Entorhinal Research Articles

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer’s disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Astrocytes mediate two forms of spike timing-dependent depression at entorhinal cortex-hippocampal synapses.

The entorhinal cortex (EC) connects to the hippocampus sending different information from cortical areas that is first processed at the dentate gyrus (DG) including spatial, limbic and sensory information. Excitatory afferents from lateral (LPP) and medial (MPP) perforant pathways of the EC connecting to granule cells of the DG play a role in memory encoding and information processing and are deeply affected in humans suffering Alzheimer's disease and temporal lobe epilepsy, contributing to the dysfunctions found in these pathologies. The plasticity of these synapses is not well known yet, as are not known the forms of long-term depression (LTD) existing at those connections. We investigated whether spike timing-dependent long-term depression (t-LTD) exists at these two different EC-DG synaptic connections in mice, and whether they have different action mechanisms. We have found two different forms of t-LTD, at LPP- and MPP-GC synapses and characterised their cellular and intracellular mechanistic requirements. We found that both forms of t-LTD are expressed presynaptically and that whereas t-LTD at LPP-GC synapses does not require NMDAR, t-LTD at MPP-GC synapses requires ionotropic NMDAR containing GluN2A subunits. The two forms of t-LTD require different group I mGluR, mGluR5 LPP-GC synapses and mGluR1 MPP-GC synapses. In addition, both forms of t-LTD require postsynaptic calcium, eCB synthesis, CB1R, astrocyte activity, and glutamate released by astrocytes. Thus, we discovered two novel forms of t-LTD that require astrocytes at EC-GC synapses.

Dysregulated Neurofluid Coupling as a New Noninvasive Biomarker for Primary Progressive Aphasia.

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolite waste from the brain whereas impairments in glymphatic clearance in PPA are poorly understood. Thus, this study aims to investigate the role of dysregulated macroscopic cerebrospinal fluid (CSF) movement in PPA. Fifty-six PPA individuals and ninety-four healthy controls were included in our analysis after excluding those with excessive head motions during the scan. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow was calculated using Pearson correlation and compared between the groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were examined. PPA subjects exhibited weaker global BOLD-CSF coupling compared to HCs, indicating impairments in glymphatic function in the patients (p = 0.01). In the PPA but not HC group, global BOLD-CSF coupling correlated with the CDR scores (p = 0.04) and hippocampal volume (p = 0.009). The observed decoupling between global brain activity and CSF flow and its association with symptomatology and brain structural changes in PPA converges with previous reports on the same measure in other neurodegenerative diseases. These findings support the potential role of global BOLD-CSF coupling as a noninvasive marker for glymphatic dysregulation in PPA.

Association of the Volumes of Limbic Brain Structures with the Development of Psychoneurological Disorders in Patients with Ischemic Stroke

Post-stroke depressive disorders (PSD) and post-stroke cognitive impairments (PCI) are frequent consequences of ischemic stroke (IS). The study was focused on exploring possible associations between relative volumes of cortical and limbic brain structures during the acute period of IS, and changes in biochemical indices of hypothalamic-pituitary-adrenal, sympathoadrenal medullary and inflammatory systems, with the development of PSD or PCI after mild or moderate IS. Patients developing PSD later on had significantly smaller relative volumes of the hippocampus, entorhinal cortex, and temporal pole versus patients without depressive symptoms. PCI development was associated with significantly smaller volumes of temporal pole and supramarginal gyrus versus patients without cognitive changes. Multiple logistic regression analysis showed higher likelihood of developing PSD in patients with smaller temporal pole volume (β0 =10.9; β = –4.27; p = 0.04) and in-creased salivary α-amylase activity (β0 = –3.55; β = 2.68e–05; p = 0.02). PCI likelihood was higher in patients with smaller supramarginal gyrus volume (β0 = 3.41; β = –0.99; p = 0.047), smaller temporal pole volume (β0 = 3.41; β = –3.12; p = 0.06), and increased hair cortisol concentration at admission (index of accumulated stress load within a month before IS; β0 = 3.41; β = –0.05; p = 0.08). The data support the hypothesis suggesting predisposition to PSD and PCI and multi hit scenarios of their pathogenesis with IS providing a final hit.

