Lesion of the hippocampus selectively enhances LEC's activity during recognition memory based on familiarity.

The sense of familiarity for events is crucial for successful recognition memory. However, the neural substrate and mechanisms supporting familiarity remain unclear. A major controversy in memory research is whether the parahippocampal areas, especially the lateral entorhinal (LEC) and the perirhinal (PER) cortices, support familiarity or whether the hippocampus (HIP) does. In addition, it is unclear if LEC, PER and HIP interact within this frame. Here, we especially investigate if LEC and PER's contribution to familiarity depends on hippocampal integrity. To do so, we compare LEC and PER neural activity between rats with intact hippocampus performing on a human to rat translational task relying on both recollection and familiarity and rats with hippocampal lesions that have been shown to then rely on familiarity to perform the same task. Using high resolution Immediate Early Gene imaging, we report that hippocampal lesions enhance activity in LEC during familiarity judgments but not PER's. These findings suggest that different mechanisms support familiarity in LEC and PER and led to the hypothesis that HIP might exert a tonic inhibition on LEC during recognition memory that is released when HIP is compromised, possibly constituting a compensatory mechanism in aging and amnesic patients.

Heterozygous GBA D409V and ATP13a2 mutations do not exacerbate pathological α-synuclein spread in the prodromal preformed fibrils model in young mice.

Autophagic dysregulation and lysosomal impairment have been implicated in the pathogenesis of Parkinson's disease, partly due to the identification of mutations in multiple genes involved in these pathways such as GBA, SNCA, ATP13a2 (also known as PARK9), TMEM175 and LRRK2. Mutations resulting in lysosomal dysfunction are proposed to contribute to Parkinson's disease by increasing α-synuclein levels, that in turn may promote aggregation of this protein. Here, we used two different genetic models-one heterozygous for a mutated form of the GBA protein (D409V), and the other heterozygous for an ATP13a2 loss-of-function mutation, to test whether these mutations exacerbate the spread of α-synuclein pathology following injection of α-synuclein preformed fibrils in the olfactory bulb of 12-week-old mice. Contrary to our hypothesis, we found that mice harboring GBA D409V+/- and ATP13a2+/- mutations did not have exacerbated behavioral impairments or histopathology (α-synuclein, LAMP2, and Iba1) when compared to their wildtype littermates. This indicates that in the young mouse brain, neither the GBA D409V mutation or ATP13a2 loss-of-function mutation accelerate the spread of α-synuclein pathology. As a consequence, we postulate that these mutations increase Parkinson's disease risk only by acting in one of the initial, upstream events in the Parkinson's disease pathogenic process. Further, the mutations, and the molecular pathways they impact, appear to play a less important role once the pathogenic process has been triggered and therefore do not specifically influence α-synuclein pathology spread.

Perirhinal damage produces modality-dependent deficits in fear learning.

The perirhinal cortex (PER) receives multimodal and unimodal sensory information from all modalities. In addition, the PER is anatomically connected with several brain regions that support fear learning. Several studies suggest that the PER is involved in fear conditioning to discontinuous auditory cues but not to continuous auditory cues. To date, studies examining the role of the PER in fear conditioning has largely focused on auditory and contextual stimuli. The present study assessed whether the role of the PER in fear conditioning would extend to visual modalities. Rodents were randomly assigned to one of four conditioned stimuli, which consisted of either a tone or a light stimulus that was either continuous or discontinuous. Pre-training excitotoxic lesions to the PER significantly reduced freezing to auditory and visual cues during the acquisition phase regardless of stimulus continuity. During subsequent testing, perirhinal lesions produced significant decreases in freezing levels to both continuous and discontinuous tones but not to either of the light CS groups. These results suggest that the PER is involved in the acquisition of fear across multiple cue modalities. However, the PER may have a more limited role in the retrieval of the fear memory dependent upon the cue modality.

Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia.

T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer's disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.

Longitudinal atrophy in early Braak regions in preclinical Alzheimer's disease.

A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-ß negative (Aß-) controls, cerebral spinal fluid p-tau positive (T+) and negative (T-) preclinical AD (Aß+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T- preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients.

