The hippocampus sits at the apex of the visual hierarchy, yet little is known about the visual properties of this core memory structure. Recent work suggests that a latent, bivalent retinotopic code persists in large-scale memory networks at the cortical apex, scaffolding interactions with sensory networks. Here, we tested whether a bivalent retinotopic code also persists within the hippocampus. To do this, we leveraged high-resolution 7T functional MRI along with voxel-scale visual population receptive field (pRF) modeling in 7 densely-sampled individuals (5 female). Our findings reveal a robust, voxel-scale retinotopic code broadly distributed across subfields and along the long axis of the human hippocampus, comprised of roughly equal proportions of pRFs with positive and negative amplitude responses to visual stimulation. Hippocampal pRFs displayed canonical visual properties, including stable valence and visual field preferences across runs and a contralateral bias. Retinotopic structure also persisted at rest: hippocampal voxels with similar pRF locations were more strongly correlated than voxels representing different visual field locations. Finally, across the ventral visual stream, the prevalence of negative-amplitude pRFs increased with mnemonic involvement, culminating in the balanced, bivalent organization within the hippocampus. These findings support the view that sensory and mnemonic systems are coupled through a shared retinotopic code at the apex of the visual hierarchy.Significance Statement The hippocampus is closely coupled to the visual system, and recent work has challenged the classical view that visual coding schemes, like retinotopy, do not persist into the hippocampus. Here, we use high-resolution precision fMRI to robustly characterize a bivalent retinotopic code in the human hippocampus, consisting of both typical positive and atypical negative responses. We further show that this code predicts functional connectivity within the hippocampus even during non-visual tasks, suggesting that this bivalent retinotopic code may reflect an intrinsic organizational principle of the hippocampus relevant for perceptual-mnemonic segregation and integration.
Normal explicit/declarative memory requires a system of anatomically related structures in the medial temporal lobe that includes the hippocampus and the entorhinal, perirhinal, and parahippocampal cortex. Although extensive medial temporal lobe damage in primates causes robust anterograde amnesia, defining the contribution of the hippocampus proper has proved challenging. We revisited that enduring puzzle here, directly addressing a number of factors suspected to contribute to conflicting results across earlier studies. Among them, we explored the effects of selective hippocampus lesions produced by two common excitotoxin methods, ibotenic acid and N-methyl-D-aspartic acid. Sample sizes were substantial, and all behavioral testing was conducted postoperatively. Performance was assessed on several standard procedures designed for monkeys, including multiple variants of the delayed nonmatching-to-sample test of visual object recognition, a series of rapidly acquired two-choice object discriminations, and a delayed response test of spatiotemporal memory. We used task-specific parametric manipulations (e.g., increasing retention intervals and reduced stimulus set size) to systematically vary demands on memory and test/retest analyses to enhance sensitivity for detecting impairment. Although both lesion groups sustained substantial hippocampal damage, their performance failed to differ from that of intact controls on any task, under any key test condition, regardless of data analytic strategy. The findings constrain plausible accounts of extant discrepancies in the literature and, moreover, highlight the need for fresh perspectives on the core operating characteristics of memory mediated by the primate hippocampus. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Atrial fibrillation (AF) is associated with cognitive decline and dementia even in the absence of clinical stroke, potentially through mechanisms such as silent infarction, small-vessel disease, hypoperfusion, and systemic inflammation. However, most previous studies have focused on global brain measures, and little is known about region-specific structural alterations, particularly within deep gray-matter structures and hippocampal subfields. Evidence regarding atrial flutter (AFL) remains limited. This study aimed to investigate the association between AF/AFL and regional brain and hippocampal subfield volumes in cognitively normal older adults. This cross-sectional analysis included 7,074 community-dwelling participants aged ≥65 years from the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD). Structural magnetic resonance imaging with 3D T1-weighted images was processed using FreeSurfer 7.0. Volumes of the cortex, cortical white matter, subcortical gray matter, eight regional