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Early stages of Alzheimer's disease (AD) are associated with volume reductions in specific subregions of the medial temporal lobe (MTL). Using a manual segmentation method-the Olsen-Amaral-Palombo (OAP) protocol-previous work in healthy older adults showed that reductions in grey matter volumes in MTL subregions were associated with lower scores on the Montreal Cognitive Assessment (MoCA), suggesting atrophy may occur prior to diagnosis of mild cognitive impairment, a condition that often progresses to AD. However, current "gold standard" manual segmentation methods are labour intensive and time consuming. Here, we examined the utility of Automatic Segmentation of Hippocampal Subfields (ASHS) to detect volumetric differences in MTL subregions of healthy older adults who varied in cognitive status as determined by the MoCA. We trained ASHS on the OAP protocol to create the ASHS-OAP atlas and then examined how well automated segmentation replicated manual segmentation. Volumetric measures obtained from the ASHS-OAP atlas were also contrasted against those from the ASHS-PMC atlas, a widely used atlas provided by the ASHS team. The pattern of volumetric results was similar between the ASHS-OAP atlas and manual segmentation for anterolateral entorhinal cortex and perirhinal cortex, suggesting that ASHS-OAP is a viable alternative to current manual segmentation methods for detecting group differences based on cognitive status. Although ASHS-OAP and ASHS-PMC produced varying volumes for most regions of interest, they both identified early signs of neurodegeneration in CA2/CA3/DG and identified marginal differences in entorhinal cortex. Our findings highlight the utility of automated segmentation methods but still underscore the need for a unified and harmonized MTL segmentation atlas.

IntroductionThe understanding of the pathological events in Alzheimer's disease (AD) has advanced dramatically, but the successful translation from rodent models into efficient human therapies is still problematic.MethodsTo examine how tau pathology can develop in the primate brain, we injected 12 macaques with a dual tau mutation (P301L/S320F) into the entorhinal cortex (ERC). An investigation was performed using high-resolution microscopy, magnetic resonance imaging (MRI), positron emission tomography (PET), and fluid biomarkers to determine the temporal progression of the pathology 3 and 6 months after the injection.ResultsUsing quantitative microscopy targeting markers for neurodegeneration and neuroinflammation, as well as fluid and imaging biomarkers, we detailed the progression of misfolded tau spreading and the consequential inflammatory response induced by glial cells.DiscussionBy combining the analysis of several in vivo biomarkers with extensive brain microscopy analysis, we described the initial steps of misfolded tau spreading and neuroinflammation in a monkey model highly translatable to AD patients.HighlightsDual tau mutation delivery in the entorhinal cortex induces progressive tau pathology in rhesus macaques. Exogenous human 4R-tau coaptates monkey 3R-tau during transneuronal spread, in a prion-like manner. Neuroinflammatory response is coordinated by microglia and astrocytes in response to tau pathology, with microglia targeting early tau pathology, while astrocytes engaged later in the progression, coincident with neuronal death. Monthly collection of CSF and plasma revealed a profile of changes in several AD core biomarkers, reflective of neurodegeneration and neuroinflammation as early as 1 month after injection.

Information processing and memorizing in the brain take place in a neural network consisting of neurons connected with each other by synapses. Meanwhile, the neural network is immersed in a common electrochemical environment with global parameters regulating the overall functions, which is barely discussed in neuromorphic devices. In this study, organic/inorganic hybrid transistors with sodium alginate as the gate dielectric layer and indium tin oxide as the channel were successfully prepared. We have not only simulated the basic properties of synapses in a single device, but, on top of that, also simulated the global regulation of information processing in the brain due to the incorporation of global grids, achieving excitatory and inhibitory synaptic weight. Moreover, the construction of a 3 × 3 synaptic array enables image learning and memorizing functions. These results demonstrate the significant advantages of electrolyte-gated transistors in enabling complex neural network connectivity and offer a promising opportunity for future artificial synapses. [ABSTRACT FROM AUTHOR]

The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimers disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing.

The temporal lobe of the human brain contains the entorhinal cortex (EC). This region of the brain is a highly interconnected integrative hub for sensory and spatial information; it also has a key role in episodic memory formation and is the main source of cortical hippocampal inputs1-4. The human EC continues to develop during childhood5, but neurogenesis and neuronal migration to the EC are widely considered to be complete by birth. Here we show that the human temporal lobe contains many young neurons migrating into the postnatal EC and adjacent regions, with a large tangential stream persisting until the age of around one year and radial dispersal continuing until around two to three years of age. By contrast, we found no equivalent postnatal migration in rhesus macaques (Macaca mulatta). Immunostaining and single-nucleus RNA sequencing of ganglionic eminence germinal zones, the EC stream and the postnatal EC revealed that most migrating cells in the EC stream are derived from the caudal ganglionic eminence and become LAMP5+RELN+ inhibitory interneurons. These late-arriving interneurons could continue to shape the processing of sensory and spatial information well into postnatal life, when children are actively interacting with their environment. The EC is one of the first regions of the brain to be affected in Alzheimers disease, and previous work has linked cognitive decline to the loss of LAMP5+RELN+ cells6,7. Our investigation reveals that many of these cells arrive in the EC through a major postnatal migratory stream in early childhood.

The olfactory system plays crucial roles in perceiving and interacting with their surroundings. Previous studies have deciphered basic odor perceptions, but how information processing in the olfactory system is associated with learning and memory is poorly understood. In this review, we summarize recent studies on the anatomy and functional dynamics of the mouse olfactory learning pathway, focusing on how neuronal circuits in the olfactory bulb (OB) and olfactory cortical areas integrate odor information in learning. We also highlight in vivo evidence for the role of the lateral entorhinal cortex (LEC) in olfactory learning. Altogether, these studies demonstrate that brain regions throughout the olfactory system are critically involved in forming and representing learned knowledge. The role of olfactory areas in learning and memory, and their susceptibility to dysfunction in neurodegenerative diseases, necessitate further research.

