Hippocampal Subregions Research Articles

Cognitive Function Assessment and Prediction for Subjective Cognitive Decline and Mild Cognitive Impairment.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative dementia. Recent studies found that subjective cognitive decline (SCD) may be the early clinical precursor that precedes mild cognitive impairment (MCI) for AD. SCD subjects with normal cognition may already have some medial temporal lobe atrophy. Although brain changes by AD have been widely studied in the literature, it is still challenging to investigate the anatomical subtle changes in SCD. This paper proposes a machine learning framework by combination of sparse coding and random forest (RF) to identify the informative imaging biomarkers for assessment and prediction of cognitive functions and their changes in individuals with MCI, SCD and normal control (NC) using magnetic resonance imaging (MRI). First, we compute the volumes from both the regions of interest from whole brain and the subregions of hippocampus and amygdala as the features of structural MRIs. Then, sparse coding is applied to identify the relevant features. Finally, the proximity-based RF is used to combine three sets of volumetric features and establish a regression model for predicting clinical scores. Our method has double feature selections to better explore the relevant features for prediction and is evaluated with the T1-weighted structural MR images from 36 MCI, 112 SCD, 78 NC subjects. The results demonstrate the effectiveness of proposed method. In addition to hippocampus and amygdala, we also found that the fimbria, basal nucleus and cortical nucleus subregions are more important than other regions for prediction of Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores and their changes.

Advances in the MRI study of connectivity structure and functional mechanism of hippocampal subregions in humans

Advances in the MRI study of connectivity structure and functional mechanism of hippocampal subregions in humans

Semantic Segmentation of Hippocampal Subregions With U-Net Architecture

The Automatic semantic segmentation of the hippocampus is an important area of research in which several convolutional neural networks (CNN) models have been used to detect the hippocampus from whole cerebral MRI. In this paper we present two convolutional neural networks the first network ( Hippocampus Segmentation Single Entity HSSE) segmented the hippocampus as a single entity and the second used to detect the hippocampal sub-regions ( Hippocampus Segmentation Multi Class HSMC), these two networks inspire their architecture of the U-net model. Two cohorts were used as training data from (NITRC) (NeuroImaging Tools & Resources Collaboratory (NITRC)) annotated by ITK-SNAP software. We analyze this networks alongside other recent methods that do hippocampal segmentation, the results obtained are encouraging and reach dice scores greater than 0.84

Reductions in Synaptic Vesicle Glycoprotein 2 Isoforms in the Cortex and Hippocampus in a Rat Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) can produce lasting cognitive, emotional, and somatic difficulties that can impact quality of life for patients living with an injury. Impaired hippocampal function and synaptic alterations have been implicated in contributing to cognitive difficulties in experimental TBI models. In the synapse, neuronal communication is facilitated by the regulated release of neurotransmitters from docking presynaptic vesicles. The synaptic vesicle glycoprotein 2 (SV2) isoforms SV2A and SV2B play central roles in the maintenance of the readily releasable pool of vesicles and the coupling of calcium to the N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex responsible for vesicle docking. Recently, we reported the findings of TBI-induced reductions in presynaptic vesicle density and SNARE complex formation; however, the effect of TBI on SV2 is unknown. To investigate this, rats were subjected to controlled cortical impact (CCI) or sham control surgery. Abundance of SV2A and SV2B were assessed at 1, 3, 7, and 14days post-injury by immunoblot. SV2A and SV2B were reduced in the cortex at several time points and in the hippocampus at every time point assessed. Immunohistochemical staining and quantitative intensity measurements completed at 14days post-injury revealed reduced SV2A immunoreactivity in all hippocampal subregions and reduced SV2B immunoreactivity in the molecular layer after CCI. Reductions in SV2A abundance and immunoreactivity occurred concomitantly with motor dysfunction and spatial learning and memory impairments in the 2weeks post-injury. These findings provide novel evidence for the effect of TBI on SV2 with implications for impaired neurotransmission neurobehavioral dysfunction after TBI.