brain areas, and hippocampal subfields were evaluated. AF/AFL was identified using electrocardiography. Adjusted mean regional brain volumes and 95% confidence intervals (CIs) were estimated using analysis of covariance. The false discovery rate was controlled using the Benjamini-Hochberg method. Additional exploratory analyses based on self-reported AF history were also performed. Stratified analyses were performed by age (<75 vs. ≥75 years) and sex. After multivariable adjustment, AF/AFL (171 participants, 2.4%) was associated with smaller volumes of the cortex, cortical white matter, and subcortical gray matter. Among regional structures, AF/AFL was significantly associated with smaller hippocampal and amygdala volumes. At the hippocampal subfield level, reduced fimbria, dentate gyrus, CA1, and subiculum volumes were observed. Analyses based on self-reported history of AF did not demonstrate significant associations with any brain regions. In stratified analyses, participants aged <75 years showed a trend toward smaller hippocampal-tail volume with a significant interaction effect, whereas women exhibited smaller hippocampal volume without a significant sex interaction. In this large community-based sample of cognitively normal older adults, AF/AFL was associated with widespread structural brain alterations and selective vulnerability in memory-related regions, including the hippocampus and amygdala, as well as specific hippocampal subfields. These findings suggest that AF/AFL may be associated with region-specific brain vulnerability before the onset of clinically apparent cognitive impairment.
A study was conducted to examine the effects of visible red light phototherapy with a wavelength of 635 nm on the expression of the neuronal protein GAP-43 in the hippocampus of rats. It was shown that the use of PBMT promotes increased GAP-43 synthesis in the hippocampus, with the maximum effect developing by the 6th day of use, which may indicate a cumulative effect of this procedure.
Lead (Pb) is associated with Alzheimer's disease (AD); however, the relationships between Pb and AD hippocampal transcription remains unclear. We evaluated overlap between Pb-response signatures and cell-type-independent AD transcriptomic signatures. Three toxicology studies (two neuronal cell lines, one mouse hippocampus) provided Pb-response genes. Five human postmortem hippocampal AD case-control transcriptional datasets (n=90 AD, n=106 normal cognition) were cell type deconvoluted and tested with beta regression. Differential gene expression, adjusted for age, sex, and estimated cell-types, were meta-analyzed. Overlapping Pb and AD genes and biological pathways were identified (p adj <0.05). Consistent Pb response was observed at 25 genes ( INPP5F , KIF20B , KIFC1 ) and 47 pathways (ensheathment of neurons, glial cell differentiation, regulation of nervous system processes). Relative to controls, AD samples had fewer neurons (-2.46%), greater microglia (0.42%), astrocytes (0.31%), oligodendrocytes (0.46%), and endothelial cells (0.95%), and 1,455 differentially expressed genes, which were enriched for cellular energy production and metabolism pathways. Six genes ( EHD3 , LAP3 , NRXN3 , PPP1R16B , RPL29 , THRA) and four pathways (synaptic vesicle maturation, vesicle docking) overlapped between Pb and AD. We identified overlapping Pb and AD transcriptomic signatures and pathways, providing molecular context for epidemiologic associations.
Neuroinflammation has been implicated in the pathogenesis of major depressive disorder (MDD), with interferon regulatory factor 1 (IRF1) playing a potential role. MicroRNAs (miRs) are also involved in MDD through posttranscriptional regulation of gene expression. This study investigated whether miR-20a-5p regulates IRF1 in MDD. IRF1 mRNA and miR-20a-5p expression levels were measured by qPCR in postmortem hippocampi from 14 MDD subjects and 14 controls, and in chronic social defeat stress (CSDS) mice. Their regulatory relationship was examined in HEK293 cells using miR-20a-5p overexpression and a dual-luciferase assay. Neuro2a cells treated with DMSO were used to evaluate the effects of cellular stress on Irf1 and miR-20a-5p expression. IRF1 mRNA and miR-20a-5p expression levels were significantly increased in both MDD hippocampi and CSDS mice. Luciferase assays showed that miR-20a-5p directly targeted the conserved seed sequence within the IRF1 3'-UTR and suppressed IRF1 expression. During the early phase of cellular stress, Irf1 mRNA was upregulated, whereas miR-20a-5p was downregulated, suggesting that stress initially induces Irf1 expression, followed by secondary regulation of miR-20a-5p. IRF1 mRNA expression was increased in the hippocampus of both MDD subjects and CSDS mice. Moreover, miR-20a-5p directly targeted the IRF1 3'-UTR, supporting a potential miR-20a-5p-IRF1 regulatory axis involved in inflammatory signaling in MDD. However, its functional significance in vivo remains to be determined.
