Cornu Ammonis Research Articles

Hippocampal hyperphosphorylated tau-induced deficiency is rescued by L-type calcium channel blockade.

Aging and Alzheimer's disease are associated with chronic elevations in neuronal calcium influx via L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer's disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood. In this study, we seeded a human tau pseudophosphorylated at 14 amino acid sites in rat hippocampal cornu ammonis 1 region to mimic soluble pretangle tau. Impaired spatial learning was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats as early as 1-3 months and worsened at 9-10 months post-infusion. Rats infused with wild-type human tau exhibited milder behavioural deficiency only at 9-10 months post-infusion. No tangles or plaques were observed in all time points examined in both human tau pseudophosphorylated at 14 amino acid sites and human tau-infused brains. However, human tau pseudophosphorylated at 14 amino acid sites-infused hippocampus exhibited a higher amount of tau phosphorylation at S262 and S356 than the human tau-infused rats at 3 months post-infusion, paralleling the behavioural deficiency observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Neuroinflammation indexed by increased Iba1 in the cornu ammonis 1 was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 but not 9 months post-infusion. Spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1-3 months post-infusion was paralleled by decreased neuronal excitability, impaired NMDA receptor-dependent long-term potentiation and augmented L-type calcium channel-dependent long-term potentiation at the cornu ammonis 1 synapses. L-type calcium channel expression was elevated in the soma of the cornu ammonis 1 neurons in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Chronic L-type calcium channel blockade with nimodipine injections for 6 weeks normalized neuronal excitability and synaptic plasticity and rescued spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats. The early onset of L-type calcium channel-mediated pretangle tau pathology and rectification by nimodipine in our model have significant implications for preclinical Alzheimer's disease prevention and intervention.

ALKBH8 contributes to neurological function through oxidative stress regulation.

Transfer RNA (tRNA) modification is essential for proper protein translation, as these modifications play important roles in several biological functions and disease pathophysiologies. AlkB homolog 8 (ALKBH8) is one of the nine mammalian ALKBH family molecules known to regulate selenoprotein translation through the modification of the wobble uridine (U34) in tRNA; however, its specific biological roles remain unclear. In this study, we investigated the role of ALKBH8 using Alkbh8-knockout (Albkh8-/-) mice, which were observed to have reduced 5-methoxycarbonylmethyluridine (mcm5U) and (S)-5-methoxycarbonylhydroxymethyluridine levels; notably, the mcm5U level was partially compensated only in the brain. The results of the novel object recognition test showed reduction in time to explore a novel object in Albkh8-/- mice; increased latency to fall in the rotarod performance test and latency to the immobility period in the forced swim test were also observed. These abnormal behaviors indicate dysfunction of the central nervous system. Furthermore, we observed reduced brain weight and ischemic pathological changes in the cerebral cortex and hippocampus in the form of weak eosin staining in the fiber tracts adjacent to the hippocampal cornu ammonis 1 region and an increase in pyramidal cells in the temporal lobe. Concordantly, we identified the differential expression of oxidative stress-related proteins and metabolites in the cerebral cortex and hippocampus using omics analyses. Finally, neurons and glial cells derived from Albkh8-/- mice show reduced mitochondrial membrane potential. Collectively, these findings indicate that ALKBH8 maintains neural function through an oxidative stress-regulatory mechanism.

Radiologic Classification of Hippocampal Sclerosis in Epilepsy.

Temporal lobe epilepsy is a common form of epilepsy that is often associated with hippocampal sclerosis (HS). Although HS is commonly considered a binary assessment in radiologic evaluation, it is known that histopathologic changes occur in distinct clusters. Some subtypes of HS only affect certain subfields, resulting in minimal changes to the overall volume of the hippocampus. This is likely a major reason why whole hippocampal volumetrics have underperformed versus expert readers in the diagnosis of HS. With recent advancements in MRI technology, it is now possible to characterize the substructure of the hippocampus more accurately. However, this is not consistently addressed in radiographic evaluations. The histologic subtype of HS is critical for prognosis and treatment decision-making, necessitating improved radiologic classification of HS. The International League Against Epilepsy (ILAE) has issued a consensus classification scheme for subtyping HS histopathologic changes. This review aims to explore how the ILAE subtypes of HS correlate with radiographic findings, introduce a grading system that integrates radiologic and pathologic reporting in HS, and outline an approach to detecting HS subtypes by using MRI. This framework will not only benefit current clinical evaluations, but also enhance future studies involving high-resolution MRI in temporal lobe epilepsy.

