Entorhinal vessel density correlates with phosphorylated tau and TDP-43 pathology.

INTRODUCTION: The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. METHODS: We imaged post mortem human tissue at 100 µm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean = 270 slices/case). Vessel density was quantified and compared per EC subfield, between EC and PC, and in relation to tau and TAR DNA-binding protein 43 (TDP-43) semiquantitative scores. RESULTS: PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP-43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. DISCUSSION: These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP-43 pathology, may be exploited in a predictive context. HIGHLIGHTS: Vessel density correlates with phosphorylated tau (p-tau) burden in entorhinal and perirhinal cortices. Perirhinal area 35 and posterior entorhinal cortex showed greatest p-tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease. We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology.

The neurophysiological mechanisms of medial prefrontal-perirhinal cortex circuit mediating temporal order memory decline in early stage of AD rats.

The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.

Chemogenetic activation of histamine neurons promotes retrieval of apparently lost memories.

Memory retrieval can become difficult over time, but it is important to note that memories that appear to be forgotten might still be stored in the brain, as shown by their occasional spontaneous retrieval. Histamine in the central nervous system is a promising target for facilitating the recovery of memory retrieval. Our previous study demonstrated that histamine H3 receptor (H3R) inverse agonists/antagonists, activating histamine synthesis and release, enhance activity in the perirhinal cortex and help in retrieving forgotten long-term object recognition memories. However, it is unclear whether enhancing histaminergic activity alone is enough for the recovery of memory retrieval, considering that H3Rs are also located in other neuron types and affect the release of multiple neurotransmitters. In this study, we employed a chemogenetic method to determine whether specifically activating histamine neurons in the tuberomammillary nucleus facilitates memory retrieval. In the novel object recognition test, control mice did not show a preference for objects based on memory 1 week after training, but chemogenetic activation of histamine neurons before testing improved memory retrieval. This selective activation did not affect the locomotor activity or anxiety-related behavior. Administering an H2R antagonist directly into the perirhinal cortex inhibited the recovery of memory retrieval induced by the activation of histamine neurons. Furthermore, we utilized the Barnes maze test to investigate whether chemogenetic activation of histamine neurons influences the retrieval of forgotten spatial memories. Control mice explored all the holes in the maze equally 1 week after training, whereas mice with chemogenetically activated histamine neurons spent more time around the target hole. These findings indicate that chemogenetic activation of histamine neurons in the tuberomammillary nucleus can promote retrieval of seemingly forgotten object recognition and spatial memories.

Association cortical areas in the mouse contain a large population of fast-spiking GABAergic neurons that do not express parvalbumin.

GABAergic neurons represent 10-15% of the neuronal population of the cortex but exert a powerful control over information flow in cortical circuits. The largest GABAergic class in the neocortex is represented by the parvalbumin-expressing fast-spiking neurons, which provide powerful somatic inhibition to their postsynaptic targets. Recently, the density of parvalbumin interneurons has been shown to be lower in associative areas of the mouse cortex as compared with sensory and motor areas. Modelling work based on these quantifications linked the low-density of parvalbumin interneurons with specific computations of associative cortices. However, it is still unknown whether the total GABAergic population of association cortices is smaller or whether another GABAergic type can compensate for the low density of parvalbumin interneurons. In the present study, we investigated these hypotheses using a combination of neuroanatomy, mouse genetics and neurophysiology. We found that the GABAergic population of association areas is comparable with that of primary sensory areas, and it is enriched of fast-spiking neurons that do not express parvalbumin and were not accounted for by previous quantifications. We developed an intersectional viral strategy to demonstrate that the population of fast-spiking neurons is comparable across cortical regions. Our results provide quantifications of the density of fast-spiking GABAergic neurons and offers new biological constrains to refine current models of cortical computations.

Selective vulnerability of the ventral hippocampus-prelimbic cortex axis parvalbumin interneuron network underlies learning deficits of fragile X mice.

