Search Results (404)

Platelets express several glycophosphatidylinositol-(GPI-) anchored receptors, mainly involved in protection against lysis by activated complements. Most of these are well-characterised and are expressed on other blood cells. More recently, CD109 with a mass of 175 kDa was also shown to be a GPI-anchored receptor, surface expressed only on activated platelets, with a role as a co-receptor for transforming growth factor-β (TGF-β). CD109 is expressed on a wide range of cells and is a marker for various types of tumors. Activated platelets express an even larger GPI-anchored receptor at about 500 kDa. We have now isolated this and identified it as fibrocystin L, also known as polycystic kidney hepatic disease L1 (PKHD1L1). Fibrocystin L, like other platelet GPI-anchored receptors, is missing or deficient in paroxysmal nocturnal hemoglobinuria. Fibrocystin L is also expressed in activated T-cells and may be involved in immune responses. Recently, there have been additional reports of PKHD1L1 expression and roles as a coat protein of hair-cell stereocilia essential for normal hearing, as well as reports of them in the dentate gyrus in mice involved in susceptibility to seizure. In all these cases, GPI anchors were not reported, but neither were they tested for. During the fluorescence microscopy studies, we used CD109 as a control and observed that it is also a granule protein that had not been previously reported. Full article

Hypoxia-inducible factors (HIF-1α, HIF-2α, HIF-3α) regulate cellular adaptation to oxygen deprivation, but their region-specific roles in Alzheimer’s disease (AD) and AD with cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC) layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant regions (CA4, DG) maintained HIF-2α and showed relative resilience, whereas vulnerable regions (CA1, CA2) exhibited HIF-1α upregulation, HIF-3α loss, and HIF-2α dysregulation. The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1α/HIF-3α regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3 vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2α in ACC neurons remains stably elevated across all conditions. Taken together, our results highlight HIF-2α as a potential contributor to regional vulnerability and raise the possibility that maintaining HIF-2α levels, in addition to or instead of modulating HIF-1α, could be worthy of further investigation in the context of AD and related vascular changes. Full article

Accurate and efficient memory processing is essential for survival. A body of ongoing work in both human subjects and animal models suggests that memory processing may differ substantially between males and females. In mice, contextual fear memory (CFM) encoding, consolidation, and recall have been well studied, and the mouse hippocampus and amygdala have been implicated in these processes. The present pilot study addresses whether the activation of these brain regions differs substantially between male and female mice at each stage of CFM processing. We find that male and female mice show no differences in sleep behavior, which is essential for CFM consolidation, following single-trial contextual fear conditioning (CFC). We also find no significant differences in CFM recall performance between male and female mice. However, females show a trend for larger increases in CA1 cFos expression, relative to males, during CFM encoding. On the other hand, only males—but not females—show an apparent increase in cFos expression among dentate gyrus (DG) granule cells during CFM consolidation. Males also show a trend for a larger apparent reduction in cFos in CA1 and CA3 during CFM consolidation, relative to females. These preliminary findings highlight the idea that the neurobiological underpinnings of memory processing may differ between males and females, even when performance during recall is identical. Full article