Unsupervised classification of brain-wide axons reveals the presubiculum neuronal projection blueprint

We present a quantitative strategy to identify all projection neuron types from a given region with statistically different patterns of anatomical targeting. We first validate the technique with mouse primary motor cortex layer 6 data, yielding two clusters consistent with cortico-thalamic and intra-telencephalic neurons. We next analyze the presubiculum, a less-explored region, identifying five classes of projecting neurons with unique patterns of divergence, convergence, and specificity. We report several findings: individual classes target multiple subregions along defined functions; all hypothalamic regions are exclusively targeted by the same class also invading midbrain and agranular retrosplenial cortex; Cornu Ammonis receives input from a single class of presubicular axons also projecting to granular retrosplenial cortex; path distances from the presubiculum to the same targets differ significantly between classes, as do the path distances to distinct targets within most classes; the identified classes have highly non-uniform abundances; and presubicular somata are topographically segregated among classes. This study thus demonstrates that statistically distinct projections shed light on the functional organization of their circuit.

Hippocampal capillary pericytes in post-stroke and vascular dementias and Alzheimer’s disease and experimental chronic cerebral hypoperfusion

Neurovascular unit mural cells called ‘pericytes’ maintain the blood-brain barrier and local cerebral blood flow. Pathological changes in the hippocampus predispose to cognitive impairment and dementia. The role of hippocampal pericytes in dementia is largely unknown. We investigated hippocampal pericytes in 90 post-mortem brains from post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), and AD-VaD (Mixed) subjects, and post-stroke non-demented survivors as well as similar age controls. We used collagen IV immunohistochemistry to determine pericyte densities and a mouse model of VaD to validate the effects of chronic cerebral hypoperfusion. Despite increased trends in hippocampal microvascular densities across all dementias, mean pericyte densities were reduced by ~25–40% in PSD, VaD and AD subjects compared to those in controls, which calculated to 14.1 ± 0.7 per mm capillary length, specifically in the cornu ammonis (CA) 1 region (P = 0.01). In mice with chronic bilateral carotid artery occlusion, hippocampal pericyte loss was ~60% relative to controls (P < 0.001). Pericyte densities were correlated with CA1 volumes (r = 0.54, P = 0.006) but not in any other sub-region. However, mice subjected to the full-time environmental enrichment (EE) paradigm showed remarkable attenuation of hippocampal CA1 pericyte loss in tandem with CA1 atrophy. Our results suggest loss of hippocampal microvascular pericytes across common dementias is explained by a vascular aetiology, whilst the EE paradigm offers significant protection.

Assessment of the mechanistic role of an Indian traditionally used ayurvedic herb Bacopa monnieri (L.)Wettst. for ameliorating oxidative stress in neuronal cells

Ethnopharmacological relevanceThis study has important ethnopharmacological implications since it systematically investigated the therapeutic potential of Bacopa monnieri(L.) Wettst. (Brahmi) in treating neurological disorders characterized by oxidative stress—a growing issue in the aging population. Bacopa monnieri, which is strongly rooted in Ayurveda, has long been recognized for its neuroprotective and cognitive advantages. The study goes beyond conventional wisdom by delving into the molecular complexities of Bacopa monnieri, particularly its active ingredient, Bacoside-A, in countering oxidative stress. The study adds to the ethnopharmacological foundation for using this herbal remedy in the context of neurodegenerative disorders by unravelling the scientific underpinnings of Bacopa monnieri's effectiveness, particularly at the molecular level, against brain damage and related conditions influenced by oxidative stress. This dual approach, which bridges traditional wisdom and modern investigation, highlights Bacopa monnieri's potential as a helpful natural remedy for oxidative stress-related neurological diseases. Aim of the studyThe aim of this study is to investigate the detailed molecular mechanism of action (in vitro, in silico and in vivo) of Bacopa monnieri (L.) Wettst. methanolic extract and its active compound, Bacoside-A, against oxidative stress in neurodegenerative disorders. Materials and methodsROS generation activity, mitochondrial membrane potential, calcium deposition and apoptosis were studied through DCFDA, Rhodamine-123, FURA-2 AM and AO/EtBr staining respectively. In silico study to check the effect of Bacoside-A on the Nrf-2 and Keap1 axis was performed through molecular docking study and validated experimentally through immunofluorescence co-localization study. In vivo antioxidant activity of Bacopa monnieri extract was assessed by screening the oxidative stress markers and stress-inducing hormone levels as well as through histopathological analysis of tissues. ResultsThe key outcome of this study is that the methanolic extract of Bacopa monnieri (BME) and its active component, Bacoside-A, protect against oxidative stress in neurodegenerative diseases. At 100 and 20 μg/ml, BME and Bacoside-A respectively quenched ROS, preserved mitochondrial membrane potential, decreased calcium deposition, and inhibited HT-22 mouse hippocampus cell death. BME and Bacoside-A regulated the Keap1 and Nrf-2 axis and their downstream antioxidant enzyme-specific genes to modify cellular antioxidant machinery. In vivo experiments utilizing rats subjected to restrained stress indicated that pre-treatment with BME (50 mg/kg) downregulated oxidative stress markers and stress-inducing hormones, and histological staining demonstrated that BME protected the neuronal cells of the Cornu Ammonis (CA1) area in the hippocampus. ConclusionsOverall, the study suggests that Bacopa monnieri(L.) Wettst. has significant potential as a natural remedy for neurodegenerative disorders, and its active compounds could be developed as new drugs for the prevention and treatment of oxidative stress-related diseases.

