Finding and Not Finding Rat Perirhinal Neuronal Responses to Novelty.

There is much evidence that the perirhinal cortex of both rats and monkeys is important for judging the relative familiarity of visual stimuli. In monkeys many studies have found that a proportion of perirhinal neurons respond more to novel than familiar stimuli. There are fewer studies of perirhinal neuronal responses in rats, and those studies based on exploration of objects, have raised into question the encoding of stimulus familiarity by rat perirhinal neurons. For this reason, recordings of single neuronal activity were made from the perirhinal cortex of rats so as to compare responsiveness to novel and familiar stimuli in two different behavioral situations. The first situation was based upon that used in "paired viewing" experiments that have established rat perirhinal differences in immediate early gene expression for novel and familiar visual stimuli displayed on computer monitors. The second situation was similar to that used in the spontaneous object recognition test that has been widely used to establish the involvement of rat perirhinal cortex in familiarity discrimination. In the first condition 30 (25%) of 120 perirhinal neurons were visually responsive; of these responsive neurons 19 (63%) responded significantly differently to novel and familiar stimuli. In the second condition eight (53%) of 15 perirhinal neurons changed activity significantly in the vicinity of objects (had "object fields"); however, for none (0%) of these was there a significant activity change related to the familiarity of an object, an incidence significantly lower than for the first condition. Possible reasons for the difference are discussed. It is argued that the failure to find recognition-related neuronal responses while exploring objects is related to its detectability by the measures used, rather than the absence of all such signals in perirhinal cortex. Indeed, as shown by the results, such signals are found when a different methodology is used. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus.

Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesized to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluA2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluA2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluA2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation.

The medial dorsal thalamic nucleus and the medial prefrontal cortex of the rat function together to support associative recognition and recency but not item recognition.

In humans recognition memory deficits, a typical feature of diencephalic amnesia, have been tentatively linked to mediodorsal thalamic nucleus (MD) damage. Animal studies have occasionally investigated the role of the MD in single-item recognition, but have not systematically analyzed its involvement in other recognition memory processes. In Experiment 1 rats with bilateral excitotoxic lesions in the MD or the medial prefrontal cortex (mPFC) were tested in tasks that assessed single-item recognition (novel object preference), associative recognition memory (object-in-place), and recency discrimination (recency memory task). Experiment 2 examined the functional importance of the interactions between the MD and mPFC using disconnection techniques. Unilateral excitotoxic lesions were placed in both the MD and the mPFC in either the same (MD + mPFC Ipsi) or opposite hemispheres (MD + mPFC Contra group). Bilateral lesions in the MD or mPFC impaired object-in-place and recency memory tasks, but had no effect on novel object preference. In Experiment 2 the MD + mPFC Contra group was significantly impaired in the object-in-place and recency memory tasks compared with the MD + mPFC Ipsi group, but novel object preference was intact. Thus, connections between the MD and mPFC are critical for recognition memory when the discriminations involve associative or recency information. However, the rodent MD is not necessary for single-item recognition memory.

Interfering with Fos expression in rat perirhinal cortex impairs recognition memory.

Previous work has shown that immunohistochemical imaging of Fos protein is a reliable marker for changes in activity related to recognition memory in the perirhinal (PRH) cortex of the medial temporal lobe; however, whether PRH Fos expression is necessary for recognition memory had not been established. To investigate this potential requirement, antisense Fos oligodeoxynucleotide (ODN) was infused locally into PRH cortex to interfere with Fos production. As in previous studies, differential Fos expression produced by viewing novel or familiar visual stimuli was measured by immunohistochemistry: antisense Fos ODN infusion into PRH cortex disrupted the normal pattern of differential Fos expression in PRH cortex. The effect of antisense Fos ODN infusion into PRH cortex was therefore sought on recognition memory. Infusion before or immediately after acquisition impaired recognition memory for objects when the memory delay was 3 or 24 h, but not when the delay was 20 min, or when the ODN was infused before retrieval after a 24-h delay. The findings indicate a role for Fos in consolidation processes underlying long-term recognition memory for objects and establish that interfering with its expression impairs recognition memory. Antisense Fos ODN infusion also impaired object-in-place recognition memory. The results demonstrate that Fos is necessary for neuronal mechanisms in PRH cortex essential to recognition memory.

A role for the CAMKK pathway in visual object recognition memory.