Sub-regional hippocampal volumes in first-episode drug-naïve major depression disorder

Hippocampal volume reduction was reported to underlie depressive symptomatology, however, the evidence to date remains inconsistent. For the complex intrinsic organization of hippocampus, the hippocampal volumes can be further divided into subfields or axial parts. The current study aimed to explore the alterations of hippocampal sub-regional volumes in first episode drug-naïve major depressive disorder (MDD) by two segmentation methods. Thirty-five first-episode drug-naïve MDD and 35 age- and gender-matched healthy controls (HC) were recruited. Volumes of three sub-regions of hippocampus along the longitudinal axis (head, body and tail) were analyzed manually and eight transverse subfields were automatically determined using FreeSurfer. An asymmetric index (AI) of volumes was defined as (∣Left − Right∣/∣Left + Right∣) * 100. There were significant reductions in the volumes of bilateral hippocampal head in MDD compared to HC. The volumes of eight subfields were not different between groups. MDD patients had higher AI values in the subfield of cornu ammonis 4/dentate gyrus than HC. The change in hippocampal sub-regional volumes might be an imaging biomarker in the first-episode, drug-naïve patients with MDD. Current findings may contribute to developing new diagnostic and therapeutic strategies for major depression.

Microglial inclusions and neurofilament light chain release follow neuronal \u03b1-synuclein lesions in long-term brain slice cultures

BackgroundProteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression.MethodsAlpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed.ResultsTo study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2–3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture’s genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions.ConclusionThe successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.

A Shift in Tissue Stiffness During Hippocampal Maturation Correlates to the Pattern of Neurogenesis and Composition of the Extracellular Matrix.

Aging changes the mechanical properties of brain tissue, such as stiffness. It has been proposed that the maintenance and differentiation of neural stem cells (NSCs) are regulated in accordance with extracellular stiffness. Neurogenesis is observed in restricted niches, including the dentate gyrus (DG) of the hippocampus, throughout mammalian lifetimes. However, profiles of tissue stiffness in the DG in comparison with the activity of NSCs from the neonatal to the matured brain have rarely been addressed so far. Here, we first applied ultrasound-based shear-wave elasticity imaging (SWEI) in living animals to assess shear modulus as in vivo brain stiffness. To complement the assay, atomic force microscopy (AFM) was utilized to determine the Young’s modulus in the hippocampus as region-specific stiffness in the brain slice. The results revealed that stiffness in the granule cell layer (GCL) and the hilus, including the subgranular zone (SGZ), increased during hippocampal maturation. We then quantified NSCs and immature neural cells in the DG with differentiation markers, and verified an overall decrease of NSCs and proliferative/immature neural cells along stages, showing that a specific profile is dependent on the subregion. Subsequently, we evaluated the amount of chondroitin sulfate proteoglycans (CSPGs), the major extracellular matrix (ECM) components in the premature brain by CS-56 immunoreactivity. We observed differential signal levels of CSPGs by hippocampal subregions, which became weaker during maturation. To address the contribution of the ECM in determining tissue stiffness, we manipulated the function of CSPGs by enzymatic digestion or supplementation with chondroitin sulfate, which resulted in an increase or decrease of stiffness in the DG, respectively. Our results illustrate that stiffness in the hippocampus shifts due to the composition of ECM, which may affect postnatal neurogenesis by altering the mechanical environment of the NSC niche.

Developmental regulation and lateralization of N-methyl-d-aspartate (NMDA) receptors in the rat hippocampus

N-methyl-d-aspartate receptors (NMDARs) are expressed abundantly in the brain and play a crucial role in the regulation of central nervous system (CNS) development, learning, and memory. During early neuronal development, NMDARs modulate neurogenesis, neuronal differentiation and migration, and synaptogenesis. The present study aimed to examine the developmental expression of NMDARs subunits, NR1 and NR2B, in the developing hippocampus of neonatal rats during the first two postnatal weeks. Fifty-four male offspring were randomly divided into three age groups, postnatal days (P) 0, 7, and 14. Real-time-PCR, western blotting, and immunohistochemistry (IHC) analyses were employed to examine and compare the hippocampal expression of the NMDA receptor subunits. The highest mRNA expression of NR1 and NR2B subunits was observed at P7, regardless of its laterality. The mRNA expression of both subunits in the right hippocampus was significantly higher than that of the left one at P0 and P7. Similarly, the highest protein level expression of NR1 and NR2B subunits was also observed at P7 in both sides hippocampi. Although the protein expression of NR1 was significantly higher on the right side in all studied days, the NR2B was significantly higher in the right hippocampus only at P7. The analysis of optical density (OD) has shown a marked increase in the distribution pattern of the NR1 and NR2B subunits at P7 in all hippocampal subregions. In conclusion, there is a marked right-left asymmetry in the expression of NR1 and NR2B subunits in the developing rat hippocampus, which might be considered as a probable mechanism for the lateral differences in the structure and function of the hippocampus in rats.