Neuronal loss is the best neuropathological substrate that correlates with cortical atrophy and dementia in Alzheimer's disease (AD). Defective GABAergic neuronal functions may lead to cortical network hyperactivity and aberrant neuronal oscillations and in consequence, generate a detrimental alteration in memory processes. In this study, using immunohistochemical and stereological approaches, we report that the two major and non-overlapping groups of inhibitory interneurons (SOM-cells and PV-cells) displayed distinct vulnerability in the perirhinal cortex of APP/PS1 mice and AD patients. SOM-positive neurons were notably sensitive and exhibited a dramatic decrease in the perirhinal cortex of 6-month-old transgenic mice (57% and 61% in areas 36 and 35, respectively) and, most importantly, in AD patients (91% in Braak V-VI cases). In addition, this interneuron degenerative process seems to occur in parallel, and closely related, with the progression of the amyloid pathology. However, the population expressing PV was unaffected in APP/PS1 mice while in AD brains suffered a pronounced and significant loss (69%). As a key component of cortico-hippocampal networks, the perirhinal cortex plays an important role in memory processes, especially in familiarity-based memory recognition. Therefore, disrupted functional connectivity of this cortical region, as a result of the early SOM and PV neurodegeneration, might contribute to the altered brain rhythms and cognitive failures observed in the initial clinical phase of AD patients. Finally, these findings highlight the failure of amyloidogenic AD models to fully recapitulate the selective neuronal degeneration occurring in humans.

The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory.

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory.

Global brain volume reductions in a sub-chronic phencyclidine animal model for schizophrenia and their relationship to recognition memory.

BACKGROUND: Cognitive deficits and structural brain changes co-occur in patients with schizophrenia. Improving our understanding of the relationship between these is important to develop improved therapeutic strategies. Back-translation of these findings into rodent models for schizophrenia offers a potential means to achieve this goal. AIMS: The purpose of this study was to determine the extent of structural brain changes and how these relate to cognitive behaviour in a sub-chronic phencyclidine rat model. METHODS: Performance in the novel object recognition task was examined in female Lister Hooded rats at one and six weeks after sub-chronic phencyclidine (2 mg/kg intra-peritoneal, n=15) and saline controls (1 ml/kg intra-peritoneal, n=15). Locomotor activity following acute phencyclidine challenge was also measured. Brain volume changes were assessed in the same animals using ex vivo structural magnetic resonance imaging and computational neuroanatomical analysis at six weeks. RESULTS: Female sub-chronic phencyclidine-treated Lister Hooded rats spent significantly less time exploring novel objects (p<0.05) at both time-points and had significantly greater locomotor activity response to an acute phencyclidine challenge (p<0.01) at 3-4 weeks of washout. At six weeks, sub-chronic phencyclidine-treated Lister Hooded rats displayed significant global brain volume reductions (p<0.05; q<0.05), without apparent regional specificity. Relative volumes of the perirhinal cortex however were positively correlated with novel object exploration time only in sub-chronic phencyclidine rats at this time-point. CONCLUSION: A sustained sub-chronic phencyclidine-induced cognitive deficit in novel object recognition is accompanied by global brain volume reductions in female Lister Hooded rats. The relative volumes of the perirhinal cortex however are positively correlated with novel object exploration, indicating some functional relevance.

Impaired perceptual integration and memory for unitized representations are associated with perirhinal cortex atrophy in Alzheimer's disease.

Unitization, the capacity to encode associations as one integrated entity, can enhance associative memory in populations with an associative memory deficit by promoting familiarity-based associative recognition. Patients with Alzheimer's disease (AD) are typically impaired in associative memory compared with healthy controls but do not benefit from unitization strategies. Using fragmented pictures of objects, this study aimed at assessing which of the cognitive processes that compose unitization is actually affected in AD: the retrieval of unitized representations itself, or some earlier stages of processing, such as the integration process at a perceptual or conceptual stage of representation. We also intended to relate patients' object unitization capacity to the integrity of their perirhinal cortex (PrC), as the PrC is thought to underlie unitization and is also one of the first affected regions in AD. We evaluated perceptual integration capacity and subsequent memory for those items that have supposedly been unitized in 23 mild AD patients and 20 controls. We systematically manipulated the level of perceptual integration during encoding by presenting object pictures that were either left intact, separated into 2 fragments, or separated into 4 fragments. Subjects were instructed to unitize the fragments into a single representation. Success of integration was assessed by a question requiring the identification of the object. Participants also underwent a structural magnetic resonance imaging examination, and measures of PrC, posterior cingulate cortex volume and thickness, and hippocampal volume, were extracted. The results showed that patients' perceptual integration performance decreased with the increased fragmentation level and that their memory for unitized representations was impaired whatever the demands in terms of perceptual integration at encoding. Both perceptual integration and memory for unitized representations were related to the integrity of the PrC, and memory for unitized representations was also related to the volume of the hippocampus. We argue that, globally, this supports representational theories of memory that hold that the role of the PrC is not only perceptual nor mnemonic but instead underlies complex object representation.