Non-motor symptoms in Parkinson's disease (PD) may be influenced by the α4β2* subtype of nicotinic acetylcholine receptors (nAChRs) present in the hippocampus (HP) and subiculum (SUB). To continue efforts in positron emission tomography (PET) diagnostics for PD, autoradiographic [18F]nifene binding to α4β2* nAChR was quantitatively assessed in the HP-SUB of PD (n = 27; 14 males and 13 females) and cognitively normal (CN) (n = 32; 16 males and 16 females) cases. Anti-ubiquitin for Lewy body and anti-α-synuclein immunostaining on adjacent slices were analyzed in QuPath, and [18F]nifene binding was quantified in OptiQuant. The SUB had greater [18F]nifene binding (51%-85%) compared to HP in all cases. Significantly higher [18F]nifene binding (>250%; p < 0.0001) was seen in PD SUB and PD HP compared to CN in both males and females. The grey matter (GM) to white matter (WM) ratio in PD = 3.53, whereas CN = 1.33, a >150% increase in PD (p < 0.0001). Binding of [18F]nifene to GM was >250% greater than WM in PD for both male and female. Male CN exhibited an increase, whereas male PD exhibited a significant decrease in [18F]nifene binding with aging, whereas females did not exhibit significant differences. In summary, α4β2* nAChR measured by [18F]nifene is significantly upregulated in the PD HP and SUB. This increased [18F]nifene binding may be of diagnostic value using PET imaging.
Chronic neuroinflammation is a major driver of cognitive decline, vascular cognitive impairment, and Alzheimer's disease. However, the spatial lipidomic alterations underlying neuroinflammatory brain injury remain poorly defined. Oxidative stress and sphingolipid dysregulation have been implicated, but their regional distribution and interplay in the brain are not well characterized. We performed positive-ion mode matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) on coronal brain sections from middle-aged spontaneously hypertensive rats (SHR), a model of chronic neuroinflammation, and normotensive Wistar-Kyoto (WKY) controls. Spatial distributions and relative abundances of multiple lipid classes, including phosphatidylcholines (PCs), sphingomyelins (SMs), hexosylceramides (HexCers), ceramides, phosphatidylserines (PSs), phosphatidylinositols (PIs), phosphatidylethanolamines (PEs), phosphatidic acids (PAs), and sulfatides, were mapped and compared between genotypes. Region-of-interest analysis was used to quantify changes across cortex, hippocampus, and white-matter tracts. SHR brains exhibited a coordinated lipidomic signature characterized by pronounced oxidative stress and membrane remodeling. Oxidized and short-chain PCs were markedly upregulated (up to 11.6-fold), while major structural diacyl PCs were broadly downregulated. Concurrently, sphingolipids were significantly altered, with robust upregulation of SM(d36:1) (7.5-fold) and multiple HexCer species (1.5-1.9-fold), accompanied by accumulation of ceramides. These changes were accompanied by heterogeneous redistribution of PS, PI, and PE species, particularly within the hippocampus. Sulfatide patterns in white-matter tracts were also altered, suggesting myelin remodeling. Region-of-interest analysis confirmed that the most pronounced lipid alterations were concentrated in the hippocampus and white-matter regions. Chronic neuroinflammation induces a spatially organized, multi-class lipid remodeling response in the brain, driven by advanced oxidative membrane damage and a shift toward a pro-apoptotic sphingolipid profile. The convergence of these pathways creates a vicious cycle of membrane injury, mitochondrial dysfunction, and sustained neuroinflammation that is especially prominent in the hippocampus and white matter. These spatially resolved findings provide direct evidence that oxidative stress and sphingolipid dysregulation are central, interrelated mechanisms contributing to neurovascular injury and increased risk of cognitive impairment. The study highlights the power of MALDI-MSI to uncover region-specific lipid pathology and identifies potential lipid-based targets for therapeutic intervention in neuroinflammatory brain disease.