The role of the CAMKK pathway in object recognition memory was investigated. Rats' performance in a preferential object recognition test was examined after local infusion into the perirhinal cortex of the CAMKK inhibitor STO-609. STO-609 infused either before or immediately after acquisition impaired memory tested after a 24 h but not a 20-min delay. Memory was not impaired when STO-609 was infused 20 min after acquisition. The expression of a downstream reaction product of CAMKK was measured by immunohistochemical staining for phospho-CAMKI(Thr177) at 10, 40, 70, and 100 min following the viewing of novel and familiar images of objects. Processing familiar images resulted in more pCAMKI stained neurons in the perirhinal cortex than processing novel images at the 10- and 40-min delays. Prior infusion of STO-609 caused a reduction in pCAMKI stained neurons in response to viewing either novel or familiar images, consistent with its role as an inhibitor of CAMKK. The results establish that the CAMKK pathway within the perirhinal cortex is important for the consolidation of object recognition memory. The activation of pCAMKI after acquisition is earlier than previously reported for pCAMKII.

MicroRNA-132 regulates recognition memory and synaptic plasticity in the perirhinal cortex.

Evidence suggests that the acquisition of recognition memory depends upon CREB-dependent long-lasting changes in synaptic plasticity in the perirhinal cortex.The CREB-responsive microRNA miR-132 has been shown to regulate synaptic transmission and we set out to investigate a role for this microRNA in recognition memory and its underlying plasticity mechanisms. To this end we mediated the specific overexpression of miR-132 selectively in the rat perirhinal cortex and demonstrated impairment in short-term recognition memory. This functional deficit was associated with a reduction in both long-term depression and long-term potentiation. These results confirm that microRNAs are key coordinators of the intracellular pathways that mediate experience-dependent changes in the brain. In addition, these results demonstrate a role for miR-132 in the neuronal mechanisms underlying the formation of short-term recognition memory.

Differing time dependencies of object recognition memory impairments produced by nicotinic and muscarinic cholinergic antagonism in perirhinal cortex.

The roles of muscarinic and nicotinic cholinergic receptors in perirhinal cortex in object recognition memory were compared. Rats' discrimination of a novel object preference test (NOP) test was measured after either systemic or local infusion into the perirhinal cortex of the nicotinic receptor antagonist methyllycaconitine (MLA), which targets alpha-7 (α7) amongst other nicotinic receptors or the muscarinic receptor antagonists scopolamine, AFDX-384, and pirenzepine. Methyllycaconitine administered systemically or intraperirhinally before acquisition impaired recognition memory tested after a 24-h, but not a 20-min delay. In contrast, all three muscarinic antagonists produced a similar, unusual pattern of impairment with amnesia after a 20-min delay, but remembrance after a 24-h delay. Thus, the amnesic effects of nicotinic and muscarinic antagonism were doubly dissociated across the 20-min and 24-h delays. The same pattern of shorter-term but not longer-term memory impairment was found for scopolamine whether the object preference test was carried out in a square arena or a Y-maze and whether rats of the Dark Agouti or Lister-hooded strains were used. Coinfusion of MLA and either scopolamine or AFDX-384 produced an impairment profile matching that for MLA. Hence, the antagonists did not act additively when coadministered. These findings establish an important role in recognition memory for both nicotinic and muscarinic cholinergic receptors in perirhinal cortex, and provide a challenge to simple ideas about the role of cholinergic processes in recognition memory: The effects of muscarinic and nicotinic antagonism are neither independent nor additive.

Separate but interacting recognition memory systems for different senses: the role of the rat perirhinal cortex.

Two different models (convergent and parallel) potentially describe how recognition memory, the ability to detect the re-occurrence of a stimulus, is organized across different senses. To contrast these two models, rats with or without perirhinal cortex lesions were compared across various conditions that controlled available information from specific sensory modalities. Intact rats not only showed visual, tactile, and olfactory recognition, but also overcame changes in the types of sensory information available between object sampling and subsequent object recognition, e.g., between sampling in the light and recognition in the dark, or vice versa. Perirhinal lesions severely impaired object recognition whenever visual cues were available, but spared olfactory recognition and tactile-based object recognition when tested in the dark. The perirhinal lesions also blocked the ability to recognize an object sampled in the light and then tested for recognition in the dark, or vice versa. The findings reveal parallel recognition systems for different senses reliant on distinct brain areas, e.g., perirhinal cortex for vision, but also show that: (1) recognition memory for multisensory stimuli involves competition between sensory systems and (2) perirhinal cortex lesions produce a bias to rely on vision, despite the presence of intact recognition memory systems serving other senses.

A critical role for long-term potentiation mechanisms in the maintenance of object recognition memory in perirhinal cortex revealed by the infusion of zeta inhibitory pseudosubstrate.

