Development and validation of a quality control procedure for automatic segmentation of hippocampal subfields.

Automatic segmentation methods for in vivo magnetic resonance imaging are increasing in popularity because of their high efficiency and reproducibility. However, automatic methods can be perfectly reliable and consistently wrong, and the validity of automatic segmentation methods cannot be taken for granted. Quality control (QC) by trained and reliable human raters is necessary to ensure the validity of automatic measurements. Yet QC practices for applied neuroimaging research are underdeveloped. We report a detailed QC and correction procedure to accompany our validated atlas for hippocampal subfield segmentation. We document a two-step QC procedure for identifying segmentation errors, along with a taxonomy of errors and an error severity rating scale. This detailed procedure has high between-rater reliability for error identification and manual correction. The latter introduces at maximum 3% error variance in volume measurement. All procedures were cross-validated on an independent sample collected at a second site with different imaging parameters. The analysis of error frequency revealed no evidence of bias. An independent rater with a third sample replicated procedures with high within-rater reliability for error identification and correction. We provide recommendations for implementing the described method along with hypothesis testing strategies. In sum, we present a detailed QC procedure that is optimized for efficiency while prioritizing measurement validity and suits any automatic atlas.

Swimming exercise prevents hippocampal dendritic spine changes and memory loss caused by aging: An application of a new semi-automated spine analysis software.

Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated with synapse function. If neurons degrade or are damaged, the spine morphology of neurons changes. Given that most commercially available spine analysis software is expensive and complex, this study investigated a semi-automated spine analysis software, CTSpine, and used previously published data to verify the accuracy of the analysis results of this software. We also applied CTSpine to understand whether aging causes alterations in the hippocampal spine morphology and whether physical exercise can impede dendritic spine changes in 20 male Sprague Dawley rats. The spines of pyramidal cells in the hippocampal Cornu Ammonis 1 (CA1) region in the aging group were more enriched in filopodium type pattern than those in the control group, whereas the spines of the exercised aging group showed a similar pattern to that of the control. No significant changes were observed in neuronal dendritic spines in other hippocampal regions. However, long-term hippocampal memory was considerably decreased in the aging group, which was reversed to some extent in the exercised aging group. CTSpine, a self-developed semi-automatic spine analysis software, showed results similar to those noted in published data and can be effectively applied to the study of dendritic patterns, including neurodevelopment and disease.

Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer's Disease Are Brain Region-Specific.

Alzheimer's disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-ß (Aß) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aß plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APPNL-F/NL-F mouse model of AD, aged-matched (2-5 and 12-16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APPNL-F/NL-F mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APPNL-F/NL-F mice showed regions of dense Aß plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis.

Proteomic Analysis of Adult Human Hippocampal Subfields Demonstrates Regional Heterogeneity in the Protein Expression.

Background: Distinct hippocampal subfields are known to get affected during aging, psychiatric disorders, and various neurological and neurodegenerative conditions. To understand the biological processes associated with each subfield, it is important to understand its heterogeneity at the molecular level. To address this lacuna, we investigated the proteomic analysis of hippocampal subfields─the cornu ammonis sectors (CA1, CA2, CA3, CA4) and dentate gyrus (DG) from healthy adult human cohorts. Findings: Microdissection of hippocampal subfields from archived formalin-fixed paraffin-embedded tissue sections followed by TMT-based multiplexed proteomic analysis resulted in the identification of 5,593 proteins. Out of these, 890 proteins were found to be differentially abundant among the subfields. Further bioinformatics analysis suggested proteins related to gene splicing, transportation, myelination, structural activity, and learning processes to be differentially abundant in DG, CA4, CA3, CA2, and CA1, respectively. A subset of proteins was selected for immunohistochemistry-based validation in an independent set of hippocampal samples. Conclusions: We believe that our findings will effectively pave the way for further analysis of the hippocampal subdivisions and provide awareness of its subfield-specific association to various neurofunctional anomalies in the future. The current mass spectrometry data is deposited and publicly made available through ProteomeXchange Consortium via the PRIDE partner repository with the data set identifier PXD029697.

Abnormal resting-state functional connectivity of hippocampal subfields in patients with major depressive disorder.