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging owing to the fragile nature of fear extinction, for which the ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low-gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells sufficed for fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhanced the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low-gamma-band oscillations that facilitate fear extinction. Finally, application of low-gamma DBS and tACS to a mouse model with persistent PTSD showed potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be stimulated for therapy to remove traumatic memory trace. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) utilizes radiotracers like [18F]fluorodeoxyglucose (FDG) to measure brain activity in health and disease. Performing behavioral tasks between the FDG injection and the PET scan allows the FDG signal to reflect task-related brain networks. Building on this principle, we introduce an approach called behavioral task–associated PET (beta-PET) consisting of two scans: the first after a mouse is familiarized with a conditioning chamber, and the second upon recall of contextual threat. Associative threat conditioning occurs between scans. Beta-PET focuses on brain regions encoding threat memory (e.g., amygdala, prefrontal cortex) and contextual aspects (e.g., hippocampus, subiculum, entorhinal cortex). Our results show that beta-PET identifies a biologically defined network encoding contextual threat memory and its uncoupling in a mouse model of long sepsis. Moreover, machine learning algorithms (linear logistic regression) and ordinal trends analysis demonstrate that beta-PET robustly predicts the behavioral defense response and its breakdown during long sepsis. [ABSTRACT FROM AUTHOR]

The epileptogenic network in temporal lobe epilepsy (TLE) contains structures of the primary and secondary olfactory cortex such as the piriform and entorhinal cortex, the amygdala, and the hippocampus. Olfactory auras and olfactory dysfunction are relevant symptoms of TLE. This study aims to characterize olfactory function in TLE using olfactory testing and olfactory functional magnetic resonance imaging (fMRI). We prospectively enrolled 20 individuals with unilateral TLE (age 45 ± 20 years [mean ± SD], 65% female, 90% right‐handed) and 20 healthy individuals (age 33 ± 15 years [mean ± SD], 35% female, 90% right‐handed). In the TLE group, the presumed seizure onset zone was left‐sided in 75%; in 45% of the individuals with TLE limbic encephalitis was the presumed etiology; and 15% of the individuals with TLE reported olfactory auras. Olfactory function was assessed with a Screening Sniffin' Sticks Test (Burkhart, Wedel, Germany) during a pre‐assessment. During a pre‐testing, all individuals were asked to rate the intensity, valence, familiarity, and associated memory of five different odors (eugenol, vanillin, phenethyl alcohol, decanoic acid, valeric acid) and a control solution. During the fMRI experiment, all individuals repeatedly smelled eugenol (positively valenced odor), valeric acid (negatively valenced odor), and the control solution and were asked to rate odor intensity on a five‐point Likert scale. We acquired functional EPI sequences and structural images (T1, T2, FLAIR). Compared to healthy individuals, individuals with TLE rated the presented odors as more neutral (two‐sided Mann–Whitney U tests, FDR‐p < 0.05) and less familiar (two‐sided Mann–Whitney U tests, FDR‐p < 0.05). fMRI data analysis revealed a reduced response contrast in secondary olfactory areas (e.g., hippocampus) connected to the limbic system when comparing eugenol and valeric acid in individuals with TLE when compared with healthy individuals. However, no lateralization effect was obtained when calculating a lateralization index by the number of activated voxels in the olfactory system (two‐sided Mann–Whitney U test; U = 176.0; p = 0.525). TLE is characterized by olfactory dysfunction and associated with hypoactivation of secondary olfactory structures connected to the limbic system. These findings contribute to our understanding of the pathophysiology of TLE. This study was preregistered on OSF Registries (www.osf.io). [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) has been suggested to increase the risk of memory decline and Alzheimer's disease (AD), the main cause of dementia in the elderly. However, direct evidence about whether COVID‐19 induces AD‐like neuropathological changes in the brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation of hyperphosphorylated tau protein in the hippocampus and medial entorhinal cortex within 4–13 months post clinically recovery from acute COVID‐19, together with prolonged activation of glia cells and increases in inflammatory factors, even though no SARS‐COV‐2 invasion was detected in these regions. By contrast, COVID‐19 did not change beta‐amyloid deposition and hippocampal neuron number, and had limited effects on AD‐related pathological phenotypes in olfactory circuits including olfactory bulb, anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. These results provide neuropathological evidences linking COVID‐19 with prognostic increase of risk for AD. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) and electromagnetic fields (EMF) have been extensively studied for their roles in neurobiology, particularly in regulating cerebral functions and synaptic plasticity. This study investigates the impact of EMFs on NO modulation and its subsequent effects on neurodevelopment, building upon prior research examining EMF exposure's consequences on Wistar albino rats. Rats were exposed perinatally to either tap water, 1 g/L of L‐arginine (LA) or 0.5 g/L of N‐methylarginine (NMA). Half of the rats in each group were also exposed to a 7‐Hz square‐wave EMF at three separate intensities (5, 50 and 500 nT) for 2–14 days following birth. Animals were allowed to develop, and their brains were harvested later in adulthood (mean age = 568.17 days, SD = 162.73). Histological analyses were used to elucidate structural changes in key brain regions. All brains were stained with Toluidine Blue O (TBO), enabling the visualization of neurons. Neuronal counts were then conducted in specific regions of interest (e.g. hippocampus, cortices, amygdala and hypothalamus). Histological analyses revealed significant alterations in neuronal density in specific brain regions, particularly in response to EMF exposure and pharmacological interventions. Notable findings include a main EMF exposure effect where increased neuronal counts were observed in the secondary somatosensory cortex under low EMF intensities (p < 0.001) and sex‐specific responses in the hippocampus, where a significant increase in neuronal counts was observed in the left CA3 region in female rats exposed to EMF compared to unexposed females (t(18) = 2.371, p = 0.029). Additionally, a significant increase in neuronal counts in the right entorhinal cortex was seen in male rats exposed to EMF compared to unexposed males (t(18) = 2.216, p = 0.040). These findings emphasize the complex interaction among sex, EMF exposure and pharmacological agents on neuronal dynamics across brain regions, highlighting the need for further research to identify underlying mechanisms and potential implications for cognitive function and neurological health in clinical and environmental contexts. [ABSTRACT FROM AUTHOR]

The hippocampus of vertebrates and the central complex of insects are both engaged by navigational tasks that require spatial memory or inference. The hippocampus builds flexible place maps of both real and abstract spaces. The insect central complex comprises ordered arrays of cells that are well suited to encode and compute with vectors. Both the hippocampus and central complex feature heading-direction signals based on ring attractor networks, and both structures receive input from partially segregated 'where' and 'what' pathways. Current understanding of the differences between vertebrate and invertebrate navigational systems might reflect ecological, historical, and methodological differences. Future comparative approaches will help to reveal fundamental relationships between brain circuits and navigational and cognitive abilities across species. Across species, navigation is crucial for finding both resources and shelter. In vertebrates, the hippocampus supports memory-guided goal-directed navigation, whereas in arthropods the central complex supports similar functions. A growing literature is revealing similarities and differences in the organization and function of these brain regions. We review current knowledge about how each structure supports goal-directed navigation by building internal representations of the position or orientation of an animal in space, and of the location or direction of potential goals. We describe input pathways to each structure – medial and lateral entorhinal cortex in vertebrates, and columnar and tangential neurons in insects – that primarily encode spatial and non-spatial information, respectively. Finally, we highlight similarities and differences in spatial encoding across clades and suggest experimental approaches to compare coding principles and behavioral capabilities across species. Such a comparative approach can provide new insights into the neural basis of spatial navigation and neural computation. [ABSTRACT FROM AUTHOR]