Brain imaging and machine learning reveal uncoupled functional network for contextual threat memory in long sepsis.

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.

Medial temporal atrophy predicts the limbic comorbidities in lewy body disease.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

Early movement restriction impairs the development of sensorimotor integration, motor skills and memory in rats: Towards a preclinical model of developmental coordination disorder?

Children with neurodevelopmental disorders, such as developmental coordination disorder (DCD), exhibit gross to fine sensorimotor impairments, reduced physical activity and interactions with the environment and people. This disorder co-exists with cognitive deficits, executive dysfunctions and learning impairments. Previously, we demonstrated in rats that limited amounts and atypical patterns of movements and somatosensory feedback during early movement restriction manifested in adulthood as degraded postural and locomotor abilities, and musculoskeletal histopathology, including muscle atrophy, hyperexcitability within sensorimotor circuitry and maladaptive cortical plasticity, leading to functional disorganization of the primary somatosensory and motor cortices in the absence of cortical histopathology. In this study, we asked how this developmental sensorimotor restriction (SMR) started to impact the integration of multisensory information and the emergence of sensorimotor reflexes in rats. We also questioned the enduring impact of SMR on motor activities, pain and memory. SMR led to deficits in the emergence of swimming and sensorimotor reflexes, the development of pain and altered locomotor patterns and posture with toe-walking, adult motor performance and night spontaneous activity. In addition, SMR induced exploratory hyperactivity, short-term impairments in object-recognition tasks and long-term deficits in object-location tasks. SMR rats displayed minor alterations in histological features of the hippocampus, entorhinal, perirhinal and postrhinal cortices yet no obvious changes in the prefrontal cortex. Taken all together, these results show similarities with the symptoms observed in children with DCD, although further exploration seems required to postulate whether developmental SMR corresponds to a rat model of DCD.

Magnetic resonance diffusion tensor imaging for detecting the cerebral microstructure changes in patients with CSVD -induced mild cognitive impairment.

Cerebral small vessel disease (CSVD)-induced mild cognitive impairment (MCI) has been linked to cognitive decline. Brain atrophy is considered the most common change in MCI patients, which can be measured by diffusion tensor imaging (DTI). The study aimed to explore the relationship between DTI parameters and cognitive function in CSVD patients with MCI. This retrospective analysis involved 185 patients with CSVD, comprising 87 cases with MCI and 98 cases without MCI (NMCI). Analyses of demographic and clinical characteristics were conducted. DTI-measured fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and entorhinal cortex regions were examined. The diagnostic values were determined using receiver-operative-curve (ROC) analysis, with the Youden Index identifying optimum sensitivity and specificity. Correlations between Montreal cognitive assessment (MoCA) scores and FA or MD in MCI patients were further assessed. No significant differences were observed in demographic and clinical characteristics between MCI and NMCI groups (all p>0.05), except for diabetes prevalence (p=0.011). Notably, the ROC analysis highlighted the diagnostic potential of FA, showing the maximum area under the curve values (Hippocampus-Left: 0.76; Hippocampus-Right: 0.66; Entorhinal cortex-Left: 0.62; Entorhinal cortex-Right: 0.64). MD exhibited a significant negative correlation with MoCA scores (Hippocampus-Left: r=-0.58, p<0.001; Hippocampus-Right: r=-0.41, p<0.001; Entorhinal cortex-Left: r=-0.49, p<0.001; Entorhinal cortex-Right: r=-0.27, p<0.001), while FA showed a significant positive correlation (Hippocampus-Left: r=0.51, p<0.001; Hippocampus-Right: r=0.31, p=0.004; Entorhinal cortex-Left: r=0.35, p<0.001; Entorhinal cortex-Right: r=0.38, p<0.001). The study demonstrates the diagnostic value of DTI parameters in CSVD patients with MCI, emphasizing the associations between microstructural brain changes and cognitive function.