In mesial temporal lobe epilepsy, resection or ablation-typically of anterior temporal structures-is highly successful in achieving seizure freedom. However, in a substantial proportion of patients, seizures recur for unclear reasons. Invasive hippocampal recordings suggest that, in some patients, hippocampal seizures are highly focal, often restricted to the anterior or posterior hippocampus. This led us to hypothesize that resection or ablation limited to the hippocampal subregion(s) involved at seizure onset is more likely to control seizures than surgery that does not address the specific onset locations. We present a case in which seizures were successfully controlled after posterior hippocampal ablation, as well as a retrospective case series of 18 patients in which 10 cases demonstrated focal onsets within the anterior or posterior hippocampus. Better outcomes occurred when surgery was concordant with the onset region(s) versus discordant (n = 7 concordant vs. 11 discordant patients, P = 0.046, Barnard Exact test). These data suggest that mesial temporal lobe epilepsy can be subdivided according to whether the hippocampal onset pattern is focal or nonfocal, and that targeting localized seizure onset zones within the hippocampus can be effective for seizure control, while limiting surgical morbidity and potentially the risk of adverse cognitive outcomes.
Memory shapes how we explore the visual world, but the neural mechanisms linking mnemonic processes to eye movements during naturalistic viewing are not well understood. Theta-band oscillatory activity in the hippocampus is time-locked with eye movements in primates, suggesting a putative mechanism for coordinating mnemonic processing and oculomotor behaviour. Yet, it remains unknown whether this coupling generalises to episodic memory-guided viewing in humans, whether slow (3-6 Hz) and fast (6-10 Hz) theta bands play dissociable functions, and whether this coupling is sensitive to the direction of upcoming eye movements. Here, we used intracranial EEG and eye-tracking data from 11 neurosurgical patients of either sex (Keles et al., 2024) to address these questions. Using fixation-locked analyses, we found that hippocampal theta dynamics differentiate memory-guided from memory-independent fixations of episodically encoded naturalistic scenes (i.e., movies) through power and coherence mechanisms that are both temporally and spectrally dissociable. First, immediately after fixations (∼0 to 250 ms), slow-theta power was more strongly suppressed during memory-guided trials (i.e., true positive, TP) than correct memory-independent trials (i.e., true negative, TN). Second, in the period around fixations (-80 to 60 ms), theta phase coherence increased independent of power during TP vs TN trials. This increase in coherence was most pronounced for contraversive relative to ipsiversive fixations, consistent with direction-sensitive hippocampal-oculomotor coordination during memory-guided viewing. Together, these findings suggest that hippocampal theta plays dissociable, time-locked roles in memory-guided fixations during naturalistic visual retrieval, supporting an ecologically relevant role for the hippocampus in coordinating memory and active visual behaviour.Significance statement Memory influences how we sample the visual environment, but the brain signals that link memory systems to eye movements are poorly understood. Using intracranial recordings from the human hippocampus during visual exploration of naturalistically encoded scenes, we demonstrate that theta-band activity differentiates memory-guided from memory-independent fixations in two ways: increased theta synchrony around fixation onset and reduced theta power modulations after fixation onset. These results reveal novel insights into how hippocampal theta helps coordinate memory-guided visual exploration.