Understanding perirhinal contributions to perception and memory: Evidence through the lens of selective perirhinal damage.

Although a memory systems view of the medial temporal lobe (MTL) has been widely influential in understanding how memory processes are implemented, a large body of work across humans and animals has converged on the idea that the MTL can support various other decisions, beyond those involving memory. Specifically, recent work suggests that perception of and memory for visual representations may interact in order to support ongoing cognition. However, given considerations involving lesion profiles in neuropsychological investigations and the correlational nature of fMRI, the precise nature of representations supported by the MTL are not well understood in humans. In the present investigation, three patients with highly specific lesions to MTL were administered a task that taxed perceptual and mnemonic judgments with highly similar face stimuli. A striking double dissociation was observed such that I.R., a patient with a cyst localized to right posterior PRc, displayed a significant impairment in perceptual discriminations, whereas patient A.N., an individual with a lesion in right posterior parahippocampal cortex and the tail of the right hippocampus, and S.D., an individual with bilateral hippocampal damage, did not display impaired performance on the perceptual task. A.N. and S.D. did, however, show impairments in memory performance, whereas patient I.R. did not. These results causally implicate right PRc in successful perceptual oddity judgments, however they suggest that representations supported by PRc are not necessary for correct mnemonic judgments, even in situations of high featural overlap.

Age-related functional changes in domain-specific medial temporal lobe pathways.

There is now converging evidence from studies in animals and humans that the medial temporal lobes (MTLs) harbor anatomically distinct processing pathways for object and scene information. Recent functional magnetic resonance imaging studies in humans suggest that this domain-specific organization may be associated with a functional preference of the anterior-lateral part of the entorhinal cortex (alErC) for objects and the posterior-medial entorhinal cortex (pmErC) for scenes. As MTL subregions are differentially affected by aging and neurodegenerative diseases, the question was raised whether aging may affect the 2 pathways differentially. To address this possibility, we developed a paradigm that allows the investigation of object memory and scene memory in a mnemonic discrimination task. A group of young (n = 43) and healthy older subjects (n = 44) underwent functional magnetic resonance imaging recordings during this novel task, while they were asked to discriminate exact repetitions of object and scene stimuli from novel stimuli that were similar but modified versions of the original stimuli ("lures"). We used structural magnetic resonance images to manually segment anatomical components of the MTL including alErC and pmErC and used these segmented regions to analyze domain specificity of functional activity. Across the entire sample, object processing was associated with activation of the perirhinal cortex (PrC) and alErC, whereas for scene processing, activation was more predominant in the parahippocampal cortex and pmErC. Functional activity related to mnemonic discrimination of object and scene lures from exact repetitions was found to overlap between processing pathways and suggests that while the PrC-alErC pathway was more involved in object discrimination, both pathways were involved in the discrimination of similar scenes. Older adults were behaviorally less accurate than young adults in discriminating similar lures from exact repetitions, but this reduction was equivalent in both domains. However, this was accompanied by significantly reduced domain-specific activity in PrC in older adults compared to what was observed in the young. Furthermore, this reduced domain-specific activity was associated to worse performance in object mnemonic discrimination in older adults. Taken together, we show the fine-grained functional organization of the MTL into domain-specific pathways for objects and scenes and their mnemonic discrimination and further provide evidence that aging might affect these pathways in a differential fashion. Future experiments will elucidate whether the 2 pathways are differentially affected in early stages of Alzheimer's disease in relation to amyloid or tau pathology.