Object recognition, the ability to discriminate between a novel and a familiar stimulus, is critically dependent upon the perirhinal cortex. Neural response reductions upon repetition of a stimulus, have been hypothesized to be the mechanism within perirhinal cortex that supports recognition memory function. Thus, investigations into the mechanisms of long-term depression (LTD) in perirhinal cortex has provided insight into the mechanism of object recognition memory formation, but the contribution of long-term potentiation (LTP) to object recognition memory formation has been less studied. Inhibition of atypical PKC activity by Zeta Inhibitory Pseudosubstrate (ZIP) impairs the maintenance of LTP but not LTD, thus here infusion of ZIP into the perirhinal cortex allowed us to investigate the contribution of LTP-like mechanisms to object recognition memory maintenance. Infusion of ZIP into the perirhinal cortex of rats 24 h after the sample phase impaired performance in an object recognition but not an object location task, in contrast infusion of ZIP into the hippocampus impaired performance in an object location but not an object recognition task. The impairment in object recognition by ZIP was prevented by administration of the peptide GluA23y, which blocks the endocytosis of GluA2 containing AMPA receptors. Finally, performance in a perceptual oddity task, which requires perirhinal cortex function, was not disrupted by ZIP. Together these results demonstrate the importance of LTP-like mechanisms to the maintenance of object recognition memory in the perirhinal cortex.

Interfering with perirhinal brain-derived neurotrophic factor expression impairs recognition memory in rats.

The role of brain-derived neurotrophic factor (BDNF) in recognition memory was investigated by locally infusing oligodeoxynucleotides (ODNs) into perirhinal cortex, a region of the temporal lobe essential for familiarity discrimination. Antisense but not sense BDNF ODN impaired consolidation of long-term (24 h) but not shorter-term (20 min) recognition memory.

Dynamics of a memory trace: effects of sleep on consolidation.

BACKGROUND: There is evidence that sleep is important for memory consolidation, but the underlying neuronal changes are not well understood. We studied the effect of sleep modulation on memory and on neuronal activity in a memory system of the domestic chick brain after the learning process of imprinting. Neurons in this system become, through imprinting, selectively responsive to a training (imprinting) stimulus and so possess the properties of a memory trace. RESULTS: The proportion of neurons responsive to the training stimulus reaches a maximum the day after training. We demonstrate that sleep is necessary for this maximum to be achieved, that sleep stabilizes the initially unstable, selective responses of neurons to the imprinting stimulus, and that for sleep to be effective, it must occur during a particular period of time after training. During this period, there is a time-dependent increase in EEG activity in the 5-6 Hz band, that is, in the lower range of the theta bandwidth. The effects of sleep disturbance on consolidation cannot be attributed to fatigue or to stress. CONCLUSIONS: We establish that long-term trace consolidation requires sleep within a restricted period shortly after learning. Undisturbed sleep is necessary for the stabilization of long-term memory, measured at the behavioral and neuronal levels, and of long-term but not short-term neuronal responsiveness to the training stimulus.

Perirhinal cortex lesions uncover subsidiary systems in the rat for the detection of novel and familiar objects.

The present study compared the impact of perirhinal cortex lesions on tests of object recognition. Object recognition was tested directly by looking at the preferential exploration of novel objects over simultaneously presented familiar objects. Object recognition was also tested indirectly by presenting just novel objects or just familiar objects, and recording exploration levels. Rats with perirhinal cortex lesions were severely impaired at discriminating a novel object from a simultaneously presented familiar object (direct test), yet displayed normal levels of exploration to novel objects presented on their own and showed normal declines in exploration times for familiar objects that were repeatedly presented (indirect tests). This effective reduction in the exploration of familiar objects after perirhinal cortex lesions points to the sparing of some recognition mechanisms. This possibility led us to determine whether rats with perirhinal cortex lesions can overcome their preferential exploration deficits when given multiple object familiarisation trials prior to that same (familiar) object being paired with a novel object. It was found that after multiple familiarisation trials, objects could now successfully be recognised as familiar by rats with perirhinal cortex lesions, both following a 90-min delay (the longest delay tested) and when object recognition was tested in the dark after familiarisation trials in the light. These latter findings reveal: (i) the presumed recruitment of other regions to solve recognition memory problems in the absence of perirhinal cortex tissue; and (ii) that these additional recognition mechanisms require more familiarisation trials than perirhinal-based recognition mechanisms.

An Infomax algorithm can perform both familiarity discrimination and feature extraction in a single network.

Psychological experiments have shown that the capacity of the brain for discriminating visual stimuli as novel or familiar is almost limitless. Neurobiological studies have established that the perirhinal cortex is critically involved in both familiarity discrimination and feature extraction. However, opinion is divided as to whether these two processes are performed by the same neurons. Previously proposed models have been unable to simultaneously extract features and discriminate familiarity for large numbers of stimuli. We show that a well-known model of visual feature extraction, Infomax, can simultaneously perform familiarity discrimination and feature extraction efficiently. This model has a significantly larger capacity than previously proposed models combining these two processes, particularly when correlation exists between inputs, as is the case in the perirhinal cortex. Furthermore, we show that once the model fully extracts features, its ability to perform familiarity discrimination increases markedly.

L-type voltage-dependent calcium channel antagonists impair perirhinal long-term recognition memory and plasticity processes.