Background: Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer's disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a 'primary age-related tauopathy' (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon's horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART. Objective: To test the 'definite PART' hypothesis. Methods: We used AT8-immunohistochemistry in 100μm sections to examine the EC, transentorhinal cortex (TRE), and Ammon's horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males). Results: 100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD. Conclusions: Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD. [ABSTRACT FROM AUTHOR]

In the entorhinal cortex (EC), attempts have been made to identify the human homologue regions of the medial (MEC) and lateral (LEC) subregions using either functional magnetic resonance imaging (fMRI) or diffusion tensor imaging (DTI). However, there are still discrepancies between entorhinal subdivisions depending on the choice of connectivity seed regions and the imaging modality used. While DTI can be used to follow the white matter tracts of the brain, fMRI can identify functionally connected brain regions. In this study, we used both DTI and resting‐state fMRI in 103 healthy adults to investigate both structural and functional connectivity between the EC and associated cortical brain regions. Differential connectivity with these regions was then used to predict the locations of the human homologues of MEC and LEC. Our results from combining DTI and fMRI support a subdivision into posteromedial (pmEC) and anterolateral (alEC) EC and reveal a confined border between the pmEC and alEC. Furthermore, the EC subregions obtained by either imaging modality showed similar distinct whole‐brain connectivity profiles. Optimizing the delineation of the human homologues of MEC and LEC with a combined, cross‐validated DTI‐fMRI approach allows to define a likely border between the two subdivisions and has implications for both cognitive and translational neuroscience research. [ABSTRACT FROM AUTHOR]

A key question for understanding the function of the hippocampus in memory is how information is recalled from the hippocampus to the neocortex. This was investigated in a neuronal network model of the hippocampal system in which "What" and "Where" neuronal firing rate vectors were applied to separate neocortical modules, which then activated entorhinal cortex "What" and "Where" modules, then the dentate gyrus, then CA3, then CA1, then the entorhinal cortex, and then the backprojections to the neocortex. A rate model showed that the whole system could be trained to recall "Where" in the neocortex from "What" applied as a retrieval cue to the neocortex, and could in principle be trained up towards the theoretical capacity determined largely by the number of synapses onto any one neuron divided by the sparseness of the representation. The trained synaptic weights were then imported into an integrate‐and‐fire simulation of the same architecture, which showed that the time from presenting a retrieval cue to a neocortex module to recall the whole memory in the neocortex is approximately 100 ms. This is sufficiently fast for the backprojection synapses to be trained onto the still active neocortical neurons during storage of the episodic memory, and this is needed for recall to operate correctly to the neocortex. These simulations also showed that the long loop neocortex–hippocampus–neocortex that operates continuously in time may contribute to complete recall in the neocortex; but that this positive feedback long loop makes the whole dynamical system inherently liable to a pathological increase in neuronal activity. Important factors that contributed to stability included increased inhibition in CA3 and CA1 to keep the firing rates low; and temporal adaptation of the neuronal firing and of active synapses, which are proposed to make an important contribution to stabilizing runaway excitation in cortical circuits in the brain. [ABSTRACT FROM AUTHOR]

The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T‐maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T‐maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off‐response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T‐maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory. [ABSTRACT FROM AUTHOR]

It has been hypothesized that differential processing occurs along the longitudinal (anterior–posterior) axis of the hippocampus. One hypothesis is that spatial memory (during both encoding and retrieval) is associated with the posterior hippocampus. An alternative hypothesis is that memory encoding (either spatial or nonspatial) is associated with the anterior hippocampus and memory retrieval is associated with the posterior hippocampus. Of importance, during spatial memory encoding, the spatial–posterior hypothesis predicts posterior hippocampal involvement, whereas the encoding–retrieval hypothesis predicts anterior hippocampal involvement. To distinguish between these hypotheses, we conducted a coordinate‐based fMRI activation likelihood estimation (ALE) meta‐analysis of 26 studies (with a total of 435 participants) that reported hippocampal activity during spatial memory encoding and/or spatial memory retrieval. Both spatial memory encoding and spatial memory retrieval produced extensive activity along the longitudinal axis of the hippocampus as well as the entorhinal cortex, the perirhinal cortex, and the parahippocampal cortex. Critically, the contrast of spatial memory encoding and spatial memory retrieval produced activations in both the anterior hippocampus and the posterior hippocampus. That spatial memory encoding produced activity in both the anterior and posterior hippocampus can be taken to reject strict forms of the spatial–posterior hypothesis, which stipulates that all forms of spatial memory produce activity in the posterior hippocampus, and the encoding–retrieval hypothesis, which stipulates that all forms of encoding versus retrieval produce activity in only the anterior hippocampus. Our results indicate that spatial memory encoding can involve the anterior hippocampus and the posterior hippocampus. [ABSTRACT FROM AUTHOR]

The entorhinal cortex (EC) and hippocampal (HC) connectivity is the main source of episodic memory formation and consolidation. The entorhinal– hippocampal (EC-HC) connection is classified as canonically glutamatergic and, more recently, has been characterized as a non-canonical GABAergic connection. Recent evidence shows that both EC and HC receive inputs from dopaminergic, cholinergic, and noradrenergic projections that modulate the mnemonic processes linked to the encoding and consolidation of memories. In the present review, we address the latest findings on the EC-HC connectivity and the role of neuromodulations during the mnemonic mechanisms of encoding and consolidation of memories and highlight the value of the cross-species approach to unravel the underlying cellular mechanisms known. Furthermore, we discuss how EC-HC connectivity early neurodegeneration may contribute to the dysfunction of episodic memories observed in aging and Alzheimer’s disease (AD). Finally, we described how exercise may be a fundamental tool to prevent or decrease neurodegeneration. [ABSTRACT FROM AUTHOR]

Head‐direction (HD) cells are a fundamental component in the hippocampal‐entorhinal circuit for spatial navigation and help maintain an internal sense of direction to anchor the orientation in space. A classical HD cell robustly increases its firing rate when the head is oriented toward a specific direction, with each cell tuned to only one direction. Although unidirectional HD cells are reported broadly across multiple brain regions, computation modelling has predicted the existence of multiple equilibrium states of HD network, which has yet to be proven. In this study, a novel HD variant of bipolar HD cells in the medial entorhinal cortex (MEC) are identified that exhibit stable double‐peaked directional tuning properties. The bipolar patterns remain stable in the darkness and across environments of distinct geometric shapes. Moreover, bipolar HD cells co‐rotate coherently with unipolar HD cells to anchor the external visual cue. The discovery reveals a new spatial cell type of bipolar HD cells, whose unique activity patterns may comprise a potential building block for a sophisticated local neural circuit configuration for the internal representation of direction. These findings may contribute to the understanding of how the brain processes spatial information by shedding light on the role of bipolar HD cells in this process. [ABSTRACT FROM AUTHOR]