Unraveling the link: white matter damage, gray matter atrophy and memory impairment in patients with subcortical ischemic vascular disease.

Prior MRI studies have shown that patients with subcortical ischemic vascular disease (SIVD) exhibited white matter damage, gray matter atrophy and memory impairment, but the specific characteristics and interrelationships of these abnormal changes have not been fully elucidated. We collected the MRI data and memory scores from 29 SIVD patients with cognitive impairment (SIVD-CI), 29 SIVD patients with cognitive unimpaired (SIVD-CU) and 32 normal controls (NC). Subsequently, the thicknesses and volumes of the gray matter regions that are closely related to memory function were automatically assessed using FreeSurfer software. Then, the volume, fractional anisotropy (FA), mean diffusivity (MD), amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values of white matter hyperintensity (WMH) region and normal-appearing white matter (NAWM) were obtained using SPM, DPARSF, and FSL software. Finally, the analysis of covariance, spearman correlation and mediation analysis were used to analyze data. Compared with NC group, patients in SIVD-CI and SIVD-CU groups showed significantly abnormal volume, FA, MD, ALFF, and ReHo values of WMH region and NAWM, as well as significantly decreased volume and thickness values of gray matter regions, mainly including thalamus, middle temporal gyrus and hippocampal subfields such as cornu ammonis (CA) 1. These abnormal changes were significantly correlated with decreased visual, auditory and working memory scores. Compared with the SIVD-CU group, the significant reductions of the left CA2/3, right amygdala, right parasubiculum and NAWM volumes and the significant increases of the MD values in the WMH region and NAWM were found in the SIVD-CI group. And the increased MD values were significantly related to working memory scores. Moreover, the decreased CA1 and thalamus volumes mediated the correlations between the abnormal microstructure indicators in WMH region and the decreased memory scores in the SIVD-CI group. Patients with SIVD had structural and functional damages in both WMH and NAWM, along with specific gray matter atrophy, which were closely related to memory impairment, especially CA1 atrophy and thalamic atrophy. More importantly, the volumes of some temporomesial regions and the MD values of WMH regions and NAWM may be potentially helpful neuroimaging indicators for distinguishing between SIVD-CI and SIVD-CU patients.

The Role of PLAG1 in Mouse Brain Development and Neurogenesis

The pleomorphic adenoma gene 1 (Plag1) is a transcription factor involved in the regulation of growth and cellular proliferation. Here, we report the spatial distribution and functional implications of PLAG1 expression in the adult mouse brain. We identified Plag1 promoter-dependent β-galactosidase expression in various brain structures, including the hippocampus, cortex, choroid plexus, subcommisural organ, ependymal cells lining the third ventricle, medial and lateral habenulae and amygdala. We noted striking spatial-restriction of PLAG1 within the cornu ammonis (CA1) region of the hippocampus and layer-specific cortical expression, with abundant expression noted in all layers except layer 5. Furthermore, our study delved into the role of PLAG1 in neurodevelopment, focusing on its impact on neural stem/progenitor cell proliferation. Loss of Plag1 resulted in reduced proliferation and decreased production of neocortical progenitors in vivo, although ex vivo neurosphere experiments revealed no cell-intrinsic defects in the proliferative or neurogenic capacity of Plag1-deficient neural progenitors. Lastly, we explored potential target genes of PLAG1 in the cortex, identifying that Neurogenin 2 (Ngn2) was significantly downregulated in Plag1-deficient mice. In summary, our study provides novel insights into the spatial distribution of PLAG1 expression in the adult mouse brain and its potential role in neurodevelopment. These findings expand our understanding of the functional significance of PLAG1 within the brain, with potential implications for neurodevelopmental disorders and therapeutic interventions.