Background/Objectives: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory approach with potential therapeutic value for cognitive impairment in Alzheimer’s disease (AD). Ferroptosis-related oxidative injury has been implicated in AD-associated neuronal dysfunction, but whether rTMS-induced functional improvement is accompanied by changes in ferroptosis-related oxidative injury remains unclear. This study evaluated the effects of high-frequency rTMS on cognitive function, hippocampal neuronal excitability, and ferroptosis-related oxidative injury in amyloid precursor protein/presenilin-1 (APP/PS1) mice, using Ferrostatin-1 (Fer-1) as a pharmacological comparator. Methods: Six-month-old female mice were used, including age-matched C57BL/6J controls and APP/PS1 mice assigned to the AD + Sham, AD + rTMS, and AD + Fer-1 groups (n = 6 per group). After 14 days of intervention, cognitive performance was assessed using behavioral tests. Whole-cell patch-clamp recordings were performed in hippocampal dentate gyrus granule neurons to evaluate neuronal excitability and voltage-gated sodium (Na⁺) and potassium (K⁺) channel properties. Biochemical assays and transmission electron microscopy were used to assess oxidative, iron-related, and mitochondrial changes, and mitochondrial ultrastructure was examined in an independent cohort (n = 3 per group) using transmission electron microscopy. Results: Compared with AD + Sham mice, high-frequency rTMS improved cognitive performance, increased evoked action potential firing, lowered the elevated action potential threshold, partially restored voltage-gated Na⁺ and K⁺ current amplitudes, and accelerated recovery of Na⁺ currents from inactivation. Fer-1 produced partially overlapping, but not identical, effects across behavioral, electrophysiological, biochemical, and ultrastructural outcomes. Both interventions increased hippocampal glutathione (GSH) levels, reduced malondialdehyde (MDA) and total iron levels, partially restored superoxide dismutase (SOD) activity, and improved mitochondrial ultrastructure and reduced the prevalence of mitochondrial profiles with small cross-sectional areas. Conclusions: High-frequency rTMS improved cognitive and hippocampal neuronal outcomes in female APP/PS1 mice. These improvements were accompanied by biochemical and mitochondrial changes compatible with attenuation of ferroptosis-related injury. However, the findings do not establish ferroptosis inhibition as either necessary or sufficient for the effects of rTMS. Full article

Monosodium glutamate (E621) is a common flavor enhancer in highly processed food. Although it makes food more enjoyable, chronic intake may lead to excitotoxicity in brain areas. The current study investigates histological and biochemical neurodegenerative alterations in the rat hippocampus following E621 administration and evaluates the potential neuroprotective properties of ascorbic acid (AA) against E621-induced adverse effects. Forty adult male albino rats were divided into four groups: control group (G1), AA group (G2), E621 group (G3), and AA + E621 group (G4). All animals received a daily intraperitoneal (IP) injection for 30 days. Hippocampal samples were processed and stained with hematoxylin and eosin (H&E), immunostained for GFAP, synaptophysin (a synaptic protein), and caspase-3, and biochemically analyzed for oxidative markers, including malondialdehyde (MDA) and superoxide dismutase (SOD). G3 exhibited significant neurodegenerative changes, characterized by pyknotic granular cells and cytoplasmic vacuolation, with significantly elevated GFAP, synaptophysin, and caspase-3 immunoreactivity in the dentate gyrus (DG). These structural deficits correlated with elevated MDA levels and reduced SOD levels in G3. In contrast, simultaneous administration of AA with E621 resulted in substantial preservation of neuronal morphology, a reduction in caspase-3 immunoreactivity, and a restoration of synaptic vesicle density in G4. E621 induces hippocampal injury by increasing ROS levels and dysregulating GFAP, synaptophysin, and caspase-3. At the same time, AA preserves neuronal integrity and synaptic homeostasis, suggesting its potential role as a protective dietary supplement against brain injury induced by the E621 flavor enhancer. Full article

The tryptophan–kynurenine pathway, mediated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), is critically involved in the pathogenesis of depression. A series of novel morpholine–coumarin derivatives were designed and synthesized as dual IDO1/TDO inhibitors. Through in vitro enzyme screening, compound 14d exhibited potent inhibitory activity with IC₅₀ values of 0.34 µM and 0.75 µM, respectively. In lipopolysaccharide (LPS)-stimulated BV2 microglial cells, 14d downregulated IDO1/TDO expression, suppressed pro-inflammatory cytokines (IL-1β, COX-2, iNOS, TNF-α), and upregulated the anti-inflammatory cytokine IL-10. In an LPS-induced acute depressive mouse model established in C57BL/6 mice, intraperitoneal administration of 14d (20 mg/kg) significantly reduced immobility time in the forced swim and tail suspension tests, without affecting spontaneous locomotor activity. Mechanistic studies revealed that 14d inhibited microglial activation in the hippocampal dentate gyrus, reduced cerebral kynurenine levels, increased serotonin content, and upregulated BDNF/PKA signaling. Molecular docking further predicted the binding interactions of 14d with the active sites of IDO1 and TDO. These findings suggest that 14d represents a promising dual IDO1/TDO inhibitor lead compound for the treatment of inflammation-associated depression through modulation of the kynurenine pathway and neuroinflammatory responses. Full article