During non-rapid eye movement (NREM) sleep, neural ensembles in the entorhinal-hippocampal circuit responsible for encoding recent memories undergo reactivation to facilitate the process of memory consolidation. This reactivation is widely acknowledged as pivotal for the formation of stable memory and its impairment is closely associated with memory dysfunction. To date, the neural mechanisms driving the reactivation of neural ensembles during NREM sleep remain poorly understood. Here, we show that the neural ensembles in the medial entorhinal cortex (MEC) that encode spatial experiences exhibit reactivation during NREM sleep. Notably, this reactivation consistently coincides with isolated theta waves. In addition, we found that the nucleus reuniens (RE) in the midline thalamus exhibits typical theta waves during NREM sleep, which are highly synchronized with those occurring in the MEC in male mice. Closed-loop optogenetic inhibition of the RE-MEC pathway specifically suppressed these isolated theta waves, resulting in impaired reactivation and compromised memory consolidation following a spatial memory task in male mice. The findings suggest that theta waves originating from the ventral midline thalamus play a role in initiating memory reactivation and consolidation during sleep. The neural mechanisms of memory consolidation during sleep are poorly understood. Here the authors show that isolated theta waves from nucleus reuniens initiate neural ensemble reactivation during sleep required for spatial memory consolidation. [ABSTRACT FROM AUTHOR]

Initial symptoms of neurodegenerative diseases are often defined by the loss of the most vulnerable neural populations specific to each disorder. In the early stages of Alzheimer's disease, vulnerable circuits in the temporal lobe exhibit diminished activity prior to overt degeneration. It remains unclear whether these functional changes contribute to regional vulnerability or are simply a consequence of pathology. We previously found that entorhinal neurons in the temporal cortex undergo cell death following transient suppression of electrical activity, suggesting a causal role for activity disruption in neurodegeneration. Here we demonstrate that electrical arrest of this circuit stimulates the injury‐response transcription factor c‐Jun. Entorhinal silencing induces transcriptional changes consistent with c‐Jun activation that share characteristics of gene signatures in other neuronal populations vulnerable to Alzheimer's disease. Despite its established role in the neuronal injury response, inhibiting c‐Jun failed to ameliorate entorhinal degeneration following activity disruption. Finally, we present preliminary evidence of integrated stress response activity that may serve as an alternative hypothesis to what drives entorhinal degeneration after silencing. Our data demonstrate that c‐Jun is activated in response to neuronal silencing in the entorhinal cortex but is decoupled from subsequent neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Patients with unruptured intracranial aneurysms (UIAs) often experience emotional changes and cognitive impairments. However, the specific mechanisms underlying these impairments are still not fully understood. Methods: In the present study, voxel-based morphometry (VBM) and surfacebased morphometry (SBM) were employed to investigate structural alterations in 49 patients diagnosed with UIAs compared with 50 healthy controls. Additionally, this study aimed to analyze the correlations among cortical morphological indices, cerebral blood perfusion values and neuropsychological test results. Results: Compared with control group, UIA patients exhibited increased gray matter volume in the right anterior orbitofrontal cortex and decreased gray matter volume in the left thalamus pulvinar and hippocampus. Furthermore, the fractal dimension was lower in the right postcentral gyrus and entorhinal cortex. The cerebral perfusion values in the abnormal brain regions demonstrated a downward trend, which was associated with a reduction in gray matter volume in the left thalamus pulvinar and hippocampus, elevated anxiety levels and impaired executive function. Conclusion: UIA patients are prone to cognitive impairment and emotional dysregulation, which are accompanied by subtle changes in local gray matter volume and decreases in fractal dimension and cerebral blood flow. These findings provide new insights into the potential mechanisms underlying the cognitive impairment observed in UIA patients. [ABSTRACT FROM AUTHOR]

High‐frequency oscillatory activity in cognition‐related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory. [ABSTRACT FROM AUTHOR]

Central nervous system neurons manifest a rich diversity of selectivity profiles--whose precise role is still poorly understood. Following the striking success of artificial networks, a major debate has emerged concerning their usefulness in explaining neuronal properties. Here we propose that finding parallels between artificial and neuronal networks is informative precisely because these systems are so different from each other. Our argument is based on an extension of the concept of convergent evolution--well established in biology--to the domain of artificial systems. Applying this concept to different areas and levels of the cortical hierarchy can be a powerful tool for elucidating the functional role of well-known cortical selectivities. Importantly, we further demonstrate that such parallels can uncover novel functionalities by showing that grid cells in the entorhinal cortex can be modeled to function as a set of basis functions in a lossy representation such as the well-known JPEG compression. Thus, contrary to common intuition, here we illustrate that finding parallels with artificial systems provides novel and informative insights, particularly in those cases that are far removed from realistic brain biology. [ABSTRACT FROM AUTHOR]