Physical activity as a promoter of stress resilience: An analysis of behavioral effects and brain connectivity with cytochrome c-oxidase activity in adult male Wistar rats

Physical activity (PA) is very beneficial for physical and mental health. This study aims to examine the resilience-inducting effect of PA in adult male Wistar rats exposed to unpredictable chronic mild stress (UCMS). Furthermore, we analyzed the influence of PA on behavioral tasks and functional brain connectivity with cytochrome c oxidase technique. The cytochrome c oxidase (CCO) is a mitochondrial enzyme involved in oxidative phosphorylation and ATP generation. For this analysis, we included five groups: Basal (n = 10, to determine the basal level of brain activity), Behav (n = 15, subjected exclusively to behavioral tests), PA (n = 10, exposed to physical activity), UCMS (n = 15, subjected to a stress protocol) and PA + UCMS (n = 15, exposed to PA prior to stress). The UCMS protocol consisted of randomly presenting several different stressors over four consecutive weeks. We evaluated several behaviors of the Behav, UCMS, and PA + UCMS groups. This assessment includes the hedonic responses using the sucrose consumption task, unconditioned anxiety with the zero maze, and coping strategies assessed with the cat odor test. The UCMS group showed an anhedonia profile and increased anxiety compared with the other groups. Although in the exposure to cat odor test, the PA + UCMS remained for the same time in the cat odor compartment as the other groups, it did not approach the odor, showing that it detected the risk. This response is more adaptive than the responses of the UCMS and Behav groups. An exploratory analysis of the cerebral connections showed an increase in CCO activity in the UCMS group compared to the other groups. This overactivity was reduced in dorsal Cornu Ammonis 3(dCA3) by prior PA. In this region, PA + UCMS showed similar activity as the groups not subjected to chronic stress. Therefore, PA can prevent the harmful effects of chronic stress on dCA3.

KEÇİBOYNUZUNUN (CERATONİA SİLİQUA L.) NİKOTİN BAZLI OKSİDATİF STRESE ETKİSİ

OBJECTIVE: In this study the antioxidant effect of carob plant, ıt's effects of nicotine-induced oxidative stress and the number of pyramidal cells in the rat hippocampus in cornu ammonis (CA) were investigated. MATERIAL AND METHODS: In the study, 28 adult Wistar Albino male rats were used. Rats are divided into four groups as control group, carob group, nicotine group and nicotine + carob group. Nicotine was applied to the experimental group, and carob extract was applied to the treatment group as well as nicotine. Superoxide dismutase (SOD), glutathione (GSH), glutathione disulfide (GSSG), total oxidant capacity (TOS), total antioxidant capacity (TAS) values were measured by spectrophotometric analysis on the lung, brain, kidney, heart and liver tissues. Oxidative stress index (OSI) and GSH / GSSG values, respectively, were calculated as TOS/TAS and GSH/GSSG rates. The number of pyramidal cells in the CA was estimated using the optical fractionator technique. RESULTS: It is seen that the TAS level in the kidney tissue of the nicotine group is significantly lower than the control and carob groups. In brain tissue, the TAS level of the nicotine group was significantly lower than that of other groups (p&amp;lt;0.001). The OSI value of the nicotine group was significantly higher in liver tissue compared to the control group (p&amp;lt;0.001). Nicotine exposure has been shown to cause a significant reduction in the number of pyramidal cells in CA. CONCLUSIONS: It is understood that Carob plant is an important phytomedical plant that has antioxidant properties against nicotine by increasing TAS level in oxidative stress formation.

A Single-Cell Transcriptomic Analysis of the Mouse Hippocampus After Voluntary Exercise

Exercise has been recognized as a beneficial factor for cognitive health, particularly in relation to the hippocampus, a vital brain region responsible for learning and memory. Previous research has demonstrated that exercise-mediated improvement of learning and memory in humans and rodents correlates with increased adult neurogenesis and processes related to enhanced synaptic plasticity. Nevertheless, the underlying molecular mechanisms are not fully understood. With the aim to further elucidate these mechanisms, we provide a comprehensive dataset of the mouse hippocampal transcriptome at the single-cell level after 4 weeks of voluntary wheel-running. Our analysis provides a number of interesting observations. For example, the results suggest that exercise affects adult neurogenesis by accelerating the maturation of a subpopulation of Prdm16-expressing neurons. Moreover, we uncover the existence of an intricate crosstalk among multiple vital signaling pathways such as NF-κB, Wnt/β-catenin, Notch, and retinoic acid (RA) pathways altered upon exercise in a specific cluster of excitatory neurons within the Cornu Ammonis (CA) region of the hippocampus. In conclusion, our study provides an important resource dataset and sheds further light on the molecular changes induced by exercise in the hippocampus. These findings have implications for developing targeted interventions aimed at optimizing cognitive health and preventing age-related cognitive decline.

