Curved multiplanar reformatting allows the accurate histological delineation of hippocampal subfields.

BACKGROUND: Hippocampal subfields perform specific roles in normal cognitive functioning and have distinct vulnerabilities in neurological disorders. However, measurement of subfields with MRI is technically difficult in the head and tail of the hippocampus. Recent studies have utilized curved multiplanar reconstruction (CMPR) to improve subfield visualization in the head and tail, but this method has not yet been applied to histological data. METHODS: We utilized BigBrain data, an open-source database of serially sectioned histological data for our analyses. The left hippocampus was segmented according to histological criteria by two raters in order to evaluate intra- and inter-rater reliability of histology-based segmentation throughout the long axis. Segmentation according to our previous protocol for the hippocampal body was then compared to these histological measurements to evaluate for histological validity. Agreement between segmentations was evaluated using Dice similarity coefficients (DSCs). RESULTS: Intra-rater reliability (DSCs) of histological segmentation was excellent for all subfields: CA1 (0.8599), CA2 (0.7586), CA3/CA4/DG (0.8907), SLM (0.9123), subiculum (0.8149). Similarly, inter-rater reliability analysis demonstrated excellent agreement (DSCs) for all subfield locations: CA1 (0.8203), CA2 (0.7253), CA3/CA4/DG (0.8439), SLM (0.8700), subiculum (0.7794). Finally, histological accuracy (DSCs) for our previous protocol was excellent for all subfields: CA1 (0.8821), CA2 (0.8810), CA3/CA4/DG (0.9802), SLM (0.9879), subiculum (0.8774). When subfields in the hippocampus head, body, and tail were analyzed independently, DSCs also showed excellent agreement. CONCLUSIONS: CMPR allows reliable subfield segmentation based on histological criteria throughout the hippocampal head, body, and tail. Our previous protocol for the hippocampal body can be applied to provide histologically valid subfield measurements throughout the entire hippocampal long axis.

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.

TDP-43 Is Associated with Subiculum and Cornu Ammonis 1 Hippocampal Subfield Atrophy in Primary Age-Related Tauopathy.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aß (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Effect of lithium in pyramidal neurons of Cornu Ammonis in an animal model.

Bipolar disorder has been associated with a decrease in hippocampal size, and lithium appears to reverse this neuroanatomical abnormality. The objective of this work was to evaluate, at a cellular level, the size of both cell body and nucleus of pyramidal neurons located throughout the Cornu Ammonis (CA1 to CA4 regions). To perform this duty, we used 16 rats that were randomized into two groups: control and dietary lithium-treated. After one month, they were sacrificed and their brains removed for histopathological analysis. Serial photos of the entire Cornu Ammonis were taken and, after dividing them into 4 regions of interest, we measured the cell body and nucleus on each pyramidal neuron belonging to the first 5 photos of each region of interest. As a result of this histological analysis, cell body area and nuclear area were significantly larger in the experimental group in a specific area of the Cornu Ammonis that could correspond to CA2 or the transition between CA1 and CA2. These results suggest that the effect of lithium is not homogeneous throughout the hippocampus and allows directing future studies to a specific area of this structure.

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.

Quantitative analysis of the optogenetic excitability of CA1 neurons.

Introduction: Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Methods: Employing state-of-the-art computational models coupled with Monte Carlo simulated light propagation, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. Results and discussion: The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitable. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.

A new AAV tool for highly preferentially targeting hippocampal CA2.

