Subicular Regions Research Articles

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.

Effects of Increased Adult Hippocampal Neurogenesis on Neuronal Output from the Subiculum to the Lateral Hippocampus under Anxiety

Numerous studies assessed the important involvement of adult hippocampal neurogenesis (AHN) in the regulation of stress. Although the precise processes underlying the promotion of AHN on the recovery of anxiety-induced symptoms have been thoroughly examined, they are still unclear.We observed the subiculum region and its neuronal output to the lateral hippocampal formation, which may serve as a conduit between AHN and the recovery from depression.In order to cultivate AHN with exercise and fluoxetine injection independently, we employed a mouse model. We then used FosTRAP2, PET, and fMRI to measure the subiculum’s neural activity during anxiety.When considered collectively, our findings imply that raising AHN in anxious mice modifies the way some subiculum neurons in the lateral hippocampal region output.

Resting-state neural activity and cerebral blood flow alterations in type 2 diabetes mellitus: Insights from hippocampal subfields.

In this study, multimodal magnetic resonance imaging (MRI) imaging was used to deeply analyze the changes of hippocampal subfields perfusion and function in patients with type 2 diabetes mellitus (T2DM), aiming to provide image basis for the diagnosis of hippocampal-related nerve injury in patients with T2DM. We recruited 35 patients with T2DM and 40 healthy control subjects (HCs). They underwent resting-state functional MRI (rs-fMRI), arterial spin labeling (ASL) scans, and a series of cognitive tests. Then, we compared the differences of two groups in the cerebral blood flow (CBF) value, amplitude of low-frequency fluctuation (ALFF) value, and regional homogeneity (ReHo) value of the bilateral hippocampus subfields. The CBF values of cornu ammonis area 1 (CA1), dentate gyrus (DG), and subiculum in the right hippocampus of T2DM group were significantly lower than those of HCs. The ALFF values of left hippocampal CA3, subiculum, and bilateral hippocampus amygdala transition area (HATA) were higher than those of HCs in T2DM group. The ReHo values of CA3, DG, subiculum, and HATA in the left hippocampus of T2DM group were higher than those of HCs. In the T2DM group, HbAc1 and FINS were negatively correlated with imaging characteristics in some hippocampal subregions. This study indicates that T2DM patients had decreased perfusion in the CA1, DG, and subiculum of the right hippocampus, and the right hippocampus subiculum was associated with chronic hyperglycemia. Additionally, we observed an increase in spontaneous neural activity within the left hippocampal CA3, subiculum, and bilateral HATA regions, as well as an enhanced local neural coordination in the left hippocampal CA3, DG, HATA, and subiculum among patients with type 2 diabetes, which may reflect an adaptive compensation for cognitive decline. However, this compensation may decline with the exacerbation of metabolic disorders.

Changes in microstructural similarity of hippocampal subfield circuits in pathological cognitive aging.

The hippocampal networks support multiple cognitive functions and may have biological roles and functions in pathological cognitive aging (PCA) and its associated diseases, which have not been explored. In the current study, a total of 116 older adults with 39 normal controls (NC) (mean age: 52.3 ± 13.64years; 16 females), 39 mild cognitive impairment (MCI) (mean age: 68.15 ± 9.28years, 14 females), and 38 dementia (mean age: 73.82 ± 8.06years, 8 females) were included. The within-hippocampal subfields and the cortico-hippocampal circuits were assessed via a micro-structural similarity network approach using T1w/T2w ratio and regional gray matter tissue probability maps, respectively. An analysis of covariance was conducted to identify between-group differences in structural similarities among hippocampal subfields. The partial correlation analyses were performed to associate changes in micro-structural similarities with cognitive performance in the three groups, controlling the effect of age, sex, education, and cerebralsmall-vesseldisease. Compared with the NC, an altered T1w/T2w ratio similarity between left CA3 and left subiculum was observed in the mild cognitive impairment (MCI) and dementia. The left CA3 was the most impaired region correlated with deteriorated cognitive performance. Using these regions as seeds for GM similarity comparisons between hippocampal subfields and cortical regions, group differences were observed primarily between the left subiculum and several cortical regions. By utilizing T1w/T2w ratio as a proxy measure for myelin content, our data suggest that the imbalanced synaptic weights within hippocampal CA3 provide a substrate to explain the abnormal firing characteristics of hippocampal neurons in PCA. Furthermore, our work depicts specific brain structural characteristics of normal and pathological cognitive aging and suggests a potential mechanism for cognitive aging heterogeneity.