High-penetrance mutations affecting mental health can involve genes ubiquitously expressed in the brain. Whether the specific patterns of dysfunctions result from ubiquitous circuit deficits or might reflect selective vulnerabilities of targetable subnetworks has remained unclear. Here, we determine how loss of ubiquitously expressed fragile X mental retardation protein (FMRP), the cause of fragile X syndrome, affects brain networks in Fmr1y/- mice. We find that in wild-type mice, area-specific knockout of FMRP in the adult mimics behavioral consequences of area-specific silencing. By contrast, the functional axis linking the ventral hippocampus (vH) to the prelimbic cortex (PreL) is selectively affected in constitutive Fmr1y/- mice. A chronic alteration in late-born parvalbumin interneuron networks across the vH-PreL axis rescued by VIP signaling specifically accounts for deficits in vH-PreL theta-band network coherence, ensemble assembly, and learning functions of Fmr1y/- mice. Therefore, vH-PreL axis function exhibits a selective vulnerability to loss of FMRP in the vH or PreL, leading to learning and memory dysfunctions in fragile X mice.

Brain areas interconnected to ventral pathway circuits are independently able to induce enhancement in object recognition memory and cause reversal in object recognition memory deficit.

AIMS: Ventral pathway circuits are constituted by the interconnected brain areas that are distributed throughout the brain. These brain circuits are primarily involved in processing of object related information in brain. However, their role in object recognition memory (ORM) enhancement remains unknown. Here, we have studied on the implication of these circuits in ORM enhancement and in reversal of ORM deficit in aging. METHODS: The brain areas interconnected to ventral pathway circuits in rat brain were activated by an expression of a protein called regulator of G-protein signaling 14 of 414 amino acids (RGS14414). RGS14414 is an ORM enhancer and therefore used here as a gain-in-function tool. ORM test and immunohistochemistry, lesions, neuronal arborization, and knockdown studies were performed to uncover the novel function of ventral pathway circuits. RESULTS: An activation of each of the brain areas interconnected to ventral pathway circuits individually induced enhancement in ORM; however, same treatment in brain areas not interconnected to ventral pathway circuits produced no effect. Further study in perirhinal cortex (PRh), area V2 of visual cortex and frontal cortex (FrC), which are brain areas that have been shown to be involved in ORM and are interconnected to ventral pathway circuits, revealed that ORM enhancement seen after the activation of any one of the three brain areas was unaffected by the lesions in other two brain areas either individually in each area or even concurrently in both areas. This ORM enhancement in all three brain areas was associated to increase in structural plasticity of pyramidal neurons where more than 2-fold higher dendritic spines were observed. Additionally, we found that an activation of either PRh, area V2, or FrC not only was adequate but also was sufficient for the reversal of ORM deficit in aging rats, and the blockade of RGS14414 activity led to loss in increase in dendritic spine density and failure in reversal of ORM deficit. CONCLUSIONS: These results suggest that brain areas interconnected to ventral pathway circuits facilitate ORM enhancement by an increase in synaptic connectivity between the local brain area circuits and the passing by ventral pathway circuits and an upregulation in activity of ventral pathway circuits. In addition, the finding of the reversal of ORM deficit through activation of an interconnected brain area might serve as a platform for developing not only therapy against memory deficits but also strategies for other brain diseases in which neuronal circuits are compromised.

Encoding of Visual Objects in the Human Medial Temporal Lobe.

The human medial temporal lobe (MTL) plays a crucial role in recognizing visual objects, a key cognitive function that relies on the formation of semantic representations. Nonetheless, it remains unknown how visual information of general objects is translated into semantic representations in the MTL. Furthermore, the debate about whether the human MTL is involved in perception has endured for a long time. To address these questions, we investigated three distinct models of neural object coding-semantic coding, axis-based feature coding, and region-based feature coding-in each subregion of the human MTL, using high-resolution fMRI in two male and six female participants. Our findings revealed the presence of semantic coding throughout the MTL, with a higher prevalence observed in the parahippocampal cortex (PHC) and perirhinal cortex (PRC), while axis coding and region coding were primarily observed in the earlier regions of the MTL. Moreover, we demonstrated that voxels exhibiting axis coding supported the transition to region coding and contained information relevant to semantic coding. Together, by providing a detailed characterization of neural object coding schemes and offering a comprehensive summary of visual coding information for each MTL subregion, our results not only emphasize a clear role of the MTL in perceptual processing but also shed light on the translation of perception-driven representations of visual features into memory-driven representations of semantics along the MTL processing pathway.