Mice hippocampus contains three prominent subregions, CA1, CA3 and DG and is well regarded as an essential multiple task processor for learning, memory and cognition based on tremendous studies on these three subregions. The narrow region sandwiched between CA1 and CA3 called CA2 has been neglected for a long time. But it raises great attentions recently since this region manifests the indispensable role in social memory. Its unique physical position connecting CA1 and CA3 suggests the potential novel functions besides social memory regulation. But the CA2 is too small to be accurately targeted. A flexible AAV tool capable of accurately and efficiently targeting this region is highly demanded. To fill this gap, we generate an AAV expressing Cre driven by the mini Map3k15 promoter, AAV/M1-Cre, which can be easily utilized to help tracing and manipulating CA2 pyramidal neurons. However, M1-Cre labeled a small percentage of M1+RGS14- neurons that do not colocalize with any RGS14+/STEP+/PEP4+/Amigo2+ pyramidal neurons. They are proved to be the mixture of normal CA2 pyramidal neurons, CA3-like neurons in CA2-CA3 mixed border, some CA2 interneurons and rarely few CA1-like neurons, which are probably the ones projecting to the revealed CA2 downstream targets, VMH, STHY and PMV in WT mice injecting this AAV/M1-Cre virus but not in Amigo2-Cre mice. Though it is still challenging to get a pure CA2 tracking and manipulation system, this tool provides a new, more flexible and extended strategy for in-depth CA2 functional study in the future.

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.

Effects of glycogen synthase kinase-3ß activity inhibition on cognitive, behavioral, and hippocampal ultrastructural deficits in adulthood associated with adolescent methamphetamine exposure.

Objective: Glycogen synthase kinase-3ß (GSK3ß) has been implicated in the maintenance of synaptic plasticity, memory process, and psychostimulant-induced behavioral effects. Hyperactive GSK3ß in the Cornu Ammonis 1 (CA1) subregion of the dorsal hippocampus (DHP) was associated with adolescent methamphetamine (METH) exposure-induced behavioral and cognitive deficits in adulthood. This study aimed to evaluate the possible therapeutic effects of GSK3ß inhibition in adulthood on adolescent METH exposure-induced long-term neurobiological deficits. Methods: Adolescent male mice were treated with METH from postnatal day (PND) 45-51. In adulthood, three intervention protocols (acute lithium chloride systemic administration, chronic lithium chloride systemic administration, and chronic SB216763 administration within CA1) were used for GSK3ß activity inhibition. The effect of GSK3ß intervention on cognition, behavior, and GSK3ß activity and synaptic ultrastructure in the DHP CA1 subregion were detected in adulthood. Results: In adulthood, all three interventions reduced adolescent METH exposure-induced hyperactivity (PND97), while only chronic systemic and chronic within CA1 administration ameliorated the induced impairments in spatial (PND99), social (PND101) and object (PND103) recognition memory. In addition, although three interventions reversed the aberrant GSK3ß activity in the DHP CA1 subregion (PND104), only chronic systemic and chronic within CA1 administration rescued adolescent METH exposure-induced synaptic ultrastructure changes in the DHP CA1 subregion (PND104) in adulthood. Conclusion: Rescuing synaptic ultrastructural abnormalities in the dHIP CA1 subregion by chronic administration of a GSK3ß inhibitor may be a suitable therapeutic strategy for the treatment of behavioral and cognitive deficits in adulthood associated with adolescent METH abuse.

Stage- and Subfield-Associated Hippocampal miRNA Expression Patterns after Pilocarpine-Induced Status Epilepticus.

OBJECTIVE: To investigate microRNA (miRNA) expression profiles before and after pilocarpine-induced status epilepticus (SE) in the cornu ammonis (CA) and dentated gyrus (DG) areas of the mouse hippocampus, and to predict the downstream proteins and related pathways based on bioinformatic analysis. METHODS: An epileptic mouse model was established using a pilocarpine injection. Brain tissues from the CA and DG were collected separately for miRNA analysis. The miRNAs were extracted using a kit, and the expression profiles were generated using the SurePrint G3 Mouse miRNA microarray and validated. The intersecting genes of TargetScan and miRanda were selected to predict the target genes of each miRNA. For gene ontology (GO) studies, the parent-child-intersection (pci) method was used for enrichment analysis, and Benjamini-Hochberg was used for multiple test correction. The Kyoto Encyclopedia of Genes and Genomes (KEGG) was used to detect disease-related pathways among the large list of miRNA-targeted genes. All analyses mentioned above were performed at the time points of control, days 3, 14, and 60 post-SE. RESULTS: Control versus days 3, 14, and 60 post-SE: in the CA area, a total of 131 miRNAs were differentially expressed; 53, 49, and 26 miRNAs were upregulated and 54, 10, and 22 were downregulated, respectively. In the DG area, a total of 171 miRNAs were differentially expressed; furthermore, 36, 32, and 28 miRNAs were upregulated and 78, 58, and 44 were downregulated, respectively. Of these, 92 changed in both the CA and DG, 39 only in the CA, and 79 only in the DG area. The differentially expressed miRNAs target 11-1630 genes. Most of these proteins have multiple functions in epileptogenesis. There were 15 common pathways related to altered miRNAs: nine different pathways in the CA and seven in the DG area. CONCLUSIONS: Stage- and subfield-associated hippocampal miRNA expression patterns are closely related to epileptogenesis, although the detailed mechanisms need to be explored in the future.