Aging is associated with progressive brain atrophy and declines in learning and memory, often attributed to hippocampal or cortical deterioration. The role of brain-derived neurotrophic factor (BDNF) in modulating the structural and functional changes in the brain and visual system, particularly in relation to BDNF Val66Met polymorphism, remains underexplored. In this present cross-sectional observational study, we aimed to assess the effects of BDNF polymorphism on brain structural integrity, cognitive function, and visual pathway alterations. A total of 108 older individuals with no evidence of dementia and a mean (SD) age of 67.3 (9.1) years were recruited from the Optic Nerve Decline and Cognitive Change (ONDCC) study cohort. The BDNF Met allele carriage had a significant association with lower entorhinal cortex volume (6.7% lower compared to the Val/Val genotype, P = 0.02) and posterior cingulate volume (3.2% lower than the Val/Val group, P = 0.03), after adjusting for confounding factors including age, sex and estimated total intracranial volumes (eTIV). No significant associations were identified between the BDNF Val66Met genotype and other brain volumetric or diffusion measures, cognitive performances, or vision parameters except for temporal retinal nerve fibre layer thickness. Small but significant correlations were found between visual structural and functional, cognitive, and brain morphological metrics. Our findings suggest that carriage of BDNF Val66Met polymorphism is associated with lower entorhinal cortex and posterior cingulate volumes and may be involved in modulating the cortical morphology along the aging process. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) has demonstrated potential in mitigating Alzheimer's disease (AD). However, the invasive nature of DBS presents challenges for its application. The olfactory bulb (OB), showing early AD‐related changes and extensive connections with memory regions, offers an attractive entry point for intervention, potentially restoring normal activity in deteriorating memory circuits. Aims: Our study examined the impact of electrically stimulating the OB on working memory as well as pathological and electrophysiological alterations in the OB, medial prefrontal cortex, hippocampus, and entorhinal cortex in amyloid beta (Aβ) AD model rats. Methods: Male Wistar rats underwent surgery for electrode implantation in brain regions, inducing Alzheimer's‐like disease. Bilateral olfactory bulb (OB) electrical stimulation was performed for 1 hour daily to the OB of stimulation group animals for 18 consecutive days, followed by the evaluations of histological, behavioral, and local field potential signal processing. Results: OB stimulation counteracted Aβ plaque accumulation and prevented AD‐induced working memory impairments. Furthermore, it prompted an increase in power across diverse frequency bands and enhanced functional connectivity, particularly in the gamma band, within the investigated regions during a working memory task. Conclusion: This preclinical investigation highlights the potential of olfactory pathway‐based brain stimulation to modulate the activity of deep‐seated memory networks for AD treatment. Importantly, the accessibility of this pathway via the nasal cavity lays the groundwork for the development of minimally invasive approaches targeting the olfactory pathway for brain modulation. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study is to examine the alterations in subcortical brain volume and cortical thickness among individuals diagnosed with Type 2 diabetes mellitus (T2DM) through the application of morphometry techniques and, additionally, to investigate the potential association between these modifications and insulin resistance (IR). Materials and methods: The present cross‐sectional study comprised a total of 121 participants (n = 48 with healthy controls [HCs] and n = 73 with T2DM) who were recruited and underwent a battery of cognitive testing and structural magnetic resonance imaging (MRI). FreeSurfer was used to process the MRI data. Analysis of covariance compared discrepancies in cortical thickness and subcortical brain volume between T2DM and HCs, adjusting for the potential confounding effects of gender, age, education, and body mass index (BMI). Exploratory partial correlations investigated links between IR and brain structure in T2DM participants. Results: Compared with HCs, individuals with T2DM demonstrated a cortical thickness decrease in the right caudal middle frontal gyrus, right pars opercularis, left precentral gyrus, and bilateral superior frontal gyrus. Furthermore, this study for T2DM found that the severity of IR was inversely related to the volume of the left putamen and left hippocampus, as well as the thickness of the left pars orbitalis, left pericalcarine, right entorhinal area, and right rostral anterior cingulate gyrus. Conclusion: The evidence for structural brain changes in T2DM was observed, and alterations in cortical thickness were concentrated in the frontal lobes. Correlations between IR and frontal cortical thinning may serve as a potential neuroimaging marker of T2DM and lead to various diabetes‐related brain complications. [ABSTRACT FROM AUTHOR]

Glial fibrillary acidic protein (GFAP) immunohistochemistry was investigated in the developing human brain using two measures; the number of GFAP‐positive cells (density, GFAP+/mm2), and a reactivity score (R‐score), which we recently introduced to indicate astrogliosis, with scores ≥120 indicative of pathological processes. The primary aim was to report on GFAP expression and cell soma size in 26 microscopically defined regions of the amygdala, basal ganglia, cerebellum, hippocampus and medulla, and to determine whether they are affected by postconceptional age (PCA) from 40 to 83 weeks. The secondary aim was to determine if GFAP expression differs according to the classification of sudden infant death syndrome (SIDS) as opposed to infant deaths of known causes, or for the presence of major SIDS risk factors of male sex, cigarette smoke exposure, upper respiratory tract infection (URTI), bed‐sharing and prone sleeping. The cerebellar molecular layer was void of GFAP+ cells, while the internal granular layer (IGL) had the highest density, with >60% of infants having an R‐Score >120. GFAP expression decreased with increasing PCA in the entorhinal and temporal cortex, subiculum and regions of the cerebellum and medulla. GFAP cell soma size corresponded with astrogliosis score and no effect of PCA was evident. Various region‐dependent GFAP expressional differences were seen according to SIDS classification and the risk factors studied. The findings indicate that the density of GFAP decreases in specific regions of the brain within the first year of postnatal development, and that reactive astrocytes are common, particularly within the early postnatal months. [ABSTRACT FROM AUTHOR]

The hippocampus is considered essential for several forms of declarative memory, including spatial and social memory. Despite the extensive research of the classic subfields of the hippocampus, the fasciola cinerea (FC)—a medially located structure within the hippocampal formation—has remained largely unexplored. In the present study, we performed a morpho‐functional characterization of principal neurons in the mouse FC. Using in vivo juxtacellular recording of single neurons, we found that FC neurons are distinct from neighboring CA1 pyramidal cells, both morphologically and electrophysiologically. Specifically, FC neurons displayed non‐pyramidal morphology and granule cell‐like apical dendrites. Compared to neighboring CA1 pyramidal neurons, FC neurons exhibited more regular in vivo firing patterns and a lower tendency to fire spikes at short interspike intervals. Furthermore, tracing experiments revealed that the FC receives inputs from the lateral but not the medial entorhinal cortex and CA3, and it provides a major intra‐hippocampal projection to the septal CA2 and sparser inputs to the distal CA1. Overall, our results indicate that the FC is a morphologically and electrophysiologically distinct subfield of the hippocampal formation; given the established role of CA2 in social memory and seizure initiation, the unique efferent intra‐hippocampal connectivity of the FC points to possible roles in social cognition and temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