A novel method for detecting heteromeric complexes at synaptic level by combining a modified method of proximity ligation assay with transmission electron microscopy

The heteromeric complexes of adenosine 2A receptor (A2AR) and N-methyl-D-aspartate receptor (NMDAR) have recently been confirmed in cell experiments, while its in situ detection at the subcellular level of brain tissue has not yet been achieved. Proximity Ligation Assay (PLA) enables the detection of low-abundance proteins and their interactions at the cellular level with high specificity and sensitivity, while Transmission electron microscope (TEM) is an excellent tool for observing subcellular structures. To develop a highly efficient and reproducible technique for in situ detection of protein interactions at subcellular levels, in this study, we modified the standard PLA sample preparation method to make the samples suitable for analysis by transmission electron microscopy. Using this technique, we successfully detected the heteromers of A2AR and NMDAR1, the essential subunit of NMDA receptor on the hippocampal synaptic structure in mice. Our results show that the distribution of this heteromer is different in different hippocampal subregions. This technique holds the potential for being a reliable method to detect protein interactions at the subcellular level and unravel their unknown functions.

The coupling of RACK1 with the beta isoform of the glucocorticoid receptor promotes resilience to chronic stress exposure

Several intracellular pathways that contribute to the adaptation or maladaptation to environmental challenges mediate the vulnerability and resilience to chronic stress. The activity of the hypothalamic-pituitary-adrenal (HPA) axis is fundamental for the proper maintenance of brain processes, and it is related to the functionality of the isoform alfa and beta of the glucocorticoid receptor (Gr), the primary regulator of HPA axis. Among the downstream effectors of the axis, the scaffolding protein RACK1 covers an important role in regulating synaptic activity and mediates the transcription of the neurotrophin Bdnf. Hence, by employing the chronic mild stress (CMS) paradigm, we studied the role of the Grβ-RACK1-Bdnf signaling in the different susceptibility to chronic stress exposure. We found that resilience to two weeks of CMS is paralleled by the activation of this pathway in the ventral hippocampus, the hippocampal subregion involved in the modulation of stress response. Moreover, the results we obtained in vitro by exposing SH-SY5Y cells to cortisol support the data we found in vivo. The results obtained add novel critical information about the link among Gr, RACK1 and Bdnf and the resilience to chronic stress, suggesting novel targets for the treatment of stress-related disorders, including depression.

Glutamatergic receptor expression changes in the Alzheimer's disease hippocampus and entorhinal cortex.

Alzheimer's Disease (AD) is the leading form of dementia worldwide. Currently, the pathological mechanisms underlying AD are not well understood. Although the glutamatergic system is extensively implicated in its pathophysiology, there is a gap in knowledge regarding the expression of glutamate receptors in the AD brain. This study aimed to characterize the expression of specific glutamate receptor subunits in post‐mortem human brain tissue using immunohistochemistry and confocal microscopy. Free‐floating immunohistochemistry and confocal laser scanning microscopy were used to quantify the density of glutamate receptor subunits GluA2, GluN1, and GluN2A in specific cell layers of the hippocampal sub‐regions, subiculum, entorhinal cortex, and superior temporal gyrus. Quantification of GluA2 expression in human post‐mortem hippocampus revealed a significant increase in the stratum (str.) moleculare of the dentate gyrus (DG) in AD compared with control. Increased GluN1 receptor expression was found in the str. moleculare and hilus of the DG, str. oriens of the CA2 and CA3, str. pyramidale of the CA2, and str. radiatum of the CA1, CA2, and CA3 subregions and the entorhinal cortex. GluN2A expression was significantly increased in AD compared with control in the str. oriens, str. pyramidale, and str. radiatum of the CA1 subregion. These findings indicate that the expression of glutamatergic receptor subunits shows brain region‐specific changes in AD, suggesting possible pathological receptor functioning. These results provide evidence of specific glutamatergic receptor subunit changes in the AD hippocampus and entorhinal cortex, indicating the requirement for further research to elucidate the pathophysiological mechanisms it entails, and further highlight the potential of glutamatergic receptor subunits as therapeutic targets.

Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats

Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

SREBP-1c Deficiency Affects Hippocampal Micromorphometry and Hippocampus-Dependent Memory Ability in Mice.