Deep Brain Stimulation for Alzheimer’s Disease and the Human Memory Circuit

AbstractBackgroundBrain lesions causing amnesia are in a memory circuit centered on the subiculum. Deep brain stimulation (DBS) sites connected to this circuit are linked to cognitive decline in Parkinson’s disease but cognitive improvement in Alzheimer’s Disease (AD). Insight into this paradox may come from directly comparing the topography of lesion and DBS‐induced effects.MethodsWe studied 53 amnesia‐causing lesion locations and 46 patients (92 DBS sites) from Phase 1 and Phase 2 randomized controlled trials of fornix DBS for AD. Connectivity between lesions and DBS sites was computed using a normative atlas of functional connectivity data from 1000 healthy subjects. Baseline cognitive scores were compared to 1‐year post‐DBS activation scores.ResultsConnectivity between AD patients' DBS sites and a subiculum region derived from amnesia‐causing brain lesions correlated with cognitive improvement (Spearman’s rho = 0.33, p = 0.027). There was a difference between sham‐first (Spearman’s rho = 0.33, p = 0.027) and stimulation‐first (Spearman’s rho = 0.25, p = 0.27) cohorts. Whole‐brain connectivity maps of the subiculum region and AD response fingerprints were aligned: 17/19 local maxima appeared in both maps, dice coefficient 0.71 (p<0.00001). Both maps showed data‐driven peaks in an overlapping subiculum region. However, DBS data showed a significant interaction effect between patient age and subiculum connectivity upon outcome in a general linear model (p = 0.031). Randomization status was controlled as a covariate and was not significant. Specifically, higher subiculum connectivity in older patients led to improved cognition, while higher connectivity in younger patients resulted in worsening cognition. The data‐driven inflection point for this interaction effect was at age 65 at any subiculum connectivity value.ConclusionOur findings suggest that lesions causing amnesia and DBS sites modulating cognition converge on common neuroanatomy. However, patient age appears to be critical variable in determining whether DBS sites connected to the subiculum result in cognitive improvement or decline. Our results provide insight into the paradox of mixed outcomes across DBS cohorts and support restricting ADvance II enrollment of fornix‐targeted DBS to patients over 65. The underlying mechanisms remain unclear, and this study must be replicated in additional datasets.

Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum

AbstractBackgroundHippocampal atrophy is one of the most characteristic biomarkers of Alzheimer’s disease (AD), and its genetic basis, as well as that of its distinct subfields, is of current interest. However, hippocampal subfields have so far only been assessed largely unrelated to brain atrophy, and the majority of studies were focused on general population samples, explicitly excluding diagnosed patients. In this study, we evaluated whether hippocampal subfields trajectories are a suitable endophenotype to discern between neurodegenerative and aging genetic influences in the Alzheimer’s continuum.MethodThe dataset includes AD patients (N = 113), mild cognitive impairment (N = 426), and control normal (CN) (N = 272) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals were evaluated with 3T MRI at baseline and every 6 months for a total of 96 months. Hippocampal subfields were extracted using longitudinal processing within FreeSurfer(6.0). We used longitudinal mixed‐effect models with random intercept for individuals to investigated the association between hippocampal subfields volumetric changes and genetic predisposition to AD, Parkinson’s disease, frontotemporal dementia (neurodegeneration), as well as intrinsic and extrinsic epigenetic clock acceleration and telomere length (biological aging). Models were adjusted by age, sex, AD‐stage and total hippocampal volume. Disease status‐specific trajectories were also assessed.ResultGenetic predisposition to biological aging (driven by genetic predisposition to telomere length) was significantly associated with subfield changes in presubiculum (β = ‐11.2, p = 4.1e‐04), parasubiculum (β = ‐4.4, padj = 4.4e‐04), molecular layer (β = 5.9, padj = 2.0e‐04), dentate gyrus (DG) (β = 5.79, padj = 4.4e‐04), CA4 (β = 7.2, padj = 4.4e‐05), and HATA (β = ‐1.7, padj = 0.027). Genetic predisposition to neurodegeneration (driven by predisposition to AD) was associated with volumetric changes in CA3 (β = 4.4, p = 0.047). In stratified models, we observed significant volumetric changes due to genetic predisposition to neurodegeneration in controls (CA1, CA4, DG, parasubiculum, molecular layer). In MCI (subiculum regions and CA4) and AD (hippocampal fissure, molecular layer and DG), volumetric changes were mostly associated with genetic predisposition to biological aging processes.ConclusionWe showed differential genetic mechanisms associated with hippocampal subfield trajectories that were specific to Alzheimer’s disease stage. These results may help elucidate new biological mechanisms in the course of the disease as well as discern additional molecular mechanisms related to neurodegeneration and aging.

Discerning neurodegenerative and aging genetic influences on hippocampal subfields trajectories in the Alzheimer’s disease continuum

AbstractBackgroundHippocampal atrophy is one of the most characteristic biomarkers of Alzheimer’s disease (AD), and its genetic basis, as well as that of its distinct subfields, is of current interest. However, hippocampal subfields have so far only been assessed largely unrelated to brain atrophy, and the majority of studies were focused on general population samples, explicitly excluding diagnosed patients. In this study, we evaluated whether hippocampal subfields trajectories are a suitable endophenotype to discern between neurodegenerative and aging genetic influences in the Alzheimer’s continuum.MethodThe dataset includes AD patients (N = 113), mild cognitive impairment (N = 426), and control normal (CN) (N = 272) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Individuals were evaluated with 3T MRI at baseline and every 6 months for a total of 96 months. Hippocampal subfields were extracted using longitudinal processing within FreeSurfer(6.0). We used longitudinal mixed‐effect models with random intercept for individuals to investigated the association between hippocampal subfields volumetric changes and genetic predisposition to AD, Parkinson’s disease, frontotemporal dementia (neurodegeneration), as well as intrinsic and extrinsic epigenetic clock acceleration and telomere length (biological aging). Models were adjusted by age, sex, AD‐stage and total hippocampal volume. Disease status‐specific trajectories were also assessed.ResultGenetic predisposition to biological aging (driven by genetic predisposition to telomere length) was significantly associated with subfield changes in presubiculum (β = ‐11.2, p = 4.1e‐04), parasubiculum (β = ‐4.4, padj = 4.4e‐04), molecular layer (β = 5.9, padj = 2.0e‐04), dentate gyrus (DG) (β = 5.79, padj = 4.4e‐04), CA4 (β = 7.2, padj = 4.4e‐05), and HATA (β = ‐1.7, padj = 0.027). Genetic predisposition to neurodegeneration (driven by predisposition to AD) was associated with volumetric changes in CA3 (β = 4.4, p = 0.047). In stratified models, we observed significant volumetric changes due to genetic predisposition to neurodegeneration in controls (CA1, CA4, DG, parasubiculum, molecular layer). In MCI (subiculum regions and CA4) and AD (hippocampal fissure, molecular layer and DG), volumetric changes were mostly associated with genetic predisposition to biological aging processes.ConclusionWe showed differential genetic mechanisms associated with hippocampal subfield trajectories that were specific to Alzheimer’s disease stage. These results may help elucidate new biological mechanisms in the course of the disease as well as discern additional molecular mechanisms related to neurodegeneration and aging.