5 mC methylation and hydroxymethylation (5hmC) are associated with Alzheimer's disease (AD). However, previous studies were limited by the absence of a 5hmC calculation. This study aims to find AD associated predictors and potential therapeutic chemicals using bioinformatics approach integrating 5 mC, 5hmC, and expression changes, and an AD mouse model. Gene expression microarray and 5 mC and 5hmC sequencing datasets were downloaded from GEO repository. 142 AD and 52 normal entorhinal cortex specimens were enrolled. Data from oxidative bisulfite sequencing (oxBS)-treated samples, which represent only 5 mC, were used to calculate 5hmC level. Functional analyses, random forest supervised classification and methylation validation were applied. Potential chemicals were predicted by CMap. Morris water maze, Y maze and novel object recognition behavior tests were performed using FAD4T AD mice model. Cortex and hippocampus tissues were isolated for immunohistochemical staining. C1QTNF5, UBD, ZFP106, NEDD1, AKT3, and MBP genes involving 13 promoter CpG sites with 5mc, 5hmC methylation and expression difference were identified. AKT3 and MBP were down-regulated in both patients and mouse model. Three CpG sites in AKT3 and MBP showed significant methylation difference on validation. FAD4T AD mice showed recession in brain functions and lower AKT3 expression in both cortex and hippocampus. Ten chemicals were predicted as potential treatments for AD. AKT3 and MBP may be associated with AD pathology and could serve as biomarkers. The ten predicted chemicals might offer new therapeutic approaches. Our findings could contribute to identifying novel markers and advancing the understanding of AD mechanisms. • It is the first study combining 5hmC with expression, mouse model validation to identify the core genes related to AD. • AKT3, MBP and other four genes involving 13 promoter CpG sites with 5mc, 5hmC and expression difference were identified. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study explored the potential of Hinoki aromatherapy to induce biomarkers of dysmenorrhea relief through working memory. Structural magnetic resonance imaging and magnetoencephalography (MEG) were used to examine their effects on neurophysiological responses to a visual working memory (VWM) test. Behavioral performance was measured to understand its effects on the overall working memory. Methods: Twenty-four healthy participants completed the VWM task during nonmenstruation and menstruation. Behavioral (accuracy and reaction time) and neurophysiological (event-related fields, source estimation, and permutation t-test on source data) measures were assessed without and with Hinoki aromatherapy. Results: A significant difference in the ratio of accuracy to reaction time was found without and with aromatherapy in participants with dysmenorrhea, suggesting that aromatherapy may improve working memory performance in this population. MEG analysis revealed high temporal resolution of evoked latency and intensity during the VWM task. Source localization of the activation aimed to identify brain areas involved in dysmenorrhea. Aromatherapy reduced signals in these areas, which may also contribute to reducing dysmenorrhea-related visual signals. Conclusions: Based on these findings, Hinoki aromatherapy may be a promising treatment option for alleviating dysmenorrhea and improving related symptoms by reducing activity in brain pain processing regions. These regions include the left entorhinal cortex, inferior temporal gyrus, primary visual cortex, retrosplenial cortex, and presubiculum. Furthermore, decreased activity in these areas with aromatherapy suggests that they could be used as biomarkers of dysmenorrhea relief. [ABSTRACT FROM AUTHOR]

Once we are born, the number and location of nerve cells in most parts of the brain remain unchanged. These types of structural changes are therefore a significant form of flexibility for the neural circuits where they occur. In humans, the postnatal birth of neurons is limited; however, neurons do continue to migrate into some brain regions throughout infancy and even into adolescence. In human infants, multiple migratory pathways deliver interneurons to destinations across the frontal and temporal lobe cortex. Shorter-range migration of excitatory neurons also appears to continue during adolescence, particularly near the amygdala paralaminar nucleus, a region that follows a delayed trajectory of growth from infancy to adulthood. The significance of the timing for when different brain regions recruit new neurons through these methods is unknown; however, both processes of protracted migration and maturation are prominent in humans. Mechanisms like these that reconfigure neuronal circuits are a substrate for critical periods of plasticity and could contribute to distinctive circuit functionality in human brains. [ABSTRACT FROM AUTHOR]

Background: The entorhinal cortex is the very earliest involvement of Alzheimer's disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI–). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI–. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12–15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD. [ABSTRACT FROM AUTHOR]

Background: The medial temporal lobe (MTL) is hypothesized to be relatively spared in early-onset Alzheimer's disease (EOAD). Yet, detailed examination of MTL subfields and drivers of atrophy in amnestic EOAD is lacking. Methods: BioFINDER-2 participants with memory impairment, abnormal amyloid-β and tau-PET were included. Forty-one amnestic EOAD individuals ≤65 years and, as comparison, late-onset AD (aLOAD, ≥70 years, n = 154) and amyloid-β-negative cognitively unimpaired controls were included. MTL subregions and biomarkers of (co-)pathologies were measured. Results: AD groups showed smaller MTL subregions compared to controls. Atrophy patterns were similar across AD groups: aLOAD showed thinner entorhinal cortices than aEOAD; aEOAD showed thinner parietal regions than aLOAD. aEOAD showed lower white matter hyperintensities than aLOAD. No differences in MTL tau-PET or transactive response DNA binding protein 43-proxy positivity were found. Conclusions: We found evidence for MTL atrophy in amnestic EOAD and overall similar levels to aLOAD of MTL tau pathology and co-pathologies. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), reports on the association between false recognition and brain structure have been inconsistent. In dementia with Lewy bodies (DLB), no such association has been reported. This study aimed to identify brain regions associated with false recognition in AD and DLB by analyzing regional gray matter volume (rGMV). We included 184 patients with AD and 60 patients with DLB. The number of false recognitions was assessed using the Alzheimer's Disease Assessment Scale' word recognition task. Brain regions associated with the number of false recognitions were examined by voxel-based morphometry analysis. The number of false recognitions significantly negatively correlated with rGMV in the bilateral hippocampus, left parahippocampal gyrus, bilateral amygdala, and bilateral entorhinal cortex in patients with AD (p < 0.05, family-wise error [FEW] corrected) and in the bilateral hippocampus, left parahippocampal gyrus, right inferior frontal gyrus, right middle frontal gyrus, right basal forebrain, right insula, left medial and lateral orbital gyri, and left fusiform in those with DLB (p < 0.05, FWE corrected). Bilateral hippocampus and left parahippocampal gyrus were associated with false recognition in both diseases. However, we found there were regions where the association between false recognition and rGMV differed from disease to disease. [ABSTRACT FROM AUTHOR]

Complex sensory information arrives in the brain from an animal's first-person ('egocentric') perspective. However, animals can efficiently navigate as if referencing map-like ('allocentric') representations. The postrhinal (POR) and retrosplenial (RSC) cortices are thought to mediate between sensory input and internal maps, combining egocentric representations of physical cues with allocentric head direction (HD) information. Here we show that neurons in the POR and RSC of female Long-Evans rats are tuned to distinct but complementary aspects of local space. Egocentric bearing (EB) cells recorded in square and L-shaped environments reveal that RSC cells encode local geometric features, while POR cells encode a more global account of boundary geometry. Additionally, POR HD cells can incorporate egocentric information to fire in two opposite directions with two oppositely placed identical visual landmarks, while only a subset of RSC HD cells possess this property. Entorhinal grid and HD cells exhibit consistently allocentric spatial firing properties. These results reveal significant regional differences in the neural encoding of spatial reference frames. Whether and how the postrhinal (POR) and retrosplenial (RSC) cortices interact with each other and impact downstream allocentric representations are not fully understood. Here authors present single neuron recordings from freely moving rats exploring different environments to reveal distinct egocentric (self-centered) and allocentric (world-centered) coding frameworks for landmarks and boundaries in interconnected cortical regions. [ABSTRACT FROM AUTHOR]