Changes in structural and functional neuroplasticity have been implicated in various neurological disorders. Sterol regulatory element-binding protein (SREBP)-1c is a critical regulatory molecule of lipid homeostasis in the brain. Recently, our findings have shown the potential involvement of SREBP-1c deficiency in the alteration of novel modulatory molecules in the hippocampus and occurrence of schizophrenia-like behaviors in mice. However, the possible underlying mechanisms, related to neuronal plasticity in the hippocampus, are yet to be elucidated. In this study, we investigated the hippocampus-dependent memory function and neuronal architecture of hippocampal neurons in SREBP-1c knockout (KO) mice. During the passive avoidance test, SREBP-1c KO mice showed memory impairment. Based on Golgi staining, the dendritic complexity, length, and branch points were significantly decreased in the apical cornu ammonis (CA) 1, CA3, and dentate gyrus (DG) subregions of the hippocampi of SREBP-1c KO mice, compared with those of wild-type (WT) mice. Additionally, significant decreases in the dendritic diameters were detected in the CA3 and DG subregions, and spine density was also significantly decreased in the apical CA3 subregion of the hippocampi of KO mice, compared with that of WT mice. Alterations in the proportions of stubby and thin-shaped dendritic spines were observed in the apical subcompartments of CA1 and CA3 in the hippocampi of KO mice. Furthermore, the corresponding differential decreases in the levels of SREBP-1 expression in the hippocampal subregions (particularly, a significant decrease in the level in the CA3) were detected by immunofluorescence. This study suggests that the contributions of SREBP-1c to the structural plasticity of the mouse hippocampus may have underlain the behavioral alterations. These findings offer insights into the critical role of SREBP-1c in hippocampal functioning in mice.

Parcellation of the Hippocampus According to Its Connection Probability with Prefrontal Cortex Subdivisions in a Malaysian Malay Population: Preliminary Findings.

BackgroundLesion studies have shown distinct roles for the hippocampus, with the dorsal subregion being involved in processing of spatial information and memory, and the ventral aspect coding for emotion and motivational behaviour. However, its structural connectivity with the subdivisions of the prefrontal cortex (PFC), the executive area of the brain that also has various distinct functions, has not been fully explored, especially in the Malaysian population.MethodsWe performed diffusion magnetic resonance imaging with probabilistic tractography on four Malay males to parcellate the hippocampus according to its relative connection probability to the six subdivisions of the PFC.ResultsOur findings revealed that each hippocampus showed putative connectivity to all the subdivisions of PFC, with the highest connectivity to the orbitofrontal cortex (OFC). Parcellation of the hippocampus according to its connection probability to the six PFC subdivisions showed variability in the pattern of the connection distribution and no clear distinction between the hippocampal subregions.ConclusionHippocampus displayed highest connectivity to the OFC as compared to other PFC subdivisions. We did not find a unifying pattern of distribution based on the connectivity-based parcellation of the hippocampus.

Fluoxetine exerts subregion/layer specific effects on parvalbumin/GAD67 protein expression in the dorsal hippocampus of male rats showing social isolation-induced depressive-like behaviour

The molecular background of depression is intensively studied in terms of alterations of inhibitory circuits, mediated by gamma aminobutyric acid (GABA) signalization. We investigated the effects of chronic social isolation (CSIS) and chronic fluoxetine (Flx) treatment (15 mg/kg/day) (3 weeks), on Parvalbumin (PV) and GAD67 expression in a layer-specific manner in rat dorsal hippocampal subregions. CSIS-induced depressive- and anxiety-like behaviours were confirmed with decrease in sucrose preference and increase in marble burying during behavioural testing, while Flx antagonized these effects. CSIS altered PV expression in stratum pyramidale (SP) of dorsal cornu ammonis 1 (dCA1) and stratum radiatum (SR) of dCA3. Flx antagonized this effect, and boosted PV expression in SP of the entire dCA and the dorsal dentate gyrus (dDG), as well as in the SR of dCA1/CA3. CSIS showed no significant effects on GAD67 expression, while Flx boosted its expression within the SR of the entire CA and SO of the dCA3. A correlation between SP of dCA1 and SR of dCA3 with regard to PV changes, implicates their possible role in the inhibitory circuit alterations. Flx-induced increase in GAD67 expression, specifically in SR of the entire dHIPP, may impose its involvement in the cell metabolic processes. Strong negative correlation between GAD67 and sucrose preference following Flx-treatment of CSIS rats was revealed. PV + cells of the SP layer of dCA1 and CA2 could be a potential target for the antidepressant action of Flx, while strong effect of Flx on GAD67 expression in the SR should be more extensively studied.