BACKGROUND: Many studies have found that the hippocampus plays a very important role in major depressive disorder (MDD). The hippocampus can be divided into three subfields: the cornu ammonis (CA), dentate gyrus (DG) and subiculum. Each subfield of the hippocampus has a unique function and are differentially associated with the pathological mechanisms of MDD. However, no research exists to describe the resting state functional connectivity of each hippocampal subfield in MDD. METHODS: Fifty-five patients with MDD and 25 healthy controls (HCs) matched for gender, age and years of education were obtained. A seed-based method that imposed a template on the whole brain was used to assess the resting-state functional connectivity (rsFC) of each hippocampal subfield. RESULTS: Patients with MDD demonstrated increased connectivity in the left premotor cortex (PMC) and reduced connectivity in the right insula with the CA seed region. Increased connectivity was reported in the left orbitofrontal cortex (OFC) and left ventrolateral prefrontal cortex (vlPFC) with the DG seed region. The subiculum seed region revealed increased connectivity with the left premotor cortex (PMC), the right middle frontal gyrus (MFG), the left ventrolateral prefrontal cortex (vlPFC) and reduced connectivity with the right insula. ROC curves confirmed that the differences between groups were statistically significant. CONCLUSION: The results suggest that the CA, DG and subiculum have significant involvement with MDD. Specifically, the abnormal functional connectivity of the CA may be related to bias of coding and integration of information in patients with MDD. The abnormal functional connectivity of the DG may be related to the impairment of working memory in patients with MDD, and the abnormal functional connectivity of the subiculum may be related to cognitive impairment and negative emotions in patients with MDD.

Hippocampal sub-regional differences in the microRNA response to forebrain ischemia.

Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.

Structural Changes in Hippocampal Subfields in Patients with Continuous Remission of Drug-Naive Major Depressive Disorder.

OBJECTIVE: Hippocampal volume is reduced in patients with major depressive disorder (MDD) compared with healthy controls. The hippocampus is a limbic structure that has a critical role in MDD. The aim of the present study was to investigate the changes in the volume of the hippocampus and its subfields in MDD patients who responded to antidepressants and subsequently were in continuous remission. SUBJECTS AND METHODS: Eighteen patients who met the following criteria were enrolled in the present study: the DSM-IV-TR criteria for MDD, drug-naïve at least 8 weeks or more, scores on the 17-items of Hamilton Rating Scale for Depression (HAMD) of 14 points or more, and antidepressant treatment response within 8 weeks and continuous remission for at least 6 months. All participants underwent T1-weighted structural MRI and were treated with antidepressants for more than 8 weeks. We compared the volumes of the hippocampus, including its subfields, in responders at baseline to the volumes at 6 months. The volumes of the whole hippocampus and the hippocampal subfields were measured using FreeSurfer v6.0. RESULTS: The volumes of the left cornu Ammonis (CA) 3 (p = 0.016) and the granule cell layer of the dentate gyrus (GC-DG) region (p = 0.021) were significantly increased after 6 months of treatment compared with those at baseline. CONCLUSIONS: Increases in volume was observed in MDD patients who were in remission for at least 6 months.

Non-linear realignment improves hippocampus subfield segmentation reliability.

Participant movement can deleteriously affect MR image quality. Further, for the visualization and segmentation of small anatomical structures, there is a need to improve image quality, specifically signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), by acquiring multiple anatomical scans consecutively. We aimed to ameliorate movement artefacts and increase SNR in a high-resolution turbo spin-echo (TSE) sequence acquired thrice using non-linear realignment in order to improve segmentation consistency of the hippocampus subfields. We assessed the method in 29 young healthy participants, 11 Motor Neuron Disease patients, and 11 age matched controls at 7T, and 24 healthy adolescents at 3T. Results show improved image segmentation of the hippocampus subfields when comparing template-based segmentations with individual segmentations with Dice overlaps N = 75; ps < 0.001 (Friedman's test) and higher sharpness ps < 0.001 in non-linearly realigned scans as compared to linearly, and arithmetically averaged scans.

Acute slice preparation for electrophysiology increases spine numbers equivalently in the male and female juvenile hippocampus: a DiI labeling study.