Effect of a New Substance with Pyridoindole Structure on Adult Neurogenesis, Shape of Neurons, and Behavioral Outcomes in a Chronic Mild Stress Model in Rats.

Despite an accumulating number of studies, treatments for depression are currently insufficient. Therefore, the search for new substances with antidepressant potential is very important. In this study, we hypothesized that treatment with a newly synthesized pyridoindole derivative compound SMe1EC2M3 would result in protective and antidepressant-like effects on behavioral outcomes and reverse the impaired adult hippocampal neurogenesis caused by chronic mild stress (CMS). We found that chronic administration of 5 mg/kg and 25 mg/kg SMe1EC2M3 to adult Sprague Dawley rats ameliorated the consequences of CMS on immobility and swimming time in a forced swim test. A slight sedative effect of the highest dose of SMe1EC2M3 in the nonstress group was observed in the open field. SMe1EC2M3 in the highest dose ameliorated CMS-induced decreases in the sucrose preference test. Administration of SMe1EC2M3 significantly increased SOX2-positive cells in the hippocampal dentate gyrus (DG) in CMS compared to control animals. A significant reduction in glial fibrillary acid protein (GFAP)-positive cells in the DG of CMS compared to control animals was observed. Administration of both 5 and 25 mg/kg SMe1EC2M3 significantly increased signal of GFAP-positive cells in the DG of CMS animals. No such effects of SMe1EC2M3 were observed in the cornu ammonis hippocampal area. Additionally, we found that incubation of primary hippocampal neurons in the presence of 1.50 µM SMe1EC2M3 significantly stimulated the length of neurites. Overall, we found that the negative effects of CMS on depression-like behavior are partially reduced by the administration of SMe1EC2M3 and are associated with changes in hippocampal neurogenesis and neuronal differentiation. SMe1EC2M3 represents a potential drug candidate with positive neuroplastic effects and neurogenesis-associated effects in therapeutic approaches to depression.

Immunohistochemical field parcellation of the human hippocampus along its antero-posterior axis

The primate hippocampus includes the dentate gyrus, cornu ammonis (CA), and subiculum. CA is subdivided into four fields (CA1-CA3, plus CA3h/hilus of the dentate gyrus) with specific pyramidal cell morphology and connections. Work in non-human mammals has shown that hippocampal connectivity is precisely patterned both in the laminar and longitudinal axes. One of the main handicaps in the study of neuropathological semiology in the human hippocampus is the lack of clear laminar and longitudinal borders. The aim of this study was to explore a histochemical segmentation of the adult human hippocampus, integrating field (medio-lateral), laminar, and anteroposterior longitudinal patterning. We provide criteria for head-body-tail field and subfield parcellation of the human hippocampus based on immunodetection of Rabphilin3a (Rph3a), Purkinje-cell protein 4 (PCP4), Chromogranin A and Regulation of G protein signaling-14 (RGS-14). Notably, Rph3a and PCP4 allow to identify the border between CA3 and CA2, while Chromogranin A and RGS-14 give specific staining of CA2. We also provide novel histological data about the composition of human-specific regions of the anterior and posterior hippocampus. The data are given with stereotaxic coordinates along the longitudinal axis. This study provides novel insights for a detailed region-specific parcellation of the human hippocampus useful for human brain imaging and neuropathology.

Changes in structural plasticity of hippocampal neurons in an animal model of multiple sclerosis.