Atrophy of lacunosum moleculare layer is important for learning and memory in APP/PS1 transgenic mice

Changes in the hippocampus are closely associated with learning and memory in Alzheimer's disease; however, it is not clear which morphological and cellular and subcellular changes are essential for learning and memory. Here, we accurately quantitatively studied the hippocampal microstructure changes in Alzheimer's disease model mice and analyzed the relationship between the hippocampal microstructure changes and learning and memory. Ten-month-old male APP/PS1 transgenic mice and age-matched nontransgenic littermate mice were randomly selected. The spatial learning and memory abilities were assessed using the Morris water maze. The volumes of each layer and numbers of neurons, dendritic spines and oligodendrocytes in the hippocampal subregions were investigated using unbiased stereological techniques. The APP/PS1 transgenic mice showed a decline in hippocampus-dependent spatial learning and memory abilities, smaller volumes of each layer (other than stratum radiatum) and fewer numbers of neurons, dendritic spine synapses and mature oligodendrocytes in the hippocampal subregions than nontransgenic mice. In particular, the decline of spatial learning ability was significantly correlated with the atrophy of lacunosum moleculare layer (LMol) and the decrease of hippocampal neurons and mature oligodendrocytes rather than dendritic spines. The CA1-3 fields (including LMol) atrophy was significantly correlated with the decrease both of neurons, dendritic spines and mature oligodendrocytes. However, the dentate gyrus atrophy was significantly correlated with the decrease of neurons and mature oligodendrocytes rather than dendritic spines. The loss of neurons, dendritic spines synapses and mature oligodendrocytes together caused the LMol atrophy and then led to a decline in hippocampus-dependent spatial learning ability in mice with Alzheimer's disease.

The 5xFAD Mouse Model of Alzheimer's Disease Displays Early Stunting of Neuronal Development in the Dentate Gyrus: a Potential Novel Treatment Window for Dementias Associated with Amyloidosis?

Approximately 5.8 million people over the age of 65 are living with Alzheimer's Disease (AD), and the number of individuals afflicted with AD is projected to double by 2050. Hallmarks of AD are intraneural plaques of amyloid-beta and neurofibrillary tangles with concomitant and progressive decline in neuro-cognitive function. Currently, there is no cure for AD, which stems partly from the sporadic nature of the disease and “after-the-fact” treatments which have failed to remediate disease progression. The goal of our lab is to elucidate early markers of AD onset prior to overt disease occurrence. To this end, we are using the 5XFAD transgenic mouse model which displays an aggressive form of amyloidosis and associated dementias, which develop because of insertion of the five most common genetic mutations associated with aberrant amyloid processing found in AD. Typically, intraneural amyloid plaques develop at 2-4 months of age in 5xFAD mice and cognitive deficits are observed at 4 to 6 months of age. The objective of our current study was to determine characteristics of hippocampal neuronal arborization in 5xFAD mice and non-transgenic (WT) littermates at at 15 days, 1-month, and 3-months of age, which is thought to be a pre-symptomatic period. Mice were euthanized in strict accordance with AALAC guidelines and approved protocols. Isolated brains from male and female 5xFAD and WT mice were fixed and Golgi stained (Rapid Stain Golgi kit, FDNeurotechnologies). Fixed tissue was sectioned by a cryostat (100 um), and slides were imaged using a Leica DM6000 at 40X. Images were then reassembled in Z-stacks and analyzed with FIJI. A Sholl analysis was performed on the hippocampal subregions of the dentate gyrus (DG), cortical area 1 (CA1), and cortical area 3 (CA3) where dendritic length was the primary endpoint. Results showed that there was no shortening at 15 days and 3-months in 5XFAD versus WT, but there was a shortening of neurites in the 5XFAD versus WT at 1-month of age, mainly within the DG (p = 0.04969; N = 6). At 1-month, the dentate gyrus neurons were 108.2μm (p = 0.04969; N = 6), or 5% shorter, with observed simplification of arborization. The other hippocampal subregions did not display significant alterations in neuronal development. These results show that at an extreme early age, 5xFAD mice already show a lack of neuronal development that occurs prior to intraneuronal amyloid plaque appearance, especially in a hippocampal subregion known to be vulnerable to AD-related neuronal loss. This subregion is especially vulnerable due to the fact that amyloid beta accumulates in this region initially, which could lead to the noted shortening in neuronal length. The DG receives input from the entorhinal cortex and is relayed to CA3 via mossy fibers, which is imperative for long-term potentiation and spatial memory. This suggests that the so-called pre-symptomatic period will have to be re-evaluated. Furthermore, our data suggest that a potential window for treatments have been found which may aid in developing novel therapeutic regimens to slow or prevent progression of AD symptomology associated with amyloidosis.