Hippocampal slices are widely used for in vitro electrophysiological experiments to study underlying mechanisms for synaptic transmission and plasticity, and there is a growing appreciation for sex differences in synaptic plasticity. To date, several studies have shown that the process of making slices from male animals can induce synaptogenesis in cornu ammonis area 1 (CA1) pyramidal cells, but there is a paucity of data for females and other brain regions. In the current study we use microcrystals of the lipophilic carbocyanine dye DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate) to stain individual neurons in the CA1 and dentate gyrus (DG) hippocampal subfields of postnatal day 21 male and female rats. We show that the preparation of sections for electrophysiology produces significant increases in spines in sections obtained from females, similar to that observed in males. We also show that the procedures used for in vitro electrophysiology also result in significant spine increases in the DG and CA1 subfields. These results demonstrate the utility of this refined DiI procedure for staining neuronal dendrites and spines. They also show, for the first time, that in vitro electrophysiology slice preparations enhance spine numbers on hippocampal cells equivalently in both juvenile females and males.NEW & NOTEWORTHY This study introduces a new DiI technique that elucidates differences in spine numbers in juvenile female and male hippocampus, and shows that slice preparations for hippocampal electrophysiology in vitro may mask these differences.

High resolution in-vivo diffusion imaging of the human hippocampus.

The human hippocampus is a key target of many imaging studies given its capacity for neurogenesis, role in long term potentiation and memory, and nearly ubiquitous involvement in neurological and psychiatric conditions. Diffusion tensor imaging (DTI) has detected microstructural abnormalities of the human hippocampus associated with various disorders, but acquisitions have typically been limited to low spatial resolution protocols designed for whole brain (e.g. > 2 mm isotropic, >8 mm3 voxels), limiting regional specificity and worsening partial volume effects. The purpose here was to develop a simple DTI protocol using readily available standard single-shot EPI at 3T, capable of yielding much higher spatial resolution images (1 x 1 x 1 mm3) of the human hippocampus in a 'clinically feasible' scan time of ~6 min. A thin slab of twenty 1 mm slices oriented along the long axis of the hippocampus enabled efficient coverage and a shorter repetition time, allowing more diffusion weighted images (DWIs) per slice per unit time. In combination with this strategy, a low b value of 500 s/mm2 was chosen to help overcome the very low SNR of a 1 x 1 x 1 mm3 EPI acquisition. 1 mm isotropic mean DWIs (averaged over 120-128 DWIs) showed excellent detail of the hippocampal architecture (e.g. morphology and digitations, sub-regions, stratum lacunosum moleculare - SLM) that was not readily visible on 2 mm isotropic diffusion images. Diffusion parameters within the hippocampus were consistent across subjects and fairly homogenous across sub-regions of the hippocampus (with the exception of the SLM and tail). However, it is expected that DTI parameters will be sensitive to microstructural changes associated with a number of clinical disorders (e.g. epilepsy, dementia) and that this practical, translatable approach for high resolution acquisition will facilitate localized detection of hippocampal pathology.

Modulating adult neurogenesis through dietary interventions.

Three areas in the brain continuously generate new neurons throughout life: the subventricular zone lining the lateral ventricles, the dentate gyrus in the hippocampus and the median eminence in the hypothalamus. These areas harbour neural stem cells, which contribute to neural repair by generating daughter cells that then become functional neurons or glia. Impaired neurogenesis leads to detrimental consequences, such as depression, decline of cognitive abilities and obesity. Adult neurogenesis is a versatile process that can be modulated either positively or negatively by many effectors, external or endogenous. Diet can modify neurogenesis both ways, either directly by ways of food-borne molecules, or possibly by the modifications induced on gut microbiota composition. It is therefore critical to define dietary strategies optimal for the maintenance of the stem cell pools.

Sports-related brain injuries: connecting pathology to diagnosis.

Brain injuries are becoming increasingly common in athletes and represent an important diagnostic challenge. Early detection and management of brain injuries in sports are of utmost importance in preventing chronic neurological and psychiatric decline. These types of injuries incurred during sports are referred to as mild traumatic brain injuries, which represent a heterogeneous spectrum of disease. The most dramatic manifestation of chronic mild traumatic brain injuries is termed chronic traumatic encephalopathy, which is associated with profound neuropsychiatric deficits. Because chronic traumatic encephalopathy can only be diagnosed by postmortem examination, new diagnostic methodologies are needed for early detection and amelioration of disease burden. This review examines the pathology driving changes in athletes participating in high-impact sports and how this understanding can lead to innovations in neuroimaging and biomarker discovery.

Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment.

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe in in vivo 3 Tesla MRI. The method performs segmentation on a T2-weighted MRI scan with 0.4 × 0.4 × 2.0 mm(3) resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi-atlas label fusion and learning-based error correction. In contrast to earlier work on automatic subfield segmentation in T2-weighted MRI [Yushkevich et al., 2010], our approach requires no manual initialization, labels hippocampal subfields over a greater anterior-posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross-validation in 29 subjects from a study of amnestic mild cognitive impairment (aMCI) and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797), and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions.

Seven-Tesla MRI and neuroimaging biomarkers for Alzheimer's disease.

The goal of this paper was to review the effectiveness of using 7-T MRI to study neuroimaging biomarkers for Alzheimer's disease (AD). The authors reviewed the literature for articles published to date on the use of 7-T MRI to study AD. Thus far, there are 3 neuroimaging biomarkers for AD that have been studied using 7-T MRI in AD tissue: 1) neuroanatomical atrophy; 2) molecular characterization of hypointensities; and 3) microinfarcts. Seven-Tesla MRI has had mixed results when used to study the 3 aforementioned neuroimaging biomarkers for AD. First, in the detection of neuroanatomical atrophy, 7-T MRI has exciting potential. Historically, noninvasive imaging of neuroanatomical atrophy during AD has been limited by suboptimal resolution. However, now there is compelling evidence that the high resolution of 7-T MRI may help overcome this hurdle. Second, in detecting the characterization of hypointensities, 7-T MRI has had varied success. PET scans will most likely continue to lead in the noninvasive imaging of amyloid plaques; however, there is emerging evidence that 7-T MRI can accurately detect iron deposits within activated microglia, which may help shed light on the role of the immune system in AD pathogenesis. Finally, in the detection of microinfarcts, 7-T MRI may also play a promising role, which may help further elucidate the relationship between cerebrovascular health and AD progression.

Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2.

In light induced retinal degeneration (LIRD) photoreceptor cell death is mediated by caspase independent mechanisms. The activation of LEI/L-DNase II pathway in this model, is due to cathepsin D release from lysosomes, although the underlying mechanism remains poorly understood. In this paper we studied the involvement of calpains in lysosomal permeabilization. We investigated, for the first time, the calpain targets at lysosomal membrane level. We found that calpain 1 is responsible for lysosomal permeabilization by cleavage of the lysosomal associated membrane protein 2 (LAMP 2). Moreover, LAMP 2 degradation and lysosomal permeabilization were rescued by calpain inhibition and the use of MEF(-/-)lamp 2 cells indicates that the cleavage of LAMP 2A is essential for this permeabilization. Finally, we found that LAMP 2 is cleaved in LIRD, suggesting that the mechanism of calpain induced lysosomal permeabilization is not exclusive of a single cell death model. Overall, these data shed new light on understanding the mechanisms of lysosomal and caspase-independent cell death and point to the original targets for development of the new therapeutic protocols.

Nicotinamide pre-treatment ameliorates NAD(H) hyperoxidation and improves neuronal function after severe hypoxia.

Prolonged hypoxia leads to irreversible loss of neuronal function and metabolic impairment of nicotinamide adenine dinucleotide recycling (between NAD(+) and NADH) immediately after reoxygenation, resulting in NADH hyperoxidation. We test whether the addition of nicotinamide (to enhance NAD(+) levels) or PARP-1 inhibition (to prevent consumption of NAD(+)) can be effective in improving either loss of neuronal function or hyperoxidation following severe hypoxic injury in hippocampal slices. After severe, prolonged hypoxia (maintained for 3min after spreading depression) there was hyperoxidation of NADH following reoxygenation, an increased soluble NAD(+)/NADH ratio, loss of neuronal field excitatory post-synaptic potential (fEPSP) and decreased ATP content. Nicotinamide incubation (5mM) 2h prior to hypoxia significantly increased total NAD(H) content, improved neuronal recovery, enhanced ATP content, and prevented NADH hyperoxidation. The nicotinamide-induced increase in total soluble NAD(H) was more significant in the cytosolic compartment than within mitochondria. Prolonged incubation with PJ-34 (>1h) led to enhanced baseline NADH fluorescence prior to hypoxia, as well as improved neuronal recovery, NADH hyperoxidation and ATP content on recovery from severe hypoxia and reoxygenation. In this acute model of severe neuronal dysfunction prolonged incubation with either nicotinamide or PJ-34 prior to hypoxia improved recovery of neuronal function, enhanced NADH reduction and ATP content, but neither treatment restored function when administered during or after prolonged hypoxia and reoxygenation.

Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus.

Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus.

Detection of altered hippocampal morphology in multiple sclerosis-associated depression using automated surface mesh modeling.

Depression is very common in multiple sclerosis (MS) but the underlying biological mechanisms are poorly understood. The hippocampus plays a key role in mood regulation and is implicated in the pathogenesis of depression. This study utilizes volumetric and shape analyses of the hippocampus to characterize neuroanatomical correlates of depression in MS. A cross-section of 109 female patients with MS was evaluated. Bilateral hippocampi were segmented from MRI scans (volumetric T1 -weighted, 1 mm(3) ) using automated tools. Shape analysis was performed using surface mesh modeling. Depression was assessed using the Center for Epidemiologic Studies-Depression (CES-D) scale. Eighty-three subjects were classified as low depression (CES-D 0-20) versus 26 subjects with high depression (CES-D ≥ 21). Right hippocampal volumes (P = 0.04) were smaller in the high depression versus the low depression groups, but there was no significant difference in left hippocampal volumes. Surface rendering analysis revealed that hippocampal shape changes in depressed patients with MS were clustered in the right hippocampus. Significant associations were found between right hippocampal shape and affective symptoms but not vegetative symptoms of depression. Our results suggested that regionally clustered reductions in hippocampal thickness can be detected by automated surface mesh modeling and may be a biological substrate of MS depression in female patients.

Therapeutic effects of a new bithiophene against aluminum -induced Alzheimer's disease in a rat model: Pathological and ultrastructural approach.

Alzheimer's disease (AD) remains of unknown etiology and lacks a cure. This study aimed to evaluate the therapeutic potential of a novel bithiophene derivative at two doses against AlCl3-induced AD in a rat model. Adult male rats (Rattus norvegicus) were divided into six groups (n=6): Group one consisted of naïve animals, group two received bithiophene (1 mg/kg) every other day for 30 days, and groups 3-6 were subjected to AlCl3 (100 mg/kg, equivalent to 20.23 mg Al3+) for 45 consecutive days. Groups four and five received low (0.5 mg/kg) or high (1 mg/kg) doses of bithiophene, respectively. Group six received memantine (20 mg/kg) daily for 30 days. All treatments were administered orally. Aluminum exposure resulted in severe degeneration of both histological and ultrastructural aspects of cells. Administration of the low dose of bithiophene significantly restored the number of CA1 pyramidal cells and the thickness of the stratum granulosum of the dentate gyrus. However, the high dose of bithiophene increased viable CA1 pyramidal cell numbers significantly without restoring the thickness of the stratum granulosum or reducing vacuolization or pyknotic changes. The low dose of bithiophene restored the normal histological and cytological structure of both cortical and hippocampal neurons affected by dementia. Further investigation is required to explore the molecular mechanisms underlying the ameliorative effects on Alzheimer's disease-induced deteriorations in the cortex and hippocampus.

Precise Definition of Porcine Hippocampal Cornu Ammonis 2: High Histoarchitectural Similarity to Humans but Unequal Sensitivity to Hypoxia.

Experimental animal studies of hypoxic-ischemic injury of the hippocampus of pigs are limited due to the unprecise definition of hippocampal subfields, cornu ammonis 1 to 4, compared to humans. Given that the pig model closely mirrors human physiology and serves as an important model for critical care research, a more precise description is necessary to draw valid conclusions applicable to human diseases. In our study, we were able to precisely define the CA2 and its adjacent regions in a domestic pig model by arginine vasopressin receptor 1B (AVPR1B) and calbindin-D28K like (CaBP-Li) expression patterns. Our findings demonstrate that the histoarchitecture of the porcine cornu ammonis subfields closely resembles that of the human hippocampus. Notably, we identified unusually strong neuronal damage in regions of the pig hippocampus following global ischemia, which are typically not susceptible to hypoxic-ischemic damage in humans.