Preventative treatment for Alzheimer's Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology. In this study using an adult-onset mouse model of Alzheimer's pathology, we uncovered a neuron-type-specific mechanism responsible for region-specific circuit dysfunction. Short-term expression of human amyloid precursor protein (hAPP) led to hyperexcitability in the entorhinal cortex, but not in isocortex, due to a distinct vulnerability of PV interneurons in the entorhinal region. [ABSTRACT FROM AUTHOR]

Our brains create new memories by capturing the 'who/what', 'where' and 'when' of everyday experiences. On a neuronal level, mechanisms facilitating a successful transfer into episodic memory are still unclear. We investigated this by measuring single neuron activity in the human medial temporal lobe during encoding of item-location associations. While previous research has found predictive effects in population activity in human MTL structures, we could attribute such effects to two specialized sub-groups of neurons: concept cells in the hippocampus, amygdala and entorhinal cortex (EC), and a second group of parahippocampal location-selective neurons. In both item- and location-selective populations, firing rates were significantly higher during successfully encoded trials. These findings are in line with theories of hippocampal indexing, since selective index neurons may act as pointers to neocortical representations. Overall, activation of distinct populations of neurons could directly support the connection of the 'what' and 'where' of episodic memory. Whether specialized neuronal firing in the human MTL predicts successful memory encoding remains unknown. Here, the authors find this to be the case for two distinct populations of single neurons responding to items and locations, respectively. [ABSTRACT FROM AUTHOR]

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer's disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies. [ABSTRACT FROM AUTHOR]

Group I metabotropic glutamate receptors (mGluRs) modulate postsynaptic neuronal excitability and epileptogenesis. We investigated roles of group I mGluRs on low extracellular Mg2+ concentration ([Mg2+]o)-induced epileptiform activity and neuronal cell death in the CA1 regions of isolated rat hippocampal slices without the entorhinal cortex using extracellular recording and propidium iodide staining. Exposure to Mg2+-free artificial cerebrospinal fluid can induce interictal epileptiform activity in the CA1 regions of rat hippocampal slices. MPEP, a mGluR 5 antagonist, significantly inhibited the spike firing of the low [Mg2+]o-induced epileptiform activity, whereas LY367385, a mGluR1 antagonist, did not. DHPG, a group 1 mGluR agonist, significantly increased the spike firing of the epileptiform activity. U73122, a PLC inhibitor, inhibited the spike firing. Thapsigargin, an ER Ca2+-ATPase antagonist, significantly inhibited the spike firing and amplitude of the epileptiform activity. Both the IP3 receptor antagonist 2-APB and the ryanodine receptor antagonist dantrolene significantly inhibited the spike firing. The PKC inhibitors such as chelerythrine and GF109203X, significantly increased the spike firing. Flufenamic acid, a relatively specific TRPC 1, 4, 5 channel antagonist, significantly inhibited the spike firing, whereas SKF96365, a relatively non-specific TRPC channel antagonist, did not. MPEP significantly decreased low [Mg2+]o DMEM-induced neuronal cell death in the CA1 regions, but LY367385 did not. We suggest that mGluR 5 is involved in low [Mg2+]oinduced interictal epileptiform activity in the CA1 regions of rat hippocampal slices through PLC, release of Ca2+ from intracellular stores and PKC and TRPC channels, which could be involved in neuronal cell death. [ABSTRACT FROM AUTHOR]

Cholecystokinin (CCK) has been confirmed to be essential in NMDA‐dependent long‐term potentiation (LTP) at mouse cortical synapses. This paper has proven that CCK is necessary for LTP induced by high‐frequency stimulation of mouse hippocampal synapses projected from the entorhinal cortex. We show that the subunit of the axonal NMDA receptor dominant modulates the activity‐induced LTP by triggering pre‐synaptic CCK release. A functional pre‐synaptic NMDA receptor is required to induce LTP mediated by the axonal Ca2+ elevation and CCK exocytosis at CCK‐specific neurons. Genetic depletion of the GluN1 subunit of NMDA receptors on CCK neurons, which projected from the entorhinal cortex largely abolished the axonal Ca2+ elevation and disturbed the secretion of CCK in hippocampus. These results demonstrate that activity‐induced LTP at the hippocampal synapse is CCK‐dependent, and CCK secretion from the axonal terminal is modulated by pre‐synaptic NMDA receptors. [ABSTRACT FROM AUTHOR]

Background: Persistent symptoms have been reported in up to 50% of the 27 million people with mild traumatic brain injuries (mTBI) every year. MRI findings are currently limited by low diagnostic and prognostic sensitivities, constraining the value of imaging in the stratification of patients following mTBI. Limbic system structures are promising brain regions in offering prognostic factors for symptom persistence following mTBI. The objective of this study was to associate volume and symmetry of limbic system structures with the presence and persistence of common symptoms in patients with mTBI. Methods: This study focused on 524 adults (aged 18–82), 58% female, with 82% injured in motor vehicle accidents and 28% reporting loss of consciousness (LOC). Magnetic resonance imaging (MRI) data included a sagittal 3D T1-weighted sequence with 1.2 mm slice thickness, with voxel sizes of 0.93 mm × 0.93 mm × 1.2 mm, obtained a median of 156 days after injury. Symptom diagnosis and persistence were collected retrospectively from patient medical records. Intracranial volume-adjusted regional volumes per side utilizing automated volumetric analysis (NeuroQuant®) were used to calculate total volume, laterality index, and side-independent asymmetry. Covariates included age, sex, LOC, and days from injury. Limbic volumetrics did not relate to symptom presentation, except the (-) association between headache presence and thalamus volume (adjusted odds ratio = 0.51, 95% confidence interval = 0.32, 0.85). Headache, balance problems, anxiety, and depression persistence was (-) associated with thalamus volume (hazard ratio (HR) 1.25 to 1.94). Longer persistence of balance problems was associated with (-) lateral orbitofrontal cortex volume (HR = 1.33) and (+) asymmetry of the hippocampus (HR = 0.27). Persistence of cognitive deficits was associated with (+) asymmetry in the caudal anterior cingulate (HR = 0.67). Depression persistence was associated with (+) asymmetry in the isthmus of the cingulate gyrus (HR = 5.39). Persistence of anxiety was associated with (-) volume of the parahippocampal gyrus (HR = 1.67), orbitofrontal cortex (HR > 1.97), and right-biased laterality of the entorhinal cortex (HR = 0.52). Conclusions: Relative volume and asymmetry of the limbic system structures in patients with mTBI are associated with the persistence of symptoms, particularly anxiety. The conclusions of this study are limited by the absence of a reference group with no mTBI. [ABSTRACT FROM AUTHOR]