Impaired perceptual discrimination of complex objects in older adults at risk for dementia.

Tau pathology accumulates in the perirhinal cortex (PRC) of the medial temporal lobe (MTL) during the earliest stages of the Alzheimer's disease (AD), appearing decades before clinical diagnosis. Here, we leveraged perceptual discrimination tasks that target PRC function to detect subtle cognitive impairment even in nominally healthy older adults. Older adults who did not have a clinical diagnosis or subjective memory complaints were categorized into "at-risk" (score <26; n = 15) and "healthy" (score ≥26; n = 23) groups based on their performance on the Montreal Cognitive Assessment. The task included two conditions known to recruit the PRC: faces and complex objects (greebles). A scene condition, known to recruit the hippocampus, and a size control condition that does not rely on the MTL were also included. Individuals in the at-risk group were less accurate than those in the healthy group for discriminating greebles. Performance on either the face or size control condition did not predict group status above and beyond that of the greeble condition. Visual discrimination tasks that are sensitive to PRC function may detect early cognitive decline associated with AD.

A role of frontal association cortex in long-term object recognition memory of objects with complex features in rats.

Perirhinal cortex is a brain area that has been considered crucial for the object recognition memory (ORM). However, with the use of an ORM enhancer named RGS14414 as gain-in-function tool, we show here that frontal association cortex and not the Perirhinal cortex is essential for the ORM of objects with complex features that consisted of detailed drawing on the object surface (complex ORM). An expression of RGS14414, in rat brain frontal association cortex, induced the formation of long-term complex ORM, whereas the expression of the same memory enhancer in Perirhinal cortex failed to produce this effect. Instead, RGS14414 expression in Perirhinal cortex caused the formation of ORM of objects with simple features that consisted of the shape of object (simple ORM). Further, a selective elimination of frontal association cortex neurons by treatment with an immunotoxin Ox7-SAP completely abrogated the formation of complex ORM. Thus, our results suggest that frontal association cortex plays a key role in processing of a high-order recognition memory information in brain.

Cardiorespiratory fitness is associated with cortical thickness of medial temporal brain areas associated with spatial cognition in young but not older adults.

Cardiorespiratory fitness has a potent effect on neurocognitive health, especially regarding the hippocampal memory system. However, less is known about the impact of cardiorespiratory fitness on medial temporal lobe extrahippocampal neocortical regions. Specifically, it is unclear how cardiorespiratory fitness modulates these brain regions in young adulthood and if these regions are differentially related to cardiorespiratory fitness in young versus older adults. The primary goal of this study was to investigate if cardiorespiratory fitness predicted medial temporal lobe cortical thickness which, with the hippocampus, are critical for spatial learning and memory. Additionally, given the established role of these cortices in spatial navigation, we sought to determine if cardiorespiratory fitness and medial temporal lobe cortical thickness would predict greater subjective sense of direction in both young and older adults. Cross-sectional data from 56 young adults (20-35 years) and 44 older adults (55-85 years) were included. FreeSurfer 6.0 was used to automatically segment participants' 3T T1-weighted images. Using hierarchical multiple regression analyses, we confirmed significant associations between greater cardiorespiratory fitness and greater left entorhinal, left parahippocampal, and left perirhinal cortical thickness in young, but not older, adults. Left parahippocampal cortical thickness interacted with age group to differentially predict subjective sense of direction in young and older adults. Young adults displayed a positive, and older adults a negative, correlation between left parahippocampal cortical thickness and sense of direction. Our findings extend previous work on the association between cardiorespiratory fitness and hippocampal subfield structure in young adults to left medial temporal lobe neocortical regions.

Computational models can distinguish the contribution from different mechanisms to familiarity recognition.