Diagnostic MRI evaluation of temporal lobe epilepsy (TLE) depends on the subjective visual interpretation of MRI images. These interpretations could be enhanced by quantitative artificial intelligence (AI) support tools. Humans often make sequential and conditional decisions during their radiological interpretations, such as whether an abnormality is present and, if present, characterizing the abnormality. It is not known whether it is superior to train AI to treat every decision separately in a similar step-wise manner or to train a model holistically on all decisions simultaneously. Here, we analysed three large epilepsy MRI datasets [n = 3676, 2320 people with epilepsy and 1356 healthy controls (HC)] to perform two tasks: (i) establish the presence of a TLE pattern on MRI and (ii) determine TLE pattern lateralization. We compared Step-wise models that independently classify TLE versus HC and lateralize patients as left TLE (L-TLE) or right TLE (R-TLE), against a simultaneous model trained to distinguish all three classes in a single step. To do this, 3D volumetric T1-weighted images were input into an EfficientNetV2 model multiple times to ensure reproducibility of results. Class prediction, model classification confidence and saliency maps were output for interpretability. Step-wise models outperformed the Simultaneous model on both tasks (both Ps < 0.001), with an average ∼2.8% accuracy increase for discriminating HC from TLE and an average 12.7% accuracy increase for distinguishing L-TLE from R-TLE. For both the Step-wise and Simultaneous models, important features discriminating TLE from HC included the known TLE limbic pattern involving the hippocampus, parahippocampal cortical regions, cingulate cortex and lateral temporal regions. However, there was less concordance between the Step-wise and Simultaneous models for the L-TLE versus R-TLE task (all Fisher's Zs > 10.5, Ps < 0.001); the Step-wise model focused less on subcortical regions such as the thalamus and hippocampus and focused more on distributed cortical pathology. Across the two Step-wise models, 95.1% of TLE patients had accurate classifications in either HC versus TLE and/or L-TLE versus R-TLE tasks. These results included 69.6% of patients being both correctly labelled as TLE and lateralized, 13.9% being correctly labelled TLE but lateralized incorrectly and 11.6% being lateralized correctly but not detected as TLE. These findings provide evidence that diagnostic tasks with simpler, Step-wise AI models may enhance diagnostic performance and interpretability in clinical workflows. Future AI clinical support tools can leverage this step-wise approach in the early identification of TLE-related structural patterns, supporting timely diagnosis and treatment decisions.
Lifelong premature ejaculation (LPE) is a prevalent male sexual dysfunction with unclear neurobiological mechanisms. Despite its high prevalence, the etiology of LPE remains debated, often attributed to psychological or biological factors. Recent neuroimaging studies have highlighted the role of central nervous system dysregulation in sexual behavior. This study investigates abnormal brain functions and altered network connectivity in LPE patients after visual sexual stimuli (VSS) using functional magnetic resonance imaging. Twenty-five LPE patients and 31 healthy controls (HCs) underwent resting-state and task-state functional magnetic resonance imaging (fMRI). Clinical data, including sexual history, self-reported intravaginal ejaculatory latency time, International Index of Erectile Function-5, the Chinese Index of Premature Ejaculation, anxiety/depression scores, and serum testosterone levels, were collected. Neuroimaging preprocessing and analysis focused on amplitude of low-frequency fluctuation, fractional ALFF, and regional homogeneity. Task-state fMRI compared brain activation patterns after VSS. Statistical analyses included voxel-based comparisons and network connectivity assessments using SPM12 and DPABI v3.0. LPE patients demonstrate distinct neurofunctional abnormalities after VSS, particularly hyperactivation in the precuneus. ‌Clinical Data‌: LPE patients exhibited significantly lower International Index of Erectile Function-5 scores and higher depression rates compared to HCs, with no differences in age, BMI, or testosterone levels. Brain Activation‌: During VSS, LPE patients showed relative signal decrease in the middle cingulate cortex and left precentral gyrus compared to HCs. Regional homogeneity analysis revealed hyperactivation in the precuneus and fusiform gyrus post-stimulus. Network Connectivity‌: Altered connectivity in premature ejaculation patients involved the fusiform gyrus (linked to posterior cingulate, hippocampus, parahippocampus, and supplementary motor areas) and the superior parietal lobule (connected to the angular gyrus). These findings suggest that aberrant central nervous system processing of sexual stimuli contributes to premature ejaculation pathophysiology, offering potential targets for neuromodulatory therapies. The study focuses on the different activation patterns of patients with LPE from the perspective of sexual arousal. The methodological aspects of research, such as the use of images or videos in sexual stimulation, remain controversial. The findings of our network analysis only demonstrated a limited number of altered functional connections, and no established network metrics were provided to substantiate the claim of extensive network disruption. These factors collectively represent important limitations of the present study. The hyperactivity in this brain region observed in patients could represent a unique response to VSS among those with LPE, ultimately leading to alterations in their ejaculatory behavior.‌‌‌.