A combined DTI-fMRI approach for optimizing the delineation of posteromedial versus anterolateral entorhinal cortex.

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.

Do total hippocampus and hippocampal subfield volumes relate to navigation ability? A call towards methodological consistency

Despite the need for successful navigation, humans vary greatly in their ability to navigate, and these individual differences may relate to variation in brain structure. While prior research provides support for a correlation between hippocampal volume and navigation ability in both navigation experts and in older individuals, this relationship is under scrutiny for healthy, young adults. We assessed 99 healthy young adults’ ability to navigate in a virtual, desktop maze and correlated their performance with total hippocampal gray matter volume. For a subset of these individuals, we further segmented the medial temporal lobe – including regions of the hippocampus – into anatomically-distinct subregions to uniquely examine the association between volumes of hippocampal subfields and navigation. Given the need to distinguish between similar-looking maze hallways and partially overlapping routes, young adults with stronger pattern separation ability may perform better in this task. Thus, we theorized that successful navigation would positively correlate with hippocampal CA3 and dentate gyrus (DG) subfield volumes due to these regions’ role in pattern separation. CA1 and entorhinal cortex (ERC) are both associated with rodent spatial memory, too, suggesting a possible relationship between their volumes and navigation performance. Consistent with our hypotheses, we observed a positive relationship between volumes of hippocampal subfields and wayfinding accuracy, while ERC and parahippocampal cortex volumes correlated with navigation efficiency. However, when analyzing total hippocampal volume, a nuanced interpretation is warranted. We found evidence of Simpson’s Paradox, where total hippocampal volume and navigation accuracy displayed no correlation in males, a negative correlation in females, yet a positive correlation when considering the full sample of males and females combined. Furthermore, no significant relationship was observed between total hippocampal volume and path efficiency. Given these findings, we urge caution in interpreting the results because these associations differ by analysis techniques (including voxel-based morphometry), after sex stratification, and with anterior and posterior hippocampal subdivisions. Overall, this study enhances our understanding of the relationship between brain volume and navigation ability for young adults but also emphasizes the need for methodological consistency across studies with respect to boundary definitions, neuroimaging techniques, statistical methods, and factors that give rise to individual differences.

Atypical antipsychotics improve dendritic spine pathology in temporal lobe cortex neurons in a developmental rodent model of schizophrenia.

"Dendritic spine pathology" refers to alterations in density and morphology of dendritic spines, crucial in corticolimbic neurons in schizophrenia. These structural neuroplasticity changes contribute to the disease's neurobiological underpinnings, alongside alterations in other brain regions, such as temporal lobe cortices like the auditory cortex (Au1) and the entorhinal cortex (Ent), involved in sensory processing, memory, and learning. The neonatal ventral hippocampus lesion (NVHL) in rats exhibits behavioral abnormalities akin to schizophrenia symptoms and corticolimbic dendritic spine pathology, mitigated by atypical antipsychotic drugs (AADs) like risperidone (RISP) and olanzapine (OLZ). This study investigated NVHL-induced dendritic spine pathology in Au1 and Ent, evaluating RISP and OLZ effects. NVHL induced dendritic spine pathology mainly by reducing the dendritic spine density in Au1 and Ent neurons; both RISP and OLZ mitigated it, increasing dendritic spine density and mushroom spine population, the ones related with synaptic strengthening, while decreasing stubby spine population. These findings underscore the role of impaired neuroplasticity in the temporal lobe cortices in schizophrenia pathophysiology and highlight the relevance of the NVHL model for studying neuroplasticity mechanisms in the disease. They also contribute to the growing understanding of targeting structural and functional neuroplasticity for novel drugs in the pharmacotherapy of the disease.

Olfactory Dysfunction and Limbic Hypoactivation in Temporal Lobe Epilepsy.

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).

Synaptic interactions between stellate cells and parvalbumin interneurons in layer 2 of the medial entorhinal cortex are organized at the scale of grid cell clusters.