Familiarity is the strange feeling of knowing that something has already been seen in our past. Over the past decades, several attempts have been made to model familiarity using artificial neural networks. Recently, two learning algorithms successfully reproduced the functioning of the perirhinal cortex, a key structure involved during familiarity: Hebbian and anti-Hebbian learning. However, performance of these learning rules is very different from one to another thus raising the question of their complementarity. In this work, we designed two distinct computational models that combined Deep Learning and a Hebbian learning rule to reproduce familiarity on natural images, the Hebbian model and the anti-Hebbian model, respectively. We compared the performance of both models during different simulations to highlight the inner functioning of both learning rules. We showed that the anti-Hebbian model fits human behavioral data whereas the Hebbian model fails to fit the data under large training set sizes. Besides, we observed that only our Hebbian model is highly sensitive to homogeneity between images. Taken together, we interpreted these results considering the distinction between absolute and relative familiarity. With our framework, we proposed a novel way to distinguish the contribution of these familiarity mechanisms to the overall feeling of familiarity. By viewing them as complementary, our two models allow us to make new testable predictions that could be of interest to shed light on the familiarity phenomenon.

Perirhinal cortex is associated with fine-grained discrimination of conceptually confusable objects in Alzheimer's disease.

The perirhinal cortex (PrC) stands among the first brain areas to deteriorate in Alzheimer's disease (AD). This study tests to what extent the PrC is involved in representing and discriminating confusable objects based on the conjunction of their perceptual and conceptual features. To this aim, AD patients and control counterparts performed 3 tasks: a naming, a recognition memory, and a conceptual matching task, where we manipulated conceptual and perceptual confusability. A structural MRI of the antero-lateral parahippocampal subregions was obtained for each participant. We found that the sensitivity to conceptual confusability was associated with the left PrC volume in both AD patients and control participants for the recognition memory task, while it was specifically associated with the volume of the left PrC in AD patients for the conceptual matching task. This suggests that a decreased volume of the PrC is related to the ability to disambiguate conceptually confusable items. Therefore, testing recognition memory or conceptual matching of easily conceptually confusable items can provide a potential cognitive marker of PrC atrophy.

Stable wide-field voltage imaging for observing neuronal plasticity at the neuronal network level.

Plasticity is the key feature of our brain function. Specifically, plasticity of hippocampal synapses is critical for learning and memory. The functional properties of the neuronal circuit change as a result of synaptic plasticity. This review summarizes the use of voltage-sensitive dyes (VSDs) to examine neuronal circuit plasticity. We will discuss the significance of plastic changes in circuit function as well as the technical issue of using VSDs. Further, we will discuss the neural circuit level plasticity of the hippocampus caused by long-term potentiation and the entorhinal-perirhinal connection. This review article is an extended version of the Japanese article, Membrane Potential Imaging with Voltage-sensitive Dye (VSD) for Long-term Recording, published in SEIBUTSU BUTSURI Vol. 61, p. 404-408 (2021).

Dissociating distinct cortical networks associated with subregions of the human medial temporal lobe using precision neuroimaging.

Tract-tracing studies in primates indicate that different subregions of the medial temporal lobe (MTL) are connected with multiple brain regions. However, no clear framework defining the distributed anatomy associated with the human MTL exists. This gap in knowledge originates in notoriously low MRI data quality in the anterior human MTL and in group-level blurring of idiosyncratic anatomy between adjacent brain regions, such as entorhinal and perirhinal cortices, and parahippocampal areas TH/TF. Using MRI, we intensively scanned four human individuals and collected whole-brain data with unprecedented MTL signal quality. Following detailed exploration of cortical networks associated with MTL subregions within each individual, we discovered three biologically meaningful networks associated with the entorhinal cortex, perirhinal cortex, and parahippocampal area TH, respectively. Our findings define the anatomical constraints within which human mnemonic functions must operate and are insightful for examining the evolutionary trajectory of the MTL connectivity across species.

Excellent Interrater Reliability for Manual Segmentation of the Medial Perirhinal Cortex.