Structural plasticity is critical for the functional diversity of neurons in the brain. Experimental autoimmune encephalomyelitis (EAE) is the most commonly used model for multiple sclerosis (MS), successfully mimicking its key pathological features (inflammation, demyelination, axonal loss, and gliosis) and clinical symptoms (motor and non-motor dysfunctions). Recent studies have demonstrated the importance of synaptic plasticity in EAE pathogenesis. In the present study, we investigated the features of behavioral alteration and hippocampal structural plasticity in EAE-affected mice in the early phase (11 days post-immunization, DPI) and chronic phase (28 DPI). EAE-affected mice exhibited hippocampus-related behavioral dysfunction in the open field test during both early and chronic phases. Dendritic complexity was largely affected in the cornu ammonis 1 (CA1) and CA3 apical and dentate gyrus (DG) subregions of the hippocampus during the chronic phase, while this effect was only noted in the CA1 apical subregion in the early phase. Moreover, dendritic spine density was reduced in the hippocampal CA1 and CA3 apical/basal and DG subregions in the early phase of EAE, but only reduced in the DG subregion during the chronic phase. Furthermore, mRNA levels of proinflammatory cytokines ( Il1β, Tnfα, and Ifnγ) and glial cell markers ( Gfap and Cd68) were significantly increased, whereas the expression of activity-regulated cytoskeleton-associated protein (ARC) was reduced during the chronic phase. Similarly, exposure to the aforementioned cytokines in primary cultures of hippocampal neurons reduced dendritic complexity and ARC expression. Primary cultures of hippocampal neurons also showed significantly reduced extracellular signal-regulated kinase (ERK) phosphorylation upon treatment with proinflammatory cytokines. Collectively, these results suggest that autoimmune neuroinflammation alters structural plasticity in the hippocampus, possibly through the ERK-ARC pathway, indicating that this alteration may be associated with hippocampal dysfunctions in EAE.

Mesial temporal lobe epilepsy and hippocampal sclerosis associated with BRAFV600E mutant neurons in the Cornu Ammonis: an uncertain pathogenesis and a diagnostic challenge.

Mesial temporal lobe epilepsy (MTLE) is a common cause of seizures, and hippocampal sclerosis (HS) is the predominant subtype. BRAFV600E mutations in MTLE-HS have only been reported infrequently. Herein, we illustrate the neurologic, radiological, and histopathological details of a patient with MTLE-HS and BRAFV600E mutant neurons. A 31-year-old male with medically refractory epilepsy presented with magnetic resonance imaging (MRI) and electroencephalography (EEG) findings typical of mesial temporal sclerosis without a mass lesion. The surgical specimens showed ILAE Type 1 HS with neurons immunopositive for BRAFV600E mutant protein distributed along the Cornu Ammonis (CA) curvature. Instead of the normal mostly perpendicular orientation of pyramidal neurons relative to the hippocampal surface, the BRAF mutant neurons were often oriented in a parallel manner. On CD34 immunostaining, sparse clusters or nodules of CD34+ stellate cells and single immunopositive stellate cells were identified. BRAFV600E or CD34 immunopositive cells were less than 1 % of total cells. The patient responded well to surgery with no further seizures after 2 years and occasional auras. Hippocampal BRAF mutant non-expansive lesion (HBNL) has been used to describe such lesions with preserved cytoarchitecture and without overt tumor mass. Others may argue for the dual pathology of HS with early ganglioglioma. Whether pre-neoplastic lesions or early tumors, these cases are important for understanding early glioneuronal tumorigenesis and suggest that BRAFV600E studies should be routinely performed on MTLE-HS cases in the setting of clinical trials. With next-generation sequencing, a FANCL deletion was detected in almost half of the alleles in our case, suggesting that many of the histologically normal-appearing cells of the hippocampus contain this alteration. FANCL mutations can result in cytogenetic anomalies and defective DNA repair and therefore may underlie the development of a low frequency BRAF alteration.

Electroacupuncture at the Dazhui and Baihui acupoints and different frequencies (10 and 50 Hz) protects against apoptosis by up-regulating ERK1/2-mediated signaling in rats after global cerebral ischemia.