A CLU/APOJ GWAS AD risk variant suppresses the astrocytic response to plaques and reduces axonal and neuritic damage in 5xFAD mice

AbstractBackgroundGenome‐Wide Association Studies (GWAS) implicate clusterin (CLU, also known as apolipoprotein J) as a risk factor for late‐onset Alzheimer’s disease (LOAD), with elevated expression of CLU being associated with increased risk of LOAD. The region surrounding the SNP risk allele rs2279590 is poorly conserved within the mouse genome. Consequently, to model the effect of the rs2279590 risk allele on development of AD‐related pathology in mice we developed mice with a partially humanized allele of Clu.MethodCRISPR was used to substitute a 2kb region of human CLU (intron 7 to exon 9) containing the enhancer region and the rs2279590 SNP variant for the orthologous region of Clu within the C57BL/6J mouse genome. Clu‐rs2279590_h2kb mice were crossed with 5xFAD mice and aged to 4 and 12. Coronal brain sections were immunolabeled to visualize dense‐core plaques (ThioS), microglia (IBA1), astrocytes (S100β and GFAP), axonal (NfL) and neuritic (LAMP1) damage, confocal images of subiculum and cortical regions were taken and analyzed using Imaris software. In addition, brain Aβ and plasma NfL levels were quantified using meso scale discovery technology.Result5xFAD;Clu‐rs2279590_h2kb showed significantly reduced microglial density compared to 5xFAD mice in both brain areas at 4 months. By 12 months of age, microglial density was comparable between genotypes in cortex while in subiculum, elevated IBA1 cell density was observed in 5xFAD;Clu‐rs2279590_h2kb mice. Clu‐rs2279590_h2kb variant in 5xFAD background increased the density of S100β astrocytes in subiculum at 4 months and decreased the total S100β volume at 12 months. Reduced GFAP (reactive astrocytes) levels were found in cortex but not subiculum at 12 months. Despite comparable plaque load and insoluble Aβ42 levels, neuritic and axonal damage was decreased in the brain of 5xFAD;Clu‐rs2279590_h2kb compared to 5xFAD mice at 12 months. Plasma NfL was also significantly decreased.ConclusionDespite the minimal impact on Aβ plaque deposition, humanization of 2kb of Clu allele and introduction of rs2279590 risk SNP suppresses astrocytic response to plaques and is protective against axonal and neuritic damage which is mirrored by the reduced levels of plasma NfL.

Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields.

While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.

Rise and fall of peroxisomes during Alzheimer´s disease: a pilot study in human brains

Peroxisomes are eukaryotic organelles that rapidly change in number depending on the metabolic requirement of distinct cell types and tissues. In the brain, these organelles are essential for neuronal migration and myelination during development and their dysfunction is associated with age-related neurodegenerative diseases. Except for one study analysing ABCD3-positive peroxisomes in neurons of the frontal neocortex of Alzheimer disease (AD) patients, no data on other brain regions or peroxisomal proteins are available. In the present morphometric study, we quantified peroxisomes labelled with PEX14, a metabolism-independent peroxisome marker, in 13 different brain areas of 8 patients each either with low, intermediate or high AD neuropathological changes compared to 10 control patients. Classification of patient samples was based on the official ABC score. During AD-stage progression, the peroxisome density decreased in the area entorhinalis, parietal/occipital neocortex and cerebellum, it increased and in later AD-stage patients decreased in the subiculum and hippocampal CA3 region, frontal neocortex and pontine gray and it remained unchanged in the gyrus dentatus, temporal neocortex, striatum and inferior olive. Moreover, we investigated the density of catalase-positive peroxisomes in a subset of patients (> 80 years), focussing on regions with significant alterations of PEX14-positive peroxisomes. In hippocampal neurons, only one third of all peroxisomes contained detectable levels of catalase exhibiting constant density at all AD stages. Whereas the density of all peroxisomes in neocortical neurons was only half of the one of the hippocampus, two thirds of them were catalase-positive exhibiting increased levels at higher ABC scores. In conclusion, we observed spatiotemporal differences in the response of peroxisomes to different stages of AD-associated pathologies.Graphical