Objective: Evaluation of interrater reliability for manual segmentation of brain structures that are affected first by neurofibrillary tau pathology in Alzheimer's disease. Method: Medial perirhinal cortex, lateral perirhinal cortex, and entorhinal cortex were manually segmented by two raters on structural magnetic resonance images of 44 adults (20 men; mean age = 69.2 ± 10.4 years). Intraclass correlation coefficients (ICC) of cortical thickness and volumes were calculated. Results: Very high ICC values of manual segmentation for the cortical thickness of all regions (0.953-0.986) and consistently lower ICC values for volume estimates of the medial and lateral perirhinal cortex (0.705-0.874). Conclusions: The applied manual segmentation protocol allows different raters to achieve remarkably similar cortical thickness estimates for regions of the parahippocampal gyrus. In addition, the results suggest a preference for cortical thickness over volume as a reliable measure of atrophy, especially for regions affected by collateral sulcus variability (i.e., medial and lateral perirhinal cortex). The results provide a basis for future automated segmentation and collection of normative data.

Running throughout Middle-Age Keeps Old Adult-Born Neurons Wired.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Rhinal and hippocampal event-related potentials as epileptogenic zone markers in the pre-surgical evaluation of temporal epilepsies: a systematic review / Potenciais evocados rinais e hipocampais como marcadores da zona epileptogênica na avaliação pré-cirúrgica das epilepsias temporais: uma revisão sistemática

Abstract Background Cognitive event-related potentials (ERPs) allow for lateralization of the epileptogenic zone (EZ) to estimate the reserve of memory in the contralateral non-epileptogenic hemisphere, and to investigate the prognosis of temporal lobe seizure control in unilateral temporal lobe epilepsy (TLE). Objective To define the accuracy of cognitive evoked anterior mesial temporal lobe (AMTL-N400) and P600 potentials in detecting the epileptogenic zone in temporal lobe epilepsy (TLE), and second, to evaluate the possibility of using them as markers of cognitive outcome. Methods The systematic review using Medline/PubMed, Embase, and Lilacs database was conducted in September 2021. Only articles published in English from 1985 to June 2021 were included. We searched for studies with: (1) depth intracranial electroencephalography (iEEG) recordings analysis of rhinal and hippocampal activity (2) correlations between ERP results obtained in the mesial temporal regions (AMTL-N400 and P600) and the epileptogenic zone. Results Six out of the seven studies included in this review defined the laterality of the epileptogenic zone (EZ) during presurgical investigation using ERPs. One study showed that the contralateral AMTL-N400 predicts seizure control. Another study found correlation between the amplitudes of the right AMTL-N400 and postoperative memory performance. Conclusions There is evidence that the reduced amplitude of the AMTL-N400 has high accuracy in identifying the epileptogenic zone, as it does in estimating the extent of seizure control and memory impairment in postoperative patients.

Resumo Antecedentes Potenciais relacionados a eventos (PREs) cognitivos permitem a lateralização da zona epileptogênica (ZE), estimar a reserva de memória no hemisfério contralateral não-epileptogênico, e estimar o prognóstico pós-operatório em pacientes com epilepsia do lobo temporal (ELT) unilateral quanto ao controle de crises. Objetivo Definir a acurácia dos potenciais evocados cognitivos do lobo temporal mesial anterior (LTMA-N400) e P600 na detecção da zona epileptogênica na epilepsia do lobo temporal (ELT), além de avaliar a possibilidade de usá-los como marcadores de desfecho cognitivo. Métodos A revisão sistemática foi realizada em setembro de 2021 usando as bases de dados Medline/PubMed, Embase e Lilacs. Apenas artigos publicados em inglês no período entre 1985 e junho de 2021 foram incluídos. Buscamos estudos com: (1) análises dos registros de electroencefalografia intracraniana (EEGi) da atividade rinal e hipocampal (2) correlações entre os resultados de PREs obtidos nas regiões temporais mesiais (AMTL-N400 e P600) e a zona epileptogênica. Resultados Seis dos sete estudos incluídos nesta revisão definiram a lateralidade da zona epileptogênica (ZE) durante a investigação pré-cirúrgica usando PREs. Um estudo mostrou que o AMTL-N400 contralateral prediz o controle das crises. Outro estudo encontrou correlação entre as amplitudes do AMTL-N400 direito e o desempenho da memória pós-operatória. Conclusões Há evidências de que a amplitude reduzida do AMTL-N400 tem alta precisão na identificação da zona epileptogênica, assim como na estimativa do prognóstico quanto ao controle de crises a longo prazo e prejuízo da memória em pacientes submetidos à cirurgia ressectiva.

Perception and Memory in the Ventral Visual Stream and Medial Temporal Lobe.

Perception and memory are traditionally thought of as separate cognitive functions, supported by distinct brain regions. The canonical perspective is that perceptual processing of visual information is supported by the ventral visual stream, whereas long-term declarative memory is supported by the medial temporal lobe. However, this modular framework cannot account for the increasingly large body of evidence that reveals a role for early visual areas in long-term recognition memory and a role for medial temporal lobe structures in high-level perceptual processing. In this article, we review relevant research conducted in humans, nonhuman primates, and rodents. We conclude that the evidence is largely inconsistent with theoretical proposals that draw sharp functional boundaries between perceptual and memory systems in the brain. Instead, the weight of the empirical findings is best captured by a representational-hierarchical model that emphasizes differences in content, rather than in cognitive processes within the ventral visual stream and medial temporal lobe.

Double dissociation of perirhinal nicotinic acetylcholine receptors and dopamine D2 receptors in modulation of object memory consolidation by nicotine, cocaine and their conditioned stimuli.

There are indications that drug conditioned stimuli (CS) may activate neurochemical systems of memory modulation that are activated by the drugs themselves. To directly test this hypothesis, a cholinergic nicotinic receptor antagonist (mecamylamine; MEC: 0, 10 or 30 µg/side) and a dopamine D2 receptor antagonist (l-741,626: 0, 0.63, 2.5 µg/side) were infused in the perirhinal cortex (PRh) to block modulation of object recognition memory consolidation induced by 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs. To establish these CSs, male Sprague-Dawley rats were confined for 2 h in a chamber, the CS+, after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, and in another chamber, the CS-, after injections of vehicle. This was repeated over 10 days (5 drug/CS+ and 5 vehicle/CS- pairings in total). It was found that the memory enhancing action of post-sample nicotine was blocked by intra-PRh infusions of both MEC doses, and 30 µg/side MEC also blocked the memory enhancing action of the nicotine CS. Interestingly, intra-PRh MEC did not block the memory enhancing effect of cocaine, nor that of the cocaine CS. In contrast, the memory enhancing action of post-sample cocaine administration was blocked by both l-741,626 doses, and 2.5 µg/side also blocked the effect of the cocaine CS, but not the memory effects of nicotine or of the nicotine CS. This functional double dissociation strongly indicates that drug CSs modulate memory consolidation by activating neural systems that are activated by the drugs themselves.

Endocytosis is required for consolidation of pattern-separated memories in the perirhinal cortex.

Introduction: The ability to separate similar experiences into differentiated representations is proposed to be based on a computational process called pattern separation, and it is one of the key characteristics of episodic memory. Although pattern separation has been mainly studied in the dentate gyrus of the hippocampus, this cognitive function if thought to take place also in other regions of the brain. The perirhinal cortex is important for the acquisition and storage of object memories, and in particular for object memory differentiation. The present study was devoted to investigating the importance of the cellular mechanism of endocytosis for object memory differentiation in the perirhinal cortex and its association with brain-derived neurotrophic factor, which was previously shown to be critical for the pattern separation mechanism in this structure. Methods: We used a modified version of the object recognition memory task and intracerebral delivery of a peptide (Tat-P4) into the perirhinal cortex to block endocytosis. Results: We found that endocytosis is necessary for pattern separation in the perirhinal cortex. We also provide evidence from a molecular disconnection experiment that BDNF and endocytosis-related mechanisms interact for memory discrimination in both male and female rats. Discussion: Our experiments suggest that BDNF and endocytosis are essential for consolidation of separate object memories and a part of a time-restricted, protein synthesis-dependent mechanism of memory stabilization in Prh during storage of object representations.