Neuropsychiatric symptoms (NPS) are risk factors for Alzheimer's disease (AD) but can also manifest secondary to AD pathology. Mild behavioral impairment (MBI) refers to later‐life emergent and persistent NPS that may mark early‐stage AD. To distinguish MBI from NPS that are transient or which represent psychiatric conditions (non‐MBI NPS), we investigated the effect of applying MBI criteria on NPS associations with AD structural imaging biomarkers and incident cognitive decline. Data for participants (n = 1273) with normal cognition (NC) or mild cognitive impairment (MCI) in the National Alzheimer's Coordinating Center Uniform Data Set were analyzed. NPS status (MBI, non‐MBI NPS) was derived from the Neuropsychiatric Inventory Questionnaire and psychiatric history. Normalized measures of bilateral hippocampal (HPC) and entorhinal cortex (EC) volume, and AD meta‐region of interest (ROI) mean cortical thickness were acquired from T1‐weighted magnetic resonance imaging scans. Multivariable linear and Cox regressions examined NPS associations with imaging biomarkers and incident cognitive decline, respectively. MBI was associated with lower volume and cortical thickness in all ROIs in both NC and MCI, except for EC volume in NC. Non‐MBI NPS were only associated with lower HPC volume in NC. Although both of the NPS groups showed higher hazards for MCI/dementia than No NPS, MBI participants showed more rapid decline. Although both types of NPS were linked to HPC atrophy, only NPS that emerged and persisted in later‐life, consistent with MBI criteria, were related to AD neurodegenerative patterns beyond the HPC. Moreover, MBI predicted faster progression to dementia than non‐MBI NPS. [ABSTRACT FROM AUTHOR]

Background: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is characterized by distinct structural and functional brain alterations, predominantly affecting the medial temporal lobes and the hippocampus. Structural connectome analysis with graph-based investigations of network properties allows for an in-depth characterization of global and local network changes and their relationship with clinical deficits in NMDAR encephalitis. Methods: Structural networks from 61 NMDAR encephalitis patients in the post-acute stage (median time from acute hospital discharge: 18 months) and 61 age- and sex-matched healthy controls (HC) were analyzed using diffusion-weighted imaging (DWI)-based probabilistic anatomically constrained tractography and volumetry of a selection of subcortical and white matter brain volumes was performed. We calculated global, modular, and nodal graph measures with special focus on default-mode network, medial temporal lobe, and hippocampus. Pathologically altered metrics were investigated regarding their potential association with clinical course, disease severity, and cognitive outcome. Results: Patients with NMDAR encephalitis showed regular global graph metrics, but bilateral reductions of hippocampal node strength (left: p = 0.049; right: p = 0.013) and increased node strength of right precuneus (p = 0.013) compared to HC. Betweenness centrality was decreased for left-sided entorhinal cortex (p = 0.042) and left caudal middle frontal gyrus (p = 0.037). Correlation analyses showed a significant association between reduced left hippocampal node strength and verbal long-term memory impairment (p = 0.021). We found decreased left (p = 0.013) and right (p = 0.001) hippocampal volumes that were associated with hippocampal node strength (left p = 0.009; right p < 0.001). Conclusions: Focal network property changes of the medial temporal lobes indicate hippocampal hub failure that is associated with memory impairment in NMDAR encephalitis at the post-acute stage, while global structural network properties remain unaltered. Graph theory analysis provides new pathophysiological insight into structural network changes and their association with persistent cognitive deficits in NMDAR encephalitis. [ABSTRACT FROM AUTHOR]

In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment. [ABSTRACT FROM AUTHOR]

Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17β‐estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein‐coupled estrogen receptor‐1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long‐Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor‐mediated excitatory synaptic currents. However, GABA receptor‐mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20‐min washout period. The inhibition of GABA‐mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2‐induced reduction in IPSCs. GPER1 can also stimulate extracellular signal‐regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2‐induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling‐mediated reduction in GABA‐mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK‐dependent alterations in synaptic transmission in other brain areas. [ABSTRACT FROM AUTHOR]

Alzheimers disease (AD) is a chronic neurodegenerative disorder characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in hippocampus, but less is known about changes in medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at 3 and 10 months of age in the 3xTg mouse model of AD pathology, using male and female mice. At 3 months of age, before the onset of memory impairments, we found early hyperexcitability in intrinsic properties of MECII stellate and pyramidal cells, but this was balanced by a relative reduction in synaptic excitation (E) compared with inhibition (I; E/I ratio), suggesting intact homeostatic mechanisms regulating MECII activity. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable, and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsic and synaptic hyperexcitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this postsymptomatic time point, which may contribute to the emergence of memory deficits in AD.SIGNIFICANCE STATEMENT AD causes cognitive deficits, but the specific neural circuits that are damaged to drive changes in memory remain unknown. Using a mouse model of AD pathology that expresses both amyloid and tau transgenes, we found that neurons in the MEC have altered excitability. Before the onset of memory impairments, neurons in layer 2 of MEC had increased intrinsic excitability, but this was balanced by reduced inputs onto the cell. However, after the onset of memory impairments, stellate cells in MEC became further hyperexcitable, with increased excitability exacerbated by increased synaptic inputs. Thus, it appears that MEC stellate cells are uniquely disrupted during the progression of memory deficits and may contribute to cognitive deficits in AD.

Hippocampal CA3 is traditionally conceptualized as a brain region within a unidirectional feedforward trisynaptic pathway that links major hippocampal subregions. Recent genomic and viral tracing studies indicate that the anatomical connectivity of CA3 and the trisynaptic pathway is more complex than initially expected and suggests that there may be cell type-specific input gradients throughout the three-dimensional hippocampal structure. In several recent studies using multiple viral tracing approaches, we describe subdivisions of the subiculum complex and ventral hippocampal CA1 that show significant back projections to CA1 and CA3 excitatory neurons. These novel connections form noncanonical circuits that run in the opposite direction relative to the well-characterized feedforward pathway. Diverse subtypes of GABAergic inhibitory neurons participate within the trisynaptic pathway. In the present study, we have applied monosynaptic retrograde viral tracing to examine noncanonical synaptic inputs from CA1 and subicular complex to the inhibitory neuron in hippocampal CA3. We quantitatively mapped synaptic inputs to CA3 inhibitory neurons to understand how they are connected within and beyond the hippocampus formation. Major brain regions that provide typical inputs to CA3 inhibitory neurons include the medial septum, the dentate gyrus, the entorhinal cortex, and CA3. Noncanonical inputs from ventral CA1 and subicular complex to CA3 inhibitory neurons follow a proximodistal topographic gradient with regard to CA3 subregions. We find novel noncanonical circuit connections between inhibitory CA3 neurons and ventral CA1, subiculum complex, and other brain regions. These results provide a new anatomical connectivity basis to further study the function of CA3 inhibitory neurons.