Accurate assessment of hippocampal volume is of significant clinical value for the early diagnosis and disease monitoring of Alzheimer's disease (AD). However, automatic segmentation of the hippocampus in MR images remains challenging due to its elongated and irregular morphology, blurred boundaries, low contrast with surrounding tissues, and substantial inter-individual anatomical variability. We propose an Edge-aware Salient Context Fusion Refinement Network (ESCFR-Net). Built upon a classic U-shaped encoder-decoder architecture, the proposed network employs a Salient Feature Enhancer to suppress background interference and enhance weak feature responses of the hippocampus. A Global Channel Context Attention (GCCA) module is introduced to model long-range spatial dependencies, while a Multi-scale Context Fusion Refinement Module (MCFRM) improves the utilization of multi-scale features. Furthermore, an Edge-Guided Refinement Attention (EGRA) module synergistically enhances edge and semantic features to precisely delineate weak boundaries. Experimental results on a self-constructed dataset comprising 225 3D-T1 MRI scans demonstrate that ESCFR-Net achieves a Dice coefficient of 0.9004, outperforming state-of-the-art methods such as SwinUNETR and PMFS-Net. Clinical association analysis, conducted on 91 healthy controls (HCs) and 91 patients with mild cognitive impairment (MCI), reveals that bilateral hippocampal volumes in MCI group are significantly smaller than those in HCs (p < 0.001). Additionally, the total hippocampal volume achieves an area under the curve (AUC) of 0.927 in distinguishing HCs from patients with MCI, with sensitivity and specificity reaching 90.11 and 83.52%, respectively. This study provides a highly accurate and robust automated hippocampal segmentation tool for early diagnosis, disease monitoring, and clinical decision-making in Alzheimer's disease.
To investigate convergent patterns of gray matter volume (GMV) alterations in temporal lobe epilepsy (TLE) and to characterize distinct gray matter atrophy patterns across subtypes of TLE. A coordinate-based meta-analysis was performed using anisotropic effect size-based signed differential mapping (AES-SDM). In addition, a complementary single-center observational cross-sectional VBM cohort including patients with hippocampal sclerosis (HS) and MRI-negative TLE (TLE-no) was analyzed to explore subgroup-related GMV alterations compared with healthy controls(HCs). The meta-analysis revealed the most consistent GMV reductions in the ipsilateral hippocampus and parahippocampal, ipsilateral inferior temporal gyrus, ipsilateral fusiform gyrus, ipsilateral insula, ipsilateral lenticular nucleus, ipsilateral cerebellum, and bilateral thalamus in TLE, compared with HCs. GMV increases of the unilateral amygdala and parahippocampal gyrus were observed in TLE without HS. In the observational cross-sectional analysis, patients with unilateral HS showed reduced GMV in the ipsilateral hippocampus, parahippocampal gyrus, fusiform gyrus, temporal gyrus, temporal pole, and thalamus, compared with HCs. Compared with the left HS, the right-sided HS group exhibited GMV atrophy in the right amygdala and cerebellum, alongside longer disease duration. In the Left-sided TLE-no patients, GMV increase was observed in the ipsilateral amygdala and parahippocampal gyrus in TLE-no. The meta-analysis identified multiple morphometric alterations in extrahippocampal regions in TLE and described GMV alteration patterns across different TLE subgroups. Complementary observational cross-sectional VBM cohort showed partially overlapping spatial patterns. GMV increases in the unilateral amygdala and parahippocampal gyrus were observed in MRI-negative TLE and should be interpreted cautiously, given the heterogeneity of this subgroup.