Carboxypeptidase E conditional knockout mice exhibit learning and memory deficits and neurodegeneration

Carboxypeptidase E (CPE) is a multifunctional protein with many nonenzymatic functions in various systems. Previous studies using CPE knock-out mice have shown that CPE has neuroprotective effects against stress and is involved in learning and memory. However, the functions of CPE in neurons are still largely unknown. Here we used a Camk2a-Cre system to conditionally knockout CPE in neurons. The wild-type, CPEflox/−, and CPEflox/flox mice were weaned, ear-tagged, and tail clipped for genotyping at 3 weeks old, and they underwent open field, object recognition, Y-maze, and fear conditioning tests at 8 weeks old. The CPEflox/flox mice had normal body weight and glucose metabolism. The behavioral tests showed that CPEflox/flox mice had impaired learning and memory compared with wild-type and CPEflox/- mice. Surprisingly, the subiculum (Sub) region of CPEflox/flox mice was completely degenerated, unlike the CPE full knockout mice, which exhibit CA3 region neurodegeneration. In addition, doublecortin immunostaining suggested that neurogenesis in the dentate gyrus of the hippocampus was significantly reduced in CPEflox/flox mice. Interestingly, TrkB phosphorylation in the hippocampus was downregulated in CPEflox/flox mice, but brain-derived neurotrophic factor levels were not. In both the hippocampus and dorsal medial prefrontal cortex, we observed reduced MAP2 and GFAP expression in CPEflox/flox mice. Taken together, the results of this study demonstrate that specific neuronal CPE knockout leads to central nervous system dysfunction in mice, including learning and memory deficits, hippocampal Sub degeneration and impaired neurogenesis.

Hippocampal metabolic subregions and networks: Behavioral, molecular, and pathological aging profiles.

Hippocampal local and network dysfunction is the hallmark of Alzheimer's disease (AD). We characterized the spatial patterns of hippocampus differentiation based on brain co-metabolism in healthy elderly participants and demonstrated their relevance to study local metabolic changes and associated dysfunction in pathological aging. The hippocampus can be differentiated into anterior/posterior and dorsal cornu ammonis (CA)/ventral (subiculum) subregions. While anterior/posterior CA show co-metabolism with different regions of the subcortical limbic networks, the anterior/posterior subiculum are parts of cortical networks supporting object-centered memory and higher cognitive demands, respectively. Both networks show relationships with the spatial patterns of gene expression pertaining to cell energy metabolism and AD's process. Finally, while local metabolism is generally lower in posterior regions, the anterior-posterior imbalance is maximal in late mild cognitive impairment with the anterior subiculum being relatively preserved. Future studies should consider bidimensional hippocampal differentiation and in particular the posterior subicular region to better understand pathological aging.

(+)-Borneol enantiomer ameliorates epileptic seizure via decreasing the excitability of glutamatergic transmission.