Intact perceptual ability, but impaired familiarity judgment, after neonatal perirhinal lesions in rhesus macaques.

The perirhinal cortex is known to support high-level perceptual abilities as well as familiarity judgments that may affect recognition memory. We tested whether poor perceptual abilities or a loss of familiarity judgment contributed to the recognition memory impairments reported earlier in monkeys with PRh lesions received in infancy (Neo-PRh) (Weiss and Bachevalier, 2016; Zeamer et al., 2015). Perceptual abilities were assessed using a version of the Visual Paired Comparison task with black&white (B&W) stimuli, and familiarity judgments were assessed using the Constant Negative task requiring repeated familiarization exposures. Adult monkeys with Neo-PRh lesions were able to recognize B&W stimuli after short delays, suggesting that their perceptual abilities were within the range of control animals. However, the same Neo-PRh monkeys were slower to acquire the Constant Negative task, requiring more exposures to objects before judging them as familiar compared to control animals. Taken together, the data help to account for the differential patterns of functional compensation on previously reported recognition tasks following neonatal versus adult-onset PRh lesions, and provide further support to the view that the PRh is involved in familiarity processes.

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice.

OBJECTIVES: Chronic cerebral hypoperfusion (CCH) can result in vascular dementia and small vessel white matter ischemic injury. These findings have previously been demonstrated in a murine experimental model of CCH secondary to bilateral common carotid artery stenosis (BCAS). This study sought to elucidate the effects of CCH on recognition memory as assessed by the novel object recognition (NOR) test and histological analysis of the hippocampus and perirhinal cortex. METHODS: Studies were performed on ten-week-old male mice using bilateral 0.18 mm microcoils to narrow the carotid arteries in accordance with prior publications. Following surgery, BCAS (n = 6) and sham (n = 6) mice were evaluated using NOR and 8-arm radial maze testing paradigms. Tissue damage was assessed using H&E staining on a parallel cohort of mice (n = 6 BCAS, n = 7 sham). RESULTS: In the NOR paradigm, BCAS mice demonstrated significant deficits in short-term memory. Consistent with prior studies, BCAS mice also performed significantly worse on 8-arm radial maze testing. BCAS mice exhibited significantly more neuronal injury in the perirhinal cortex when compared to sham-operated mice. However, no significant differences in neuronal damage were observed in the CA1 region of the hippocampus. DISCUSSION: Experimental CCH secondary to BCAS results in recognition memory deficits on NOR testing. Damage to the perirhinal cortex, rather than to the hippocampus, may underlie this impairment.

Perirhinal cortex involvement in allocentric spatial learning in the rat: Evidence from doubly marked tasks.

It has recently been suggested that the different cortices of the medial temporal lobe support a mixture of object and spatial processing functions, challenging the anterior model that emphasized a strict functional differentiation between regions. However, for some structures, the perirhinal cortex (Prh) for example, a number of studies using lesion methods have shown a profound deficit exclusively in tasks involving object learning but not allocentric spatial learning. It may be that the learning paradigms used in previous studies have not been sensitive enough to detect a possible allocentric deficit in Prh-lesioned animals. To examine whether Prh lesions critically affect allocentric spatial learning, experimental and control rats were trained in two doubly marked navigation tasks. In experiment 1, the use of either one of two different memory systems, allocentric versus egocentric, made it possible to locate the goal arm in a four-arm radial maze. In experiment 2, rats had to choose between an allocentric versus a S-R/habit strategy, both of which predicted the location of the goal arm. Results showed that both experimental and control animals learned both navigation tasks well, reaching the same level of performance at the end of training. However, a probe test performed 1 day after the learning ended revealed that Prh-damaged animals learned both tasks predominantly using a non-allocentric strategy. Specifically, in lesioned subjects the percentage of egocentric correct responses (experiment 1) and the percentage of habit-based correct responses (experiment 2) was significantly higher than in the control rats. On the other hand, in both experiments, control rats in the probe test presented a significantly higher number of allocentric correct responses than the lesioned subjects. These results clearly suggest that Prh is normally needed for using allocentric strategies in order to solve a navigation problem. © 2017 Wiley Periodicals, Inc.