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.

Hyperammonaemia induces mitochondrial dysfunction and neuronal cell death.

Background & Aims: In cirrhosis, astrocytic swelling is believed to be the principal mechanism of ammonia neurotoxicity leading to hepatic encephalopathy (HE). The role of neuronal dysfunction in HE is not clear. We aimed to explore the impact of hyperammonaemia on mitochondrial function in primary co-cultures of neurons and astrocytes and in acute brain slices of cirrhotic rats using live cell imaging. Methods: To primary cocultures of astrocytes and neurons, low concentrations (1 and 5 µM) of NH4Cl were applied. In rats with bile duct ligation (BDL)-induced cirrhosis, a model known to induce hyperammonaemia and minimal HE, acute brain slices were studied. One group of BDL rats was treated twice daily with the ammonia scavenger ornithine phenylacetate (OP; 0.3 g/kg). Fluorescence measurements of changes in mitochondrial membrane potential (Δψm), cytosolic and mitochondrial reactive oxygen species (ROS) production, lipid peroxidation (LP) rates, and cell viability were performed using confocal microscopy. Results: Neuronal cultures treated with NH4Cl exhibited mitochondrial dysfunction, ROS overproduction, and reduced cell viability (27.8 ± 2.3% and 41.5 ± 3.7%, respectively) compared with untreated cultures (15.7 ± 1.0%, both p <0.0001). BDL led to increased cerebral LP (p = 0.0003) and cytosolic ROS generation (p <0.0001), which was restored by OP (both p <0.0001). Mitochondrial function was severely compromised in BDL, resulting in hyperpolarisation of Δψm with consequent overconsumption of adenosine triphosphate and augmentation of mitochondrial ROS production. Administration of OP restored Δψm. In BDL animals, neuronal loss was observed in hippocampal areas, which was partially prevented by OP. Conclusions: Our results elucidate that low-grade hyperammonaemia in cirrhosis can severely impact on brain mitochondrial function. Profound neuronal injury was observed in hyperammonaemic conditions, which was partially reversible by OP. This points towards a novel mechanism of HE development. Lay summary: The impact of hyperammonaemia, a common finding in patients with liver cirrhosis, on brain mitochondrial function was investigated in this study. The results show that ammonia in concentrations commonly seen in patients induces severe mitochondrial dysfunction, overproduction of damaging oxygen molecules, and profound injury and death of neurons in rat brain cells. These findings point towards a novel mechanism of ammonia-induced brain injury in liver failure and potential novel therapeutic targets.

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.

Medial Temporal Lobe Anatomy.

The medial temporal lobe (MTL) is a complex anatomic region encompassing the hippocampal formation, parahippocampal region, and amygdaloid complex. To enable the reader to understand the well-studied regional anatomic relationships and cytoarchitecture that form the basis of functional connectivity, the authors have created a detailed yet approachable anatomic reference for clinicians and scientists, with special attention to MR imaging. They have focused primarily on the hippocampal formation, discussing its gross structural features, anatomic relationships, and subfield anatomy and further discuss hippocampal terminology and development, hippocampal connectivity, normal anatomic variants, clinically relevant disease processes, and automated hippocampal segmentation software.

A stereological study reveals nanoscale-alumina induces cognitive dysfunction in mice related to hippocampal structural changes.