The perirhinal cortex of the temporal lobe is essential for the familiarity discrimination component of recognition memory. In view of the importance of changes in calcium ion concentration for synaptic plasticity, the present study examined the effects of L-type voltage-dependent calcium channel (VDCC) antagonism on rat perirhinal-based familiarity discrimination processes and plasticity including long-term depression (LTD), long-term potentiation (LTP), and depotentiation. Single doses of three different types of L-type VDCC antagonists, verapamil, diltiazem, and nifedipine, administered systemically, or verapamil administered locally into the perirhinal cortex, impaired acquisition of long-term (24 h) but not shorter-term (20 min) recognition memory. L-type VDCC antagonism also disrupted memory retrieval after 24 h but not 20 min. Differential neuronal activation produced by viewing novel or familiar visual stimuli was measured by Fos expression. L-type VDCC antagonism by verapamil in perirhinal cortex during memory acquisition disrupted the normal pattern of differential Fos expression, so paralleling the antagonist-induced memory impairment. In slices of perirhinal cortex maintained in vitro, verapamil was without effect on baseline excitability or LTP but blocked LTD and depotentiation. The consistency of effects across the behavioral and cellular levels of analysis provides strong evidence for the involvement of perirhinal L-type VDCCs in long-term recognition memory processes.

Recognition memory: material, processes, and substrates.

The proposal that a system centering on the perirhinal cortex is responsible for familiarity discrimination, particularly for single items, whereas a system centering on the hippocampus is responsible for recollective and more complex associational aspects of recognition memory is reviewed in the light of recent findings. In particular, the proposal is reviewed in relation to recent animal work with rats and results from human clinical studies. Notably, progress has been made in determining potential neural memory substrate mechanisms within the perirhinal cortex in rats. Recent findings have emphasized the importance of specifying the type of material, the type of test, and the strategy used by subjects to solve recognition memory tests if substrates are to be accurately inferred. It is to be expected that the default condition is that both the hippocampal and perirhinal systems will contribute to recognition memory performance. Indeed, rat lesion experiments provide examples of where cooperation between both systems is essential. Nevertheless, there remain examples of the independent operation of the hippocampal and perirhinal systems. Overall, it is concluded that most, though not all, of the recent findings are in support of the proposal. However, there is also evidence that the systems involved in recognition memory need to include structures outside the medial temporal lobe: there are significant but as yet only partially defined roles for the prefrontal cortex and sensory association cortices in recognition memory processes.

Learning-specific changes in long-term depression in adult perirhinal cortex.

Learning is widely believed to involve synaptic plasticity, using mechanisms such as those used in long-term potentiation (LTP). We assess whether the mechanisms used in alternative forms of plasticity, long-term depression (LTD) and depotentiation, play a role in learning. We have exploited the involvement of the perirhinal cortex in two different forms of learning to compare simultaneously, within the same brain region, their effects on LTD and depotentiation. Multiple-exposure learning but not single-exposure learning in vivo prevented, in a muscarinic receptor-dependent manner, subsequent induction of LTD and depotentiation, but not LTP, in perirhinal cortex in vitro. The contrast in the effects of the two types of learning under these particular experimental conditions indicate that the in vitro change is unlikely to be attributable to synapse-specific plastic changes registering the precise details of the individual learned associations. Instead, it is concluded that the lack of LTD and depotentiation arises from, and establishes the importance of, a learning-related generalized change in plasticity gain. The existence of this additional mechanism has important implications for interpretations of how plasticity relates to learning.

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.

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.

The topography of activity transmission between lateral entorhinal cortex and subfield CA1 of the hippocampus.

It is important to establish how information is transmitted through the hippocampal formation because of the structure's critical role in memory and spatial processing. Here we provide evidence that challenges the hypothesis that information is processed in parallel closed entorhinal-CA1 loops. We tested the hypothesis by mapping, throughout hippocampal subfield CA1, field potentials evoked by stimulation of different sites in lateral entorhinal cortex in awake rats, thereby establishing the topography of electrophysiological transmission between the entorhinal cortex and CA1. The results established that antidromic and orthodromic responses evoked from the same entorhinal site occurred in spatially separated CA1 areas, with antidromic responses being located more septally than orthodromic responses. Thus, an entorhinal site receives information from a CA1 area located closer to the septal pole of the hippocampus and transmits it to the next CA1 area located closer to the temporal pole. Accordingly, processing in the hippocampal formation is by open rather than closed loops. Activation occurred first in CA1 close to its septal pole and spread towards its temporal pole. Four successively activated CA1 areas, oriented at an angle to the longitudinal axis of the hippocampus, were distinguished. Overall, the findings indicate that information can potentially be transmitted from the septal to the temporal end of the hippocampal formation via an ordered succession of hippocampal and entorhinal areas that form a three-dimensional spiral pathway.