Interactions between excitatory and inhibitory neurons are critical to computations in cortical circuits but their organization is difficult to assess with standard electrophysiological approaches. Within the medial entorhinal cortex, representation of location by grid and other spatial cells involves circuits in layer 2 in which excitatory stellate cells interact with each other via inhibitory parvalbumin expressing interneurons. Whether this connectivity is structured to support local circuit computations is unclear. Here, we introduce strategies to address the functional organization of excitatory-inhibitory interactions using crossed Cre- and Flp-driver mouse lines to direct targeted presynaptic optogenetic activation and postsynaptic cell identification. We then use simultaneous patch-clamp recordings from postsynaptic neurons to assess their shared input from optically activated presynaptic populations. We find that extensive axonal projections support spatially organized connectivity between stellate cells and parvalbumin interneurons, such that direct connections are often, but not always, shared by nearby neurons, whereas multisynaptic interactions coordinate inputs to neurons with greater spatial separation. We suggest that direct excitatory-inhibitory synaptic interactions may operate at the scale of grid cell clusters, with local modules defined by excitatory-inhibitory connectivity, while indirect interactions may coordinate activity at the scale of grid cell modules.

Evidence for convergence of distributed cortical processing in band-like functional zones in human entorhinal cortex.

The wide array of cognitive functions associated with the hippocampus is supported through interactions with the cerebral cortex. However, most of the direct cortical input to the hippocampus originates in the entorhinal cortex, forming the hippocampal-entorhinal system. In humans, the role of the entorhinal cortex in mediating hippocampal-cortical interactions remains unknown. In this study, we used precision neuroimaging to examine the distributed cortical anatomy associated with the human hippocampal-entorhinal system. Consistent with animal anatomy, our results associate different subregions of the entorhinal cortex with different parts of the hippocampus long axis. Furthermore, we find that the entorhinal cortex comprises three band-like zones that are associated with functionally distinct cortical networks. Importantly, the entorhinal cortex bands traverse the proposed human homologs of rodent lateral and medial entorhinal cortices. Finally, we show that the entorhinal cortex is a major convergence area of distributed cortical processing and that the topography of cortical networks associated with the anterior medial temporal lobe mirrors the macroscale structure of high-order cortical processing.

Reverse engineering of feedforward cortical-Hippocampal microcircuits for modelling neural network function and dysfunction

Engineered biological neural networks are indispensable models for investigation of neural function and dysfunction from the subcellular to the network level. Notably, advanced neuroengineering approaches are of significant interest for their potential to replicate the topological and functional organization of brain networks. In this study, we reverse engineered feedforward neural networks of primary cortical and hippocampal neurons, using a custom-designed multinodal microfluidic device with Tesla valve inspired microtunnels. By interfacing this device with nanoporous microelectrodes, we show that the reverse engineered multinodal neural networks exhibit capacity for both segregated and integrated functional activity, mimicking brain network dynamics. To advocate the broader applicability of our model system, we induced localized perturbations with amyloid beta to study the impact of pathology on network functionality. Additionally, we demonstrate long-term culturing of subregion- and layer specific neurons extracted from the entorhinal cortex and hippocampus of adult Alzheimer’s-model mice and rats. Our results thus highlight the potential of our approach for reverse engineering of anatomically relevant multinodal neural networks to study dynamic structure-function relationships in both healthy and pathological conditions.

Increasing Adult Hippocampal Neurogenesis affects Neuronal Output Pattern from the Ventral Subiculum to the Hypothalamus