Depression is a highly recurrent psychiatric disorder characterized by persistent low mood, anhedonia, and sleep disturbances. The clinical diagnosis of depression currently relies primarily on clinical interviews and standardized assessment scales, lacking objective biological markers. This increases the risk of misdiagnosis and missed diagnosis, while also limiting the precise differentiation of disease subtypes and the individualized prediction of treatment response. Identifying reliable biomarkers has therefore become a major research focus. This study, based on bioinformatics analysis of the GEO database, found that fibroblast growth factor 13 (FGF13) was significantly reduced in the serum of patients with major depressive disorder (MDD). FGF13 belongs to the fibroblast homologous factor (FHF) family and is enriched in neurons of the brain, where it regulates neuronal excitability and synaptic plasticity. However, the role of FGF13 in depression remains unclear. Based on the results of the bioinformatics analysis, experimental validation demonstrated that Fgf13 expression was significantly reduced in corticosterone (CORT)-induced PC12 and SH-SY5Y cells, as well as in the hippocampus of chronic unpredictable mild stress (CUMS) rats, as shown by qRT-PCR and Western blot analyses. Functional experiments demonstrated that FGF13 overexpression enhanced the expression of synaptic plasticity-related proteins (Syn, PSD95, BDNF) and anti-apoptotic protein (Bcl-2), while suppressing pro-apoptotic proteins (Bax, Cleaved-caspase-3) and activating the PI3K/AKT pathway. These effects were markedly reversed by treatment with the PI3K inhibitor LY294002. Furthermore, FGF13 overexpression improved neuronal apoptosis and morphological damage in the hippocampus of CUMS rats. Serum ELISA analysis revealed significantly reduced FGF13 levels in patients with depression. Logistic regression analysis showed a negative association between FGF13 expression and depression risk, while ROC analysis demonstrated good diagnostic performance (AUC = 0.936). Collectively, these findings suggest that FGF13 participates in the pathogenesis of depression by regulating synaptic plasticity and neuronal apoptosis and may serve as a promising biomarker and potential therapeutic target.
Neonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. Rat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 min. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. Twelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. This novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. This study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. nGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. Neonatal CA/CPR induces global cerebral ischemia, which uniquely allows investigation of hindbrain structures, such as the cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia.
The hippocampus is essential for efficient navigation. Although lack of visual experience from birth induces volumetric and structural modifications to the hippocampus, tactile and auditory navigation remain partially preserved in congenitally blind (CB) individuals. Structural studies in this population have relied on global volume or tail-body-head segmentations, leaving the contributions of individual hippocampal subfields to navigation unresolved. We investigated hippocampal subfield volumes and their association with navigational learning in CB adults compared to sighted controls. Structural MRI data were analyzed using probabilistic cytoarchitectonic ROIs to quantify volumes of Cornu Ammonis (CA), Fascia Dentata (FD), Subiculum (SUB), and the Hippocampal-Amygdaloid Transition Area (HATA). Participants performed obstacle detection and avoidance tasks with a tactile sensory substitution device in a real-world obstacle course. CB participants showed significant volume reductions in left CA and FD compared to sighted controls after total brain volume correction. Obstacle detection learning was associated with bilateral CA and SUB volumes in sighted controls, whereas in CB participants it was selectively associated with right CA and right HATA volumes. Obstacle avoidance learning showed no robust hippocampal associations in either group. Our results indicate that hippocampal subfield-navigation associations are selective and component-dependent in the absence of vision, rather than reflecting uniform hippocampal involvement.