Hippocampal Subregion and Gene Detection in Alzheimer's Disease Based on Genetic Clustering Random Forest.

The distinguishable subregions that compose the hippocampus are differently involved in functions associated with Alzheimer’s disease (AD). Thus, the identification of hippocampal subregions and genes that classify AD and healthy control (HC) groups with high accuracy is meaningful. In this study, by jointly analyzing the multimodal data, we propose a novel method to construct fusion features and a classification method based on the random forest for identifying the important features. Specifically, we construct the fusion features using the gene sequence and subregions correlation to reduce the diversity in same group. Moreover, samples and features are selected randomly to construct a random forest, and genetic algorithm and clustering evolutionary are used to amplify the difference in initial decision trees and evolve the trees. The features in resulting decision trees that reach the peak classification are the important “subregion gene pairs”. The findings verify that our method outperforms well in classification performance and generalization. Particularly, we identified some significant subregions and genes, such as hippocampus amygdala transition area (HATA), fimbria, parasubiculum and genes included RYR3 and PRKCE. These discoveries provide some new candidate genes for AD and demonstrate the contribution of hippocampal subregions and genes to AD.

Dietary Supplementation of Fenugreek Seed Extract and Choline-Docosahexaenoic acid on Oxidative Stress and Neurodegeneration in Ovariectomized Rats with Bilateral Common Carotid Artery Occlusion

As impairment of memory and ischemic brain injury is more common in female of menopausal age, the current study aims to evaluate the protective role of fenugreek seed extract and choline-Docosahexaenoic acid (DHA) on cognitive behavior, oxidative stress and neurodegeneration in ovariectomized-cerebral ischemic rats. Cerebral ischemia was induced by bilateral common carotid artery occlusion (BCCAO) surgery to ovariectomized adult female wistar rats. Fenugreek, choline-DHA and combination of fenugreek with choline-DHA was supplemented for 30days after ovariectomy and continued for 14 more days after BCCAO surgery. Effect of this supplementation on learning and memory, brain oxidative stress and neurodegeneration in the CA1, CA3 hippocampal sub-regions were analyzed. Ovariectomized-cerebral ischemic rats demonstrated learning and memory impairment when subjected to passive avoidance task. Further, these rats also had increased brain oxidative stress, and neurodegeneration in CA1, CA3 sub-regions of hippocampus. Conversely, combined supplementation of fenugreek with choline-DHA to ovariectomized-cerebral ischemic rats exhibited a significant improvement in their learning and memory abilities, with reduced oxidative stress and neurodegeneration in CA1 and CA3 sub-regions of hippocampus.

Sex Differences in Re-experiencing Symptoms Between Husbands and Wives Who Lost Their Only Child in China: A Resting-State Functional Connectivity Study of Hippocampal Subfields.

Background: Losing one’s only child may lead to post-traumatic stress disorder (PTSD), of which re-experiencing is the core symptom. However, neuroimaging studies of sex differences in re-experiencing in the context of the trauma of losing one’s only child and PTSD are scarce; comparisons of the functional networks from the hippocampal subfields to the thalamus might clarify the neural basis.Methods: Thirty couples without any psychiatric disorder who lost their only child (non-PTSD group), 55 patients with PTSD, and 50 normal controls underwent resting-state functional magnetic resonance imaging. The functional connectivity (FC) from the hippocampal subregions to the thalamus and the correlations of FC with re-experiencing symptoms were analyzed within and between the sexes.Results: Compared with husbands without PTSD, wives without PTSD had higher re-experiencing symptoms and weaker FC between the right hippocampal cornu ammonis 3 (RCA3) and the right thalamus (RT; RCA3-RT). Moreover, only the correlation between the RCA3-RT FC and re-experiencing in wives without PTSD was significant. Among the three groups, only the RCA3-RT FC in female subjects was markedly different. Additionally, the RCA3-RT FC in wives without PTSD was remarkably lower relative to female patients with PTSD.Conclusion: Wives without PTSD who lost their only child had worse re-experiencing symptoms relative to their husbands, which was associated with the FC alteration between the hippocampal subregions and the thalamus. Importantly, the low level of the RCA3-RT FC may play a potentially protective role against the development of PTSD in wives who have lost their only child.