Epilepsy is one common brain disorder, which is not well controlled by current pharmacotherapy. In this study we characterized the therapeutic potential of borneol, a plant-derived bicyclic monoterpene compound, in the treatment of epilepsy and elucidated the underlying mechanisms. The anti-seizure potency and properties of borneol were assessed in both acute and chronic mouse epilepsy models. Administration of (+)-borneol (10, 30, 100 mg/kg, i.p.) dose-dependently attenuated acute epileptic seizure in maximal-electroshock seizure (MES) and pentylenetetrazol (PTZ)-induced seizure models without obvious side-effect on motor function. Meanwhile, (+)-borneol administration retarded kindling-induced epileptogenesis and relieved fully kindled seizures. Importantly, (+)-borneol administration also showed therapeutic potential in kainic acid-induced chronic spontaneous seizure model, which was considered as a drug-resistant model. We compared the anti-seizure efficacy of 3 borneol enantiomers in the acute seizure models, and found (+)-borneol being the most satisfying one with long-term anti-seizure effect. In electrophysiological study conducted in mouse brain slices containing the subiculum region, we revealed that borneol enantiomers displayed different anti-seizure mechanisms, (+)-borneol (10 μM) markedly suppressed the high frequency burst firing of subicular neurons and decreased glutamatergic synaptic transmission. In vivo calcium fiber photometry analysis further verified that administration of (+)-borneol (100 mg/kg) inhibited the enhanced glutamatergic synaptic transmission in epilepsy mice. We conclude that (+)-borneol displays broad-spectrum anti-seizure potential in different experimental models via decreasing the glutamatergic synaptic transmission without obvious side-effect, suggesting (+)-borneol as a promising anti-seizure compound for pharmacotherapy in epilepsy.

ABCA7*V1599M variant in 5xFAD mice mediates differences in amyloid‐beta pathology and reactive gliosis

AbstractBackgroundIn several large genome‐wide association studies (GWAS), genetic polymorphisms of ATP‐binding cassette transporter subfamily A member 7 (Abca7) have been identified as a risk factor for late‐onset Alzheimer’s Disease (LOAD). ABCA7 is a member of a family of ATP‐binding cassette (ABC) transporters and functions as a transmembrane protein mediating the release of cholesterols and phospholipids from cellular membranes. Previous studies have also proposed its role in mediating phagocytic clearance of amyloid beta (Aβ) oligomers within macrophages in the brain.MethodTo study the effects of ABCA7 on the development of AD relevant pathologies we introduced an equivalent coding sequence change that has been identified as a risk variant for LOAD (V1613M) into the C57BL/6 mouse genome using CRISPR/Cas9 (V1599M). We set out to characterize the ABCA7V1599M variant and investigate its impact on AD pathology when crossed with 5xFAD transgenic mice, generating four distinct groups: WT, ABCA7V1599M homozygous, 5xFAD, and 5xFAD x ABCA7V1599M homozygous. Characterization was performed using histological staining and biochemical approaches.ResultCoronal brain sections from 4‐month‐old mice (n=5‐6 mice/sex/genotype) revealed significantly reduced burden of dense‐core Aβ plaques in confocal images of both subiculum and visual cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice characterized by reduced Thioflavin‐S staining. Biochemical analysis mirrored these findings and demonstrated reductions of both soluble and insoluble Aβ40 and Aβ42 levels within these same brain regions. To examine reactive gliosis to plaque burden, we immuno‐stained for ionized calcium binding adaptor molecule 1 (IBA1) and glial fibrillary protein (GFAP) to visualize microglia and reactive astrocytes, respectively. Confocal analysis revealed reduced densities of both IBA1+ microglia and GFAP+ reactive astrocytes within subiculum and cortical regions of 5xFAD x ABCA7V1599M mice compared to 5xFAD mice. We also found reduced plaque‐associated neuritic damage in 5xFAD x ABCA7V1599M mice upon immuno‐staining for lysosome‐associated membrane glycoprotein 1 (LAMP1) to examine neuritic dystrophyConclusionTogether, these results characterize the effects of the Abca7em1Aduci allele and its ABCA7V1599M missense mutation on 5xFAD‐mediated pathology, specifically in Aβ plaque development, glial morphology, and neuritic damage.

Structure-Function Dissociations of Human Hippocampal Subfield Stiffness and Memory Performance.