Adult Hippocampal Neurogenesis, or AHN, has been discovered to alleviate anxiety and depressive behavior, thus leading to the presumption that the mechanisms underlying it might be somewhat linked to the regulatory circuitry of anxiety and depression. The subiculum is a region of the Hippocampus connecting the CA1 neurons and the Entorhinal cortex. It is the main output region of the Hippocampus. A great portion of the subiculum neurons form neuronal projections to the lateral hypothalamus, which is known to play a crucial role in the regulation of anxiety via hormone secretion in both rodents and humans. Thus, we hypothesize that Adult Hippocampal Neurogenesis regulates anxiety via altering the neural output from the subiculum to the lateral hypothalamus. In this research proposal we aim to prove that increasing AHN causes a direct impact on neuronal activity in the main output region of the Hippocampus--the subiculum region, under the effect of anxiety. This study uses the Fos-TRAP2 model to induce tdTomato expression in neurons with high recent activity while the mice was under the effect of corticosterone-induced anxiety. We compare the amount of TRAPed neurons in the subiculum region of the brain during anxiety, in mice with and without weeks of voluntary exercise (running), which leads to an increased neurogenesis. This provides insight into the effects of AHN on the subiculum-hypothalamus pathway, thus the mechanisms underlying its effect of anxiety alleviation.

Brain aging and Alzheimer's disease, a perspective from non-human primates.

Brain aging is compared between Cercopithecinae (macaques and baboons), non-human Hominidae (chimpanzees, orangutans, and gorillas), and their close relative, humans. β-amyloid deposition in the form of senile plaques (SPs) and cerebral β-amyloid angiopathy (CAA) is a frequent neuropathological change in non-human primate brain aging. SPs are usually diffuse, whereas SPs with dystrophic neurites are rare. Tau pathology, if present, appears later, and it is generally mild or moderate, with rare exceptions in rhesus macaques and chimpanzees. Behavior and cognitive impairment are usually mild or moderate in aged non-human primates. In contrast, human brain aging is characterized by early tau pathology manifested as neurofibrillary tangles (NFTs), composed of paired helical filaments (PHFs), progressing from the entorhinal cortex, hippocampus, temporal cortex, and limbic system to other brain regions. β-amyloid pathology appears decades later, involves the neocortex, and progresses to the paleocortex, diencephalon, brain stem, and cerebellum. SPs with dystrophic neurites containing PHFs and CAA are common. Cognitive impairment and dementia of Alzheimer's type occur in about 1-5% of humans aged 65 and about 25% aged 85. In addition, other proteinopathies, such as limbic-predominant TDP-43 encephalopathy, amygdala-predominant Lewy body disease, and argyrophilic grain disease, primarily affecting the archicortex, paleocortex, and amygdala, are common in aged humans but non-existent in non-human primates. These observations show that human brain aging differs from brain aging in non-human primates, and humans constitute the exception among primates in terms of severity and extent of brain aging damage.

Isolated theta waves originating from the midline thalamus trigger memory reactivation during NREM sleep in mice

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.

Chemogenetic neuronal silencing decouples c-Jun activation from cell death in the temporal cortex.

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.

Systematic review on resting-state fMRI in people with AUD and people who binge drink.

Resting-state functional magnetic resonance imaging (rsfMRI) has become ubiquitous in neuroimaging to study disorders, including alcohol use disorder (AUD), given its potential to serve as a biomarker of psychiatric symptoms. The number of techniques, sample heterogeneity, and findings demand the assessment of results to identify potential biomarkers for the development of treatment. This systematic review aimed to synthesize the alcohol rsfMRI literature by summarizing the results by analysis approach and groups to examine these findings in the context of the neurobiology of addiction model. Three databases were systematically searched, resulting in the inclusion of 17 studies with a total of 784 participants (387 were people with AUD, 38 engaged in binge drinking, and 359 were controls). Seed-based functional connectivity studies were the most prominent. Compared to controls, people who binge drink and people with AUD showed greater connectivity of the Middle Frontal Gyrus-a region associated with the preoccupation/anticipation stage of the theory. Regions of the prefrontal and limbic cortex were most consistently reported in studies. The different types of analyses, sample size, and variability in the sample may have contributed to differences reported across studies. This review synthesizes and examines the results of different studies using the neurobiology of addiction theory, which may inform future studies on potential regions of interest, recruitment approaches, and analysis methods. Standardizing the methods for such a heterogeneous population could lead to more rapid development of neurobiologically-informed treatments for AUD.