Sleep deprivation is a recognized risk factor for neuroinflammatory and neurodegenerative disorders. Dopamine signaling through D2 receptors (DRD2) has emerged as a potential immunomodulatory pathway in the central nervous system. The present study investigated whether activation of DRD2 by quinpirole (QUIN) modulates astrocytic and microglial responses and NF-κB nuclear translocation in a murine model of rapid eye movement sleep deprivation (RSD). Male CD1 mice were subjected to 72 h of RSD and treated with QUIN (2 mg/kg/day). GFAP, Iba-1, and NF-κB expression were evaluated in hippocampal subregions (CA1, CA3, dentate gyrus) and the medial parietal cortex using immunofluorescence and confocal microscopy. RSD increased GFAP and Iba-1 expression and induced morphological changes consistent with glial activation. Notably, RSD increased NF-κB nuclear expression in microglia. QUIN administration reduced Iba-1 expression, attenuated microglial morphological alterations, and reduced NF-κB nuclear expression across all analyzed regions, even in RSD-subjected mice. These findings suggest that DRD2 activation exerts anti-inflammatory effects in the brain during REM sleep deprivation and that dopaminergic signaling may represent a key target for neuroinflammation associated with sleep loss. Full article

Background/Objectives: To investigate the immediate regulatory effects of magnetic stimulation with different parameters on the excitability of glutamatergic neurons and GABAergic neurons in the mouse hippocampal dentate gyrus (DG), and to analyze the underlying mechanisms using the Hodgkin–Huxley (HH) model. Methods: Whole-cell patch-clamp recordings were performed on acute brain slices to measure changes in resting membrane potential (RMP), the number of action potentials (APs) evoked by 500-ms long-duration stimulation, as well as AP threshold, peak, half-width, maximum rising slope, and maximum falling slope under magnetic stimulation at various frequencies (1, 10, 20 Hz) and intensities (50, 75 mT). An improved HH model was established based on experimental data to analyze the dynamic changes in gating variables under magnetic stimulation. Results: High-frequency magnetic stimulation (10–20 Hz) significantly increased the number of APs in both neuron types. In glutamatergic neurons, the number of APs increased from 10.12 ± 0.52 in the control group to 15.62 ± 0.84 in the 20 Hz-75 mT group; in GABAergic neurons, it increased from 7.88 ± 0.40 to 12.62 ± 0.53. Magnetic stimulation also depolarized RMP and significantly altered multiple AP waveform parameters in both neuron types. Glutamatergic neurons showed a more distinct frequency dependence, whereas GABAergic neurons were more sensitive to changes in both frequency and intensity in terms of RMP and multiple waveform parameters. Simulation results showed that the 1 Hz conditions produced negligible changes in AP firing, gating-variable dynamics, and steady-state ion-channel parameters compared with the Control condition. In contrast, high-frequency stimulation enhanced the dynamic changes of sodium and potassium channel gating variables and altered their voltage-dependent steady-state properties. Specifically, sodium channel activation shifted toward more negative potentials, whereas sodium channel inactivation and potassium channel activation shifted toward more depolarized potentials. Conclusions: Under the experimental conditions of this study, magnetic stimulation immediately enhanced the excitability of glutamatergic and GABAergic neurons in the hippocampal dentate gyrus of male mice in a frequency-dependent manner. The modified HH model reproduced both the weak effects under low-frequency stimulation and the enhanced excitability under high-frequency stimulation, suggesting that these immediate effects may be related to frequency-dependent changes in the gating kinetics and voltage-dependent properties of sodium and potassium channels. Full article