Aging and neurodegenerative diseases lead to decline in thinking and memory ability. The subfields of the hippocampus (HCsf) play important roles in memory formation and recall. Imaging techniques sensitive to the underlying HCsf tissue microstructure can reveal unique structure-function associations and their vulnerability in aging and disease. The goal of this study was to use magnetic resonance elastography (MRE), a noninvasive MR imaging-based technique that can quantitatively image the viscoelastic mechanical properties of tissue to determine the associations of HCsf stiffness with different cognitive domains across the lifespan. Eighty-eight adult participants completed the study (age 23-81 years, male/female 36/51), in which we aimed to determine which HCsf regions most strongly correlated with different memory performance outcomes and if viscoelasticity of specific HCsf regions mediated the relationship between age and performance. Our results revealed that both interference cost on a verbal memory task and relational memory task performance were significantly related to cornu ammonis 1-2 (CA1-CA2) stiffness (p = 0.018 and p = 0.011, respectively), with CA1-CA2 stiffness significantly mediating the relationship between age and interference cost performance (p = 0.031). There were also significant associations between delayed free verbal recall performance and stiffness of both the dentate gyrus-cornu ammonis 3 (DG-CA3; p = 0.016) and subiculum (SUB; p = 0.032) regions. This further exemplifies the functional specialization of HCsf in declarative memory and the potential use of MRE measures as clinical biomarkers in assessing brain health in aging and disease.SIGNIFICANCE STATEMENT Hippocampal subfields are cytoarchitecturally unique structures involved in distinct aspects of memory processing. Magnetic resonance elastography is a technique that can noninvasively image tissue viscoelastic mechanical properties, potentially serving as sensitive biomarkers of aging and neurodegeneration related to functional outcomes. High-resolution in vivo imaging has invigorated interest in determining subfield functional specialization and their differential vulnerability in aging and disease. Applying MRE to probe subfield-specific cognitive correlates will indicate that measures of subfield stiffness can determine the integrity of structures supporting specific domains of memory performance. These findings will further validate our high-resolution MRE method and support the potential use of subfield stiffness measures as clinical biomarkers in classifying aging and disease states.

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.

Dissecting the brain's fear systems responding to snake threats.

We examined the behavioural responses and Fos expression pattern of rats that were exposed to snake threats from shed snakeskin and a live snake. We differentiated the behavioural responses and the pattern of Fos expression in response to the odour cues and mild threat from a live snake. Animals exposed to the snake odour alone or to the confined snake showed a great deal of risk assessment. Conversely, the intensification of odour during exposure to the live snake decreased the threat ambiguity, and the animals froze for a significantly longer period. Our Fos analysis showed that a pathway formed by the posteroventral part of the medial amygdalar nucleus to the central part of the ventromedial hypothalamic nucleus appeared to be solely responsive to odour cues. In addition, we showed increased Fos expression in a parallel circuit comprising the lateral amygdalar nucleus, ventral subiculum, lateral septum, and juxtadorsomedial region of the lateral hypothalamic area that is responsive to both the odour and mild threat from a live snake. This path is likely to process the environmental boundaries of the threat to be avoided. Both paths merge into the dorsal premammillary nucleus and periaqueductal grey sites, which all increase Fos expression in response to the snake threats and are likely to organize the defensive responses. Moreover, we found that the snake threat mobilized the Edinger-Westphal and supraoculomotor nuclei, which are involved in stress adaptation and attentional mechanisms.

Age-related volumetric alterations in hippocampal subiculum region are associated with reduced retention of the “when” memory component

Although age-related differences in episodic memory function are well established, the differential reduction in fine-grain memory components and its underlying hippocampal mechanism remains unclear. Hence, the current study investigated, first, age-related differences in the recollection of the four components (who, when, where, and what) of verbal episodic memory and, second, these components’ associations with volumetric alterations in the hippocampal subfields. A total of 60 older and younger adults completed the Logical Memory test. The measurements of the volumes of the hippocampal subfields were obtained. The results revealed that older age was associated with poorer learning performance for when, where, and what components but not for who component; the reduced learning scores were differentially correlated with the age-related regional vulnerability of the dentate gyrus, CA1 subfield, and subiculum. The age-related vulnerability in the retention of the when component was associated with smaller subiculum, CA1, CA4, and dentate gyrus, but a reduction in the subiculum alone mediated the inverse relationship between age and the retention score for the when component. Our findings underscore the value of differentiating between memory components in evaluations of verbal contextual episodic memory which allows the analyst to examine aging-related associations between subtle cognitive changes and hippocampal substructures.