Aluminum (Al) is known to induce neurotoxicity in both humans and rodents. Recent evidence has indicated that the toxicity of Al Oxide (Al2O3) nanoparticles (Al-NP), one of the most abundantly used engineered nanoparticles, is far greater than that of Al itself. To date, however, no information is available regarding the effect of Al-NP on the stereological parameters of hippocampus. In particular, no stereological studies have evaluated the effect of Al-NP on hippocampal CA1, dentate gyrus volume, and number of pyramidal and granular cells. Thus, the present study aimed to take a multidimensional approach to assess the concomitant cognitive, stereological, and apoptotic changes induced by a five-day Al-NP ingestion (10 mg/kg/day) in mice. The results demonstrated that the five-day Al-NP ingestion elicited a reduced preference to explore a novel object in the novel object recognition test (a hippocampal-dependent task). Perhaps contributing to this memory deficit, Al-NP induced additional alterations in the hippocampus of male NMRI mice in terms of (1) hippocampal volume (decreased the volume of the whole hippocampus, CA1, and dentate gyrus regions), (2) cell number (decreased the number of CA1 pyramidal neurons and dentate gyrus granular cells), and (3) increased cleaved caspase-3 in the whole hippocampus. These results provided new mechanistic insight to understand the impairing effect of AL-NP on the hippocampal function and structure.

MRI volumetric changes in hippocampal subfields in psychosis: a protocol for a systematic review and meta-analysis.

BACKGROUND: The hippocampus has for long been known for its ability to form new, declarative memory. However, emerging findings across conditions in the psychosis spectrum also implicate its role in emotional regulation. Systematic reviews have demonstrated consistent volume atrophic changes in the hippocampus. The aim of the systematic review and metanalysis which will follow from this protocol will be to investigate the volume-based neuroimaging findings across each of the subfields of the hippocampus in psychosis independent of diagnosis. METHODS: Volume changes across subfields of the hippocampus in psychotic illnesses will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MRI neuroimaging studies of patients with a definitive diagnosis of psychosis (including brief pre-diagnostic states) will be included. Studies lacking adequate controls, illicit drug use, medical psychosis, history of other significant psychiatric comorbidities, or emphasis on age groups above 65 or below 16 will be excluded. Subfields investigated will include the CA1, CA2/3, CA4, subiculum, presubiculum, parasubiculum, dentate gyrus, stratum, molecular layer, granular cell layer, entorhinal cortex, and fimbria. Two people will independently screen abstracts from the output of the search to select suitable studies. This will be followed by the two reviewers performing a full-text review of the studies which were selected based on suitable abstracts. One reviewer will independently perform all the data extraction, and another reviewer will then systemically check all the extracted information using the original articles to ensure accuracy. Statistical analysis will be performed using the metafor and meta-packages in R Studio with the application of the random-effects model. DISCUSSION: This study will provide insight into the volumetric changes in psychosis of the subfields of the hippocampus, independent of diagnosis. This may shed light on the intricate neural pathology which encompasses psychosis and will open avenues for further exploration of the structures identified as potential drivers of volume change. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020199558.

Volume deficits in hippocampal subfields in unaffected relatives of schizophrenia patients with high genetic loading but without any psychiatric symptoms.

BACKGROUND: Hippocampal volume changes have been reported in schizophrenia patients and their relatives and are proposed to contribute to the pathophysiology of schizophrenia. However, volume changes in the total hippocampus have not been consistently reported in relatives. The hippocampus consists of multiple subregions, and based on previous inconsistent results, subtle changes in specific subregions may occur in relatives. Here, we examined the subregion volumes in unaffected, high-functioning relatives (URs) without any psychiatric symptoms with high genetic loading with at least one first-degree relative diagnosed with schizophrenia and at least one or more other affected first- to third-degree relatives. METHODS: We acquired structural magnetic resonance imaging data from 50 URs, 101 first-episode psychosis (FEP) patients, and 101 healthy controls (HCs). The cornu ammonis (CA), dentate gyrus, and subiculum subfields were automatically segmented using FreeSurfer 7.1.0. Each subregion volume was compared across the groups. RESULTS: Compared with the HCs, the URs had a significant volume reduction in the left anterior CA (p = 0.039, Cohen's d = 0.480). In addition, the URs had a significantly larger right posterior subiculum (p = 0.001, Cohen's d = 0.541) than the FEP. CONCLUSIONS: The smaller left anterior CA in the URs may reflect their genetic vulnerability to schizophrenia and supports previous findings suggesting specific vulnerability in this region. The volume differences between the URs and FEP patients in the right posterior subiculum may suggest that a smaller volume in this region may reflect a risk for schizophrenia other than genetic vulnerability.