Lead exposure remains a pervasive environmental and public health threat, imposing a substantial burden of neurodevelopmental and cognitive dysfunction, yet safe mechanism-oriented interventions remain limited. Genistein, a soybean-derived isoflavone with antioxidant and neuroprotective potential, may counter heavy metal-induced neural injury; however, whether its efficacy is associated with redox–metabolic remodeling is unclear. Here, we evaluated genistein in lead-exposed C57BL/6J mice and lead-challenged HT22 hippocampal neurons. Genistein improved novel-arm exploration and spatial memory without altering locomotor or swimming performance, and attenuated neuronal disorganization and apoptosis in hippocampal CA1, CA3 and dentate gyrus regions. These protective effects were accompanied by reduced blood and hippocampal lead accumulation, restored glutathione redox balance, enhanced antioxidant capacity, preserved mitochondrial integrity, and suppressed Bax/Caspase-3-associated apoptotic signaling. Importantly, because genistein also reduced hippocampal lead accumulation, the in vivo neuroprotection may reflect both reduced target-tissue lead burden and improved glutathione-related redox homeostasis. Untargeted metabolomics identified 59 genistein-responsive metabolites enriched mainly in glutathione metabolism, oxidative phosphorylation, and ascorbate/aldarate metabolism, linking metabolic remodeling to behavioral recovery and reduced oxidative-apoptotic injury. In HT22 cells, blockade of glutathione synthesis by buthionine sulfoximine markedly weakened genistein-mediated cytoprotection, mitochondrial membrane potential recovery, and apoptosis inhibition. Collectively, genistein mitigates lead-induced hippocampal neurotoxicity and cognitive impairment by restoring glutathione-centered redox–mitochondrial homeostasis, supporting its further development as a mechanistically defined dietary candidate for environmental pollutant-associated neural injury. Full article

Temporal lobe epilepsy (TLE) is a common drug-resistant epilepsy characterized by recurrent seizures, cognitive impairment, aberrant adult hippocampal neurogenesis, inhibitory circuit disruption, and persistent inflammatory remodeling. Current anti-seizure medications primarily offer symptomatic control and do not target the progressive structural and functional deterioration of epileptic hippocampal networks. Here, we investigated whether local nerve growth factor (NGF)-hydrogel delivery during the latent phase after status epilepticus could mitigate hippocampal pathological remodeling and improve long-term outcomes in a kainic acid (KA)-induced mouse model (utilizing C57BL/6J and Nestin-CreERT2 mice). Animals were randomly assigned to three groups: the saline control group, the untreated KA epilepsy group, and the KA + NGF-hydrogel treatment group. NGF-hydrogel was administered into hippocampal Cornu Ammonis 1 (CA1) beginning 3 days post-kainic acid and repeated every 15 days. Histological, immunofluorescence, circuit-tracing, electrophysiology, electroencephalography (EEG), and behavioral assessments were used to evaluate neurogenesis, microenvironment, circuit readouts, seizure burden, and cognition. NGF-hydrogel treatment was associated with preserved dentate gyrus neural stem cell populations, improved newborn granule cell localization and maturation, attenuated neuroinflammation and gliosis, and partial recovery of inhibitory interneuron markers. These changes were accompanied by improved hippocampal circuit readouts, reduced chronic spontaneous seizure burden, and enhanced recognition and spatial memory. Our findings indicate that local NGF-hydrogel delivery following status epilepticus is associated with improved hippocampal remodeling and functional outcomes, and suggest that biomaterial-based neurotrophic support may be a promising strategy for providing targeted neuroprotection and facilitating excitatory/inhibitory (E/I) balance reconstruction in the epileptic hippocampus. Full article

Background: Glucagon-like peptide-1 receptor (GLP1R) agonists, particularly semaglutide, show neuroprotective effects in genetic models of Alzheimer’s disease (AD). However, their delayed and long-term effects in sporadic AD, such as the intracerebroventricular streptozotocin (STZ) injection, remain insufficient. It is unclear how long the effects of GLP1R agonists persist after discontinuation and whether a single course can suppress progressive neurodegeneration. This study aimed to evaluate the delayed effects of semaglutide administration on morphological changes in neurons and glial cells in the hippocampus associated with cognitive impairment in an STZ-induced rat model of AD. Methods: Rats received bilateral intracerebroventricular STZ injections (3 mg/kg) followed by a 5-week course of intraperitