faster learning in humans relative to monkeys, we found equivalent neural signals differentiating new versus highly familiar stimuli, first stimulus presentation, trial outcome, and learning strength in the entorhinal cortex and hippocampus of both species. Thus, the use of parallel behavioral tasks and analyses in monkeys and humans revealed conserved patterns of neural activity across the medial temporal lobe during an associative learning task.     

Monitoring the mind: the neurocognitive correlates of metamemory

Memory performance in everyday life is often far from perfect and therefore needs to be monitored and controlled by metamemory evaluations, such as judgments of learning (JOLs). JOLs support monitoring for goal-directed modification of learning. Behavioral studies suggested retrieval processes as providing a basis for JOLs. Previous functional imaging research on JOLs found a dissociation between processes underlying memory prediction, located in the medial prefrontal cortex (mPFC), and actual encoding success, located in the medial temporal lobe. However, JOL-specific neural correlates could not be identified unequivocally, since JOLs were given simultaneously with encoding. Here, we aimed to identify the neurocognitive basis of JOLs, i.e., the cognitive processes and neural correlates of JOL, separate from initial encoding. Using functional magnetic resonance imaging (fMRI), we implemented a face-name paired associative design. In general, we found that actual memory success was associated with increased brain activation of the hippocampi bilaterally, whereas predicted memory success was accompanied by increased activation in mPFC, orbital frontal and anterior cingulate cortices. Masking brain activation during predicted memory success with activation during retrieval success revealed BOLD increases of the mPFC. Our findings indicate that JOLs actually incorporate retrieval processes.     

Associative fear learning enhances sparse network coding in primary sensory cortex

Several models of associative learning predict that stimulus processing changes during association formation. How associative learning reconfigures neural circuits in primary sensory cortex to "learn" associative attributes of a stimulus remains unknown. Using 2-photon in vivo calcium imaging to measure responses of networks of neurons in primary somatosensory cortex, we discovered that associative fear learning, in which whisker stimulation is paired with foot shock, enhances sparse population coding and robustness of the conditional stimulus, yet decreases total network activity. Fewer cortical neurons responded to stimulation of the trained whisker than in controls, yet their response strength was enhanced. These responses were not observed in mice exposed to a nonassociative learning procedure. Our results define how the cortical representation of a sensory stimulus is shaped by associative fear learning. These changes are proposed to enhance efficient sensory processing after associative learning.     

Human hippocampal neurons predict how well word pairs will be remembered

What is the neuronal basis for whether an experience is recalled or forgotten? In contrast to recognition, recall is difficult to study in nonhuman primates and rarely is accessible at the single neuron level in humans. We recorded 128 medial temporal lobe (MTL) neurons in patients implanted with intracranial microelectrodes while they encoded and recalled word paired associates. Neurons in the amygdala, entorhinal cortex, and hippocampus showed altered activity during encoding (9%), recall (22%), and both task phases (23%). The responses of hippocampal neurons during encoding predicted whether or not subjects later remembered the pairs successfully. Entorhinal cortex neuronal activity during retrieval was correlated with recall success. These data provide support at the single neuron level for MTL contributions to encoding and retrieval, while also suggesting there may be differences in the level of contribution of MTL regions to these memory processes.