This study assessed the effects of electroacupuncture (EA) stimulation at different frequencies at the Dazhui and Baihui acupoints in the subacute phase after transient global cerebral ischemia (GCI). Rats were subjected to GCI for 25 min, followed by reperfusion for 7 days. EA at acupoints was performed at 10, 30, or 50 Hz, 1 day after reperfusion and then once daily for 6 consecutive days. EA at acupoints at 10 and 50 Hz effectively down-regulated apoptosis in the hippocampal cornu ammonis 1(CA1) area and ameliorated memory deficits. Moreover, EA treatment at 10 and 50 Hz markedly increased phospho (p)-extracellular signal-regulated protein kinase 1/2 (ERK1/2), p-ERK1/2/neuronal nuclei (NeuN), p-cAMP response element-binding protein (CREB)/p-ERK1/2, B-cell lymphoma-2 (Bcl-2)/p-CREB, and X-linked inhibitor of apoptosis protein/NeuN expression levels and decreased Bcl-2 homologous antagonist/killer, second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI, cytochrome c, cleaved caspase-3, and apoptosis-inducing factor expression levels. Furthermore, 10-Hz EA treatment effectively increased p-p38 mitogen-activated protein kinase (MAPK), p-p38 MAPK/NeuN, and p-CREB/p-p38 MAPK expression levels. Pretreatment with U0126 (ERK1/2 inhibitor) completely abrogated the effects of 10- and 50-Hz EA treatments on the aforementioned protein expression levels. Similarly, pretreatment with SB203580 (p38 MAPK inhibitor) completely abrogated the effects of 10-Hz treatment on the aforementioned protein expression levels. The effects of 10- and 50-Hz EA treatments on mitochondria-related apoptosis can be attributed to the activation of ERK1/2/p38 MAPK/CREB/Bcl-2- and ERK1/2/CREB/Bcl-2-mediated signaling, respectively, in the hippocampal CA1 area at 7 days after transient GCI.

Hippocampal formation-inspired global self-localization: quick recovery from the kidnapped robot problem from an egocentric perspective.

It remains difficult for mobile robots to continue accurate self-localization when they are suddenly teleported to a location that is different from their beliefs during navigation. Incorporating insights from neuroscience into developing a spatial cognition model for mobile robots may make it possible to acquire the ability to respond appropriately to changing situations, similar to living organisms. Recent neuroscience research has shown that during teleportation in rat navigation, neural populations of place cells in the cornu ammonis-3 region of the hippocampus, which are sparse representations of each other, switch discretely. In this study, we construct a spatial cognition model using brain reference architecture-driven development, a method for developing brain-inspired software that is functionally and structurally consistent with the brain. The spatial cognition model was realized by integrating the recurrent state-space model, a world model, with Monte Carlo localization to infer allocentric self-positions within the framework of neuro-symbol emergence in the robotics toolkit. The spatial cognition model, which models the cornu ammonis-1 and -3 regions with each latent variable, demonstrated improved self-localization performance of mobile robots during teleportation in a simulation environment. Moreover, it was confirmed that sparse neural activity could be obtained for the latent variables corresponding to cornu ammonis-3. These results suggest that spatial cognition models incorporating neuroscience insights can contribute to improving the self-localization technology for mobile robots. The project website is https://nakashimatakeshi.github.io/HF-IGL/.

Minocycline Acts as a Neuroprotective Agent Against Tramadol-Induced Neurodegeneration: Behavioral and Molecular Evidence.

Previous evidence indicates that tramadol (TRA) can lead to neurodegenerative events and minocycline (MIN) has neuroprotective properties. The current research evaluated the neuroprotective effects of MIN for TRA-promoted neurodegeneration. Sixty adult male rats were placed into the following groups: 1 (received 0.7 ml/rat of normal saline, IP), 2 (received 50 mg/kg of TRA, i.p.), 3, 4, 5 (administered TRA as 50 mg/kg simultaneously with MIN at 20, 40, and 60 mg/kg, IP, respectively), and 6 (received MIN alone as 60 mg/kg, IP). The treatment procedure was 21 days. An open field test (OFT) was used to measure motor activity and anxiety-related behavior. Furthermore, oxidative stress; hippocampal inflammation; apoptotic parameters as well as activity of mitochondrial complexes I, II, III, and IV; ATP levels; and mitochondrial membrane potential (MMP) were evaluated. In addition, histomorphological alteration was assessed in two regions of the hippocampus: Cornu Ammonis (CA1) and dentate gyrus (DG). MIN treatment could inhibit TRA-induced anxiety and motor activity disturbances (P < 0.05). In addition, MIN could attenuate reactive oxygen species (ROS), H2O2, oxidized glutathione (GSSG), and malondialdehyde (MDA) level (P < 0.05), while there was increased reduced glutathione (GSH), total antioxidant capacity (TAC), ATP, MMP, and BCL2 levels (P < 0.05) and also elevation of SOD, GPX, GSR (P < 0.05), and mitochondrial complexes I, II, III, and IV activity (P < 0.05) in TRA-treated rats. In consistence with these findings, MIN could reduce TNF/TNF-α, IL1B/IL1-β, BAX, and CASP3 levels (P < 0.05) in TRA-treated rats. MIN also restored the quantitative (P < 0.05) and qualitative histomorphological sequels of TRA in both CA1 and DG areas of the hippocampus. MIN probably has repositioning capability for inhibition of TRA-induced neurodegeneration via modulation of inflammation, oxidative stress, apoptosis, and mitochondrial disorders.

Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study.

It is well known that there are significant differences in the prevalence of chronic pain between males and females. Human and animal imaging studies have shown that chronic pain profoundly alters the structure and function of brain regions. However, there is limited research on the sex-specific mechanisms underlying the brain plasticity and adaptive changes associated with chronic pain. In this article, we conducted a multimodal study to evaluate how nerve injury-induced chronic pain affects the brain. Male and female Sprague-Dawley (SD) rats with spared nerve injury (SNI) model underwent resting-state functional magnetic resonance imaging (rs-fMRI) (male sham group: n = 18; male SNI group: n = 18; female sham group: n = 20; female SNI group: n = 18) and magnetic resonance diffusion tensor imaging (DTI) (male sham group: n = 23; male SNI group: n = 21; female sham group: n = 20; female SNI group: n = 21) scanning. ICA method, Fractional amplitude of low-frequency fluctuations (fALFF), immunofluorescence staining, and graph theory analysis was utilized to extract the rs-fMRI changes of brain regions of each group. Using SNI model, which promotes long-lasting mechanical allodynia, we found that neuropathic pain deeply modified the intrinsic organization of the brain functional network in male and female rats (main effect of operation: F = 298.449, P < 0.001). 64 independent components (ICs) in the brain were divided and assigned to 16 systems. In male rats, we observed significant alterations in the microstructure of the hippocampal cornu ammonis 1 and cornu ammonis 2 (CA1/CA2) region, as indicated by increased mean diffusivity (MD) (CA1_L: P = 0.02; CA1_R: P = 0.031; CA2_L: P = 0.035; CA2_R: P = 0.015) and radial diffusivity (RD) (CA1_L: P = 0.028; CA1_R: P = 0.033; CA2_L: P = 0.037; CA2_R: P = 0.038) values, along with enhanced activating transcription factor 3 (ATF3) expression. Conversely, in female rats, we found significant increases in the fractional amplitude of low frequency fluctuations (fALFF) value within the hippocampal dentate gyrus (DG) (F = 5.419, P = 0.023), accompanied by elevated c-Fos signal (F = 6.269, P = 0.031). Furthermore, graph theory analysis revealed notable differences in the small-world network of the hippocampal system in female rats, characterized by reduced small-world attributes and increased inter-nodal transmission efficiency. Our study indicates sex differences in structural and functional alterations in the hippocampal system in rats under chronic pain conditions. The results suggest that the hippocampus system plays an important role in the different mechanisms of chronic pain in different sexes. These findings provide reliable insights to explore the complex mechanisms underlying sex differences in chronic pain.

Beta-sitosterol mitigates cognitive deficit and hippocampal neurodegeneration in mice with trimethyltin-induced toxicity.

The present study investigated the neural health benefit of beta-sitosterol (BSS) against trimethyltin (TMT)-induced neurodegeneration in mice. Forty male Institute of Cancer Research (ICR) mice were randomly divided into Sham-veh, TMT-veh, TMT-BSS50, and TMT-BSS100. A one-time intraperitoneal injection of 2.6 mg/kg of TMT was given to mice in TMT groups. Vehicle (veh), BSS 50 mg/kg or BSS 100 mg/kg were orally given for 2 weeks. Spatial learning and memory were evaluated. Brain oxidative status, hippocampal neuropathology, and reactive astrocytes were done. White matter pathology was also evaluated. The results indicated the massy effect of TMT on induced motor ability and spatial memory deficits in accordance with increased neuronal degeneration in Cornus ammonis (CA) 1, CA3, and dentate gyrus (DG) and internal capsule white matter damage. TMT also induced the reduction of reactive astrocytes in CA1 and DG. Brain's catalase activity was significantly reduced by TMT, but not in mice with BSS treatments. Both doses of BSS treatment exhibited improvement in motor ability and spatial memory deficits in accordance with the activation of reactive astrocytes in CA1, CA3, and DG. However, they successfully prevented the increase of neuronal degeneration in CA1 found only with the BSS dose of 100 mg/kg, and it was indicated as the effective dose for neuroprotection in the vulnerable brain area. This study demonstrated mitigative effects of BSS against motor ability and memory deficits with neural health benefits, including a protective effect against CA1 neurodegeneration and a nurturing effect on hippocampal reactive astrocytes.