Pain Relief Reverses Hippocampal Abnormalities in Trigeminal Neuralgia.

Chronic pain patients frequently report memory and concentration difficulties. Objective testing in this population points to poor performance on memory and cognitive tests, and increased comorbid anxiety and depression. Recent evidence has suggested convergence between chronic pain and memory deficits onto the hippocampus. The hippocampus consists of heterogenous subfields involved in memory consolidation, behavior regulation, and stress modulation. Despite significant studies outlining hippocampal changes in human and chronic pain animal models, the effect of pain relief on hippocampal abnormalities remains unknown. Trigeminal neuralgia (TN) is a chronic neuropathic pain disorder which is highly amenable to surgical interventions, providing a unique opportunity to investigate the effect of pain relief. This study investigates the effect of pain relief on hippocampal subfields in TN. Anatomical MR images of 61 TN patients were examined before and 6 months after surgery. Treatment responders (n = 47) reported 95% pain relief, whereas non-responders (n = 14) reported 40% change in pain on average. At baseline, patients had smaller hippocampal volumes, compared to controls. After surgery, responders' hippocampal volumes normalized, largely driven by CA2/3, CA4, and dentate gyrus, which are involved in memory consolidation and neurogenesis. We propose that hippocampal atrophy in TN is pain-driven and successful treatment normalizes such abnormalities. PERSPECTIVE: Chronic pain patients have structural abnormalities in the hippocampus and its subfields. Pain relief normalizes these structural abnormalities and impacts patients in a sex-dependent manner.

Brain Factor-7® Improves Cognitive Impairment Following Transient Ischemia and Reperfusion Injury in Gerbil Forebrain through Promoting Remyelination and Restoring Cholinergic and Glutamatergic Neurotransmission in the Hippocampus.

BACKGROUND: Ischemia and reperfusion injury in the brain triggers cognitive impairment which are accompanied by neuronal death, loss of myelin sheath and decline in neurotransmission. In this study, we investigated whether therapeutic administration of Brain Factor-7® (BF-7®; a silk peptide) in ischemic gerbils which were developed by transient (five minutes) ischemia and reperfusion in the forebrain (tFI/R) improved cognitive impairment. METHODS: Short-term memory and spatial memory functions were assessed by passive avoidance test and Barnes maze test, respectively. To examine neuronal change in the hippocampus, cresyl violet staining, immunohistochemistry for neuronal nuclei and fluoro Jade B histofluorescence were performed. We carried out immunohistochemistry for myelin basic protein (a marker for myelin) and receptor interacting protein (a marker for oligodendrocytes). Furthermore, immunohistochemistry for vesicular acetylcholine transporter (as a cholinergic transporter) and vesicular glutamate transporter 1 (as a glutamatergic synapse) was done. RESULTS: Administration of BF-7® significantly improved tFI/R-induced cognitive impairment. tFI/R-induced neuronal death was found in the Cornu Ammonis 1 (CA1) subfield of the hippocampus from five days after tFI/R. Treatment with BF-7® following tFI/R did not restore the death (loss) of CA1 neurons following tFI/R. However, BF-7® treatment to the ischemic gerbils significantly improved remyelination and proliferation of oligodendrocytes in the hippocampus with ischemic injury. Treatment with BF-7® to the ischemic gerbils significantly restored vesicular acetylcholine transporter-immunoreactive and vesicular glutamate transporter 1-immunoreactive structures in the hippocampus with ischemic injury. CONCLUSIONS: Based on these results, we suggest that BF-7® can be utilized for improving cognitive impairments induced by ischemic injury as an additive for health/functional foods and/or medicines.