Serotonin transporter in the temporal lobe, hippocampus and amygdala in SUDEP.

Several lines of evidence link deficient serotonin function and SUDEP. Chronic treatment with serotonin reuptake inhibitors (SRIs) reduces ictal central apnoea, a risk factor for SUDEP. Reduced medullary serotonergic neurones, modulators of respiration in response to hypercapnia, were reported in a SUDEP post‐mortem series. The amygdala and hippocampus have high serotonergic innervation and are functionally implicated in seizure‐related respiratory dysregulation. We explored serotonergic networks in mesial temporal lobe structures in a surgical and post‐mortem epilepsy series in relation to SUDEP risk. We stratified 75 temporal lobe epilepsy patients with hippocampal sclerosis (TLE/HS) into high (N = 16), medium (N = 11) and low risk (N = 48) groups for SUDEP based on generalised seizure frequency. We also included the amygdala in 35 post‐mortem cases, including SUDEP (N = 17), epilepsy controls (N = 10) and non‐epilepsy controls (N = 8). The immunohistochemistry labelling index (LI) and axonal length (AL) of serotonin transporter (SERT)‐positive axons were quantified in 13 regions of interest with image analysis. SERT LI was highest in amygdala and subiculum regions. In the surgical series, higher SERT LI was observed in high risk than low risk cases in the dentate gyrus, CA1 and subiculum (p < 0.05). In the post‐mortem cases higher SERT LI and AL was observed in the basal and accessory basal nuclei of the amygdala and peri‐amygdala cortex in SUDEP compared to epilepsy controls (p < 0.05). Patients on SRI showed higher SERT in the dentate gyrus (p < 0.005) and CA4 (p < 0.05) but there was no difference in patients with or without a psychiatric history. Higher SERT in hippocampal subfields in TLE/HS cases with SUDEP risk factors and higher amygdala SERT in post‐mortem SUDEP cases than epilepsy controls supports a role for altered serotonergic networks involving limbic regions in SUDEP. This may be of functional relevance through reduced 5‐HT availability.

Analysis of Hippocampus Evolution Patterns and Prediction of Conversion in Mild Cognitive Impairment Using Multivariate Morphometry Statistics.

Mild cognitive impairment (MCI), which is generally regarded as the prodromal stage of Alzheimer's disease (AD), is associated with morphological changes in brain structures, particularly the hippocampus. However, the indicators for characterizing the deformation of hippocampus in conventional methods are not precise enough and ignore the evolution information with the course of disease. The purpose of this study was to investigate the temporal evolution pattern of MCI and predict the conversion of MCI to AD by using the multivariate morphometry statistics (MMS) as fine features. First, we extracted MMS features from MRI scans of 64 MCI converters (MCIc), 81 MCI patients who remained stable (MCIs), and 90 healthy controls (HC). To make full use of the time information, the dynamic MMS (DMMS) features were defined. Then, the areas with significant differences between pairs of the three groups were analyzed using statistical methods and the atrophy/expansion were identified by comparing the metrics. In parallel, patch selection, sparse coding, dictionary learning and maximum pooling were used for the dimensionality reduction and the ensemble classifier GentleBoost was used to classify MCIc and MCIs. The longitudinal analysis revealed that the atrophy of both MCIc and MCIs mainly distributed in dorsal CA1, then spread to subiculum and other regions gradually, while the atrophy area of MCIc was larger and more significant. And the introduction of longitudinal information promoted the accuracy to 91.76% for conversion prediction. The dynamic information of hippocampus holds a huge potential for understanding the pathology of MCI.