Our modern environment - with its artificial lighting, irregular work hours, and frequent travel - often disrupts our circadian rhythms, which can lead to health problems, particularly in learning and memory. This is especially concerning given the aging population and the rising prevalence of dementia. Yet, the biological mechanisms linking circadian disruption to cognitive impairment remain poorly understood. At the molecular level, genetic techniques have been used to attenuate or abolish expression of key genes involved in circadian rhythms and these manipulations have detrimental effects on memory function. However, whether environmentally induced circadian disruption, impairs memory via changes in overall gene expression levels in the hippocampus or rather via changes in the coordinated rhythmic patterns of circadian expression across groups of genes is less known. Here, we examined how environmental circadian disruption affects the expression of genes involved in the circadian clock and memory in the hippocampus of rats using a forced desynchrony model. Circadian disruption changed the rhythmic properties of gene expression in most genes assessed but had no measurable effect on average expression levels across the day. These findings suggest that the inability to maintain circadian synchrony rather than overall expression may underlie the cognitive deficits observed in circadian-related disorders.
Stress-related psychiatric disorders are increasingly common conditions that are notoriously difficult to treat. Identifying the factors that increase the risk of these conditions and defining the biological mechanisms through which they promote the development of these disorders could inform disease pathophysiology and reveal novel therapeutic strategies to improve mental health. Clinical findings suggest that oral antibiotics increase the risk of depression and anxiety, but preclinical studies have had mixed results. Administering antibiotics to rodents has been reported to induce depression- or anxiety-like behavior in some studies but to protect against stress-induced increases in depression- and anxiety-like behavior in others. The reasons for these discrepancies are unclear. The current study examined the effects of antibiotics on stress susceptibility in a model of sub-chronic stress in male and female c57BL/6 mice. Following exposure to oral antibiotics and/or stress, mice were tested in a panel of behavioral assays prior to their brains being examined for potential changes in hippocampal neurogenesis and microglial number. Overall, our results indicate that antibiotics increased susceptibility to stress in several assays, and some of these effects were more pronounced in females than males. Exposure to antibiotics also reduced the proliferation of progenitor cells in the hippocampus of unstressed, but not stressed, animals of both sexes but did not significantly impact the number of microglia or immature neurons in the hippocampus. Future work should examine additional potential mechanisms through which antibiotics impact stress susceptibility and behavior in males and females.
The hippocampus participates in crucial functions such as memory consolidation, spatial processing and emotional regulation that require diverse input from multiple cortical areas that is funneled through the upper layers of the entorhinal cortex (EC), mostly from layer II to the dentate gyrus (DG). Traditional models of the hippocampal formation described 200,000 EC layer II neurons projecting to 1 million granule cells (GCs) in the rat, rendering low divergence (1:5), with each EC neuron establishing about 18,000 synapses with GCs and each GC receiving about 4000 synapses from EC neurons. In this manuscript, we update this model of connectivity incorporating new features described in the last three decades that include updated populations of EC layer II neurons obtained with design-based stereology, a revised definition of EC layer II based on molecular criteria and selecting reelin expressing neurons as the only layer II neurons projecting to the hippocampus. The updated model shows ~80,000 neurons from EC layer II projecting to the DG, ~45,000 from the medial entorhinal cortex (MEC) and ~35,000 from the lateral entorhinal cortex (LEC) with high divergence of 1:20 and 1:30. We also show that EC layer II neurons may establish ~90,000-115,000 synapses on GCs, while GCs receive about 8000 synapses from EC layer II neurons. We estimate a ~25% redundancy in the connectivity, so each EC neuron may contact ~68,000-86,000 GCs and each GC would be contacted by ~3000 neurons from MEC and 3000 from LEC. In addition, we quantitatively assess a potential projection of mossy cells to the middle molecular layer described in mice, which could have an impact on GC inhibition. Overall, we produced a detailed, complete, and updated quantitative model of EC projections to the DG that reveals a much more divergent and richer projection than previously described, with implications for functional models (e.g., pattern separation) and more widely for building realistic hippocampal models or establishing comparisons across species.