Multi-template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability.

RATIONAL: The human perirhinal cortex (PRC) plays critical roles in episodic and semantic memory and visual perception. The PRC consists of Brodmann areas 35 and 36 (BA35, BA36). In Alzheimer's disease (AD), BA35 is the first cortical site affected by neurofibrillary tangle pathology, which is closely linked to neural injury in AD. Large anatomical variability, manifested in the form of different cortical folding and branching patterns, makes it difficult to segment the PRC in MRI scans. Pathology studies have found that in ~97% of specimens, the PRC falls into one of three discrete anatomical variants. However, current methods for PRC segmentation and morphometry in MRI are based on single-template approaches, which may not be able to accurately model these discrete variants METHODS: A multi-template analysis pipeline that explicitly accounts for anatomical variability is used to automatically label the PRC and measure its thickness in T2-weighted MRI scans. The pipeline uses multi-atlas segmentation to automatically label medial temporal lobe cortices including entorhinal cortex, PRC and the parahippocampal cortex. Pairwise registration between label maps and clustering based on residual dissimilarity after registration are used to construct separate templates for the anatomical variants of the PRC. An optimal path of deformations linking these templates is used to establish correspondences between all the subjects. Experimental evaluation focuses on the ability of single-template and multi-template analyses to detect differences in the thickness of medial temporal lobe cortices between patients with amnestic mild cognitive impairment (aMCI, n=41) and age-matched controls (n=44). RESULTS: The proposed technique is able to generate templates that recover the three dominant discrete variants of PRC and establish more meaningful correspondences between subjects than a single-template approach. The largest reduction in thickness associated with aMCI, in absolute terms, was found in left BA35 using both regional and summary thickness measures. Further, statistical maps of regional thickness difference between aMCI and controls revealed different patterns for the three anatomical variants.

Chronic rhein treatment improves recognition memory in high-fat diet-induced obese male mice.

High-fat (HF) diet modulates gut microbiota and increases plasma concentration of lipopolysaccharide (LPS) which is associated with obesity and its related low-grade inflammation and cognitive decline. Rhein is the main ingredient of the rhubarb plant which has been used as an anti-inflammatory agent for several millennia. However, the potential effects of rhein against HF diet-induced obesity and its associated alteration of gut microbiota, inflammation and cognitive decline have not been studied. In this study, C57BL/6J male mice were fed an HF diet for 8 weeks to induce obesity, and then treated with oral rhein (120 mg/kg body weight/day in HF diet) for a further 6 weeks. Chronic rhein treatment prevented the HF diet-induced recognition memory impairment assessed by the novel object recognition test, neuroinflammation and brain-derived neurotrophic factor (BDNF) deficits in the perirhinal cortex. Furthermore, rhein inhibited the HF diet-induced increased plasma LPS level and the proinflammatory macrophage accumulation in the colon and alteration of microbiota, including decreasing Bacteroides-Prevotella spp. and Desulfovibrios spp. DNA and increasing Bifidobacterium spp. and Lactobacillus spp. DNA. Moreover, rhein also reduced body weight and improved glucose tolerance in HF diet-induced obese mice. In conclusion, rhein improved recognition memory and prevented obesity in mice on a chronic HF diet. These beneficial effects occur via the modulation of microbiota, hypoendotoxinemia, inhibition of macrophage accumulation, anti-neuroinflammation and the improvement of BDNF expression. Therefore, supplementation with rhein-enriched food or herbal medicine could be beneficial as a preventive strategy for chronic HF diet-induced cognitive decline, microbiota alteration and neuroinflammation.

Impaired assessment of cumulative lifetime familiarity for object concepts after left anterior temporal-lobe resection that includes perirhinal cortex but spares the hippocampus.

The ability to recognize the prior occurrence of objects can operate effectively even in the absence of successful recollection of episodic contextual detail about a relevant past object encounter. The pertinent process, familiarity assessment, is typically probed in humans with recognition-memory tasks that include an experimentally controlled study phase for a list of items. When meaningful stimuli such as words or pictures of common objects are employed, participants must judge familiarity with reference to the recent experimental encounter rather than their lifetime of autobiographical experience, which may have involved hundreds or thousands of exposures across numerous episodic contexts. Humans can, however, also judge the cumulative familiarity of objects concepts they have encountered over their lifetime. At present, little is known about the cognitive and neural mechanisms that support this ability. Here, we tested an individual (NB) with a rare left anterior temporal-lobe lesion that included perirhinal cortex but spared the hippocampus, who had previously been found to exhibit selective impairments in familiarity assessment on verbal recognition-memory tasks. As NB exhibits normal recollection abilities, her case presents a unique opportunity to examine potential links between both types of familiarity. In Experiment 1, we demonstrated that NB's impairment in making recognition judgments affects cumulative frequency judgments for exposure to concept names in a recent study episode. Experiments 2 and 3 revealed, with a task borrowed from the semantic-memory literature, that NB's impairments do indeed extend to abnormalities in judging cumulative lifetime familiarity for object concepts. These abnormalities were not limited to verbal processing, and were present even when pictures were offered as additional cues. Moreover, they showed sensitivity to concept structure as reflected in semantic feature norms; we only observed them for judgments on object concepts with high feature overlap. In Experiment 4, we found that an amnesic patient (HC) with previously established deficits in autobiographical recollection, due to a selective lesion of the extended hippocampal system, does not exhibit any abnormalities in assessing lifetime familiarity. Together, these findings provide support for a functional link between the assessment of recent changes in familiarity, as probed with experimental study-test paradigms, and cumulative lifetime familiarity based on autobiographical experience accrued outside the laboratory. They argue in favor of the notion that familiarity is closely related to the representation of concept knowledge, likely through computations in perirhinal cortex.

Infliximab ameliorates AD-associated object recognition memory impairment.

Dysfunctions in the perirhinal cortex (PRh) are associated with visual recognition memory deficit, which is frequently detected in the early stage of Alzheimer's disease. Muscarinic acetylcholine receptor-dependent long-term depression (mAChR-LTD) of synaptic transmission is known as a key pathway in eliciting this type of memory, and Tg2576 mice expressing enhanced levels of Aß oligomers are found to have impaired mAChR-LTD in this brain area at as early as 3 months of age. We found that the administration of Aß oligomers in young normal mice also induced visual recognition memory impairment and perturbed mAChR-LTD in mouse PRh slices. In addition, when mice were treated with infliximab, a monoclonal antibody against TNF-α, visual recognition memory impaired by pre-administered Aß oligomers dramatically improved and the detrimental Aß effect on mAChR-LTD was annulled. Taken together, these findings suggest that Aß-induced inflammation is mediated through TNF-α signaling cascades, disturbing synaptic transmission in the PRh, and leading to visual recognition memory deficits.

Perirhinal cortex supports tactual discrimination tasks with increasing levels of complexity: Retrograde effect.

Recent studies have suggested that the perirhinal cortex (Prh) supports representations of feature conjunctions in the visual modality during the acquisition/encoding of complex discriminations. To extend this idea to other sensory modalities and to another stage of the discrimination process, we studied the effect of Prh lesions on the expression of a series of tactual discrimination tasks learned preoperatively. These tasks differed from one another in the degree of feature overlap of the stimuli and in the difficulty of the task. During pre- and post-operative testing phases, rats had to discriminate among 3 stimuli simultaneously exposed in 3 arms of a 4-arm plus-shaped maze. Prh-damaged rats showed a profound impairment in the expression of tactual discrimination tasks when the stimuli had a high or intermediate degree of feature ambiguity, but not when they had a low degree of ambiguity (experiments 1a-1c). In order to experimentally dissociate between subregions within the medial temporal lobe, experiment 2 was conducted to show that hippocampal lesions did not cause any impairment in task expression even when the stimuli had a high degree of feature ambiguity. When the tactual discrimination tasks used simple/individual nonoverlapping features of the stimuli (size), Prh lesions did not affect the expression of these discriminations despite the high level of difficulty of these tasks (experiments 3a and 3b). These findings suggest that, in the somatosensory modality, the Prh plays an essential role in the processing of complex stimuli with overlapping features but not in simple tactual discriminations. Furthermore, the Prh is necessary not just during acquisition but also during expression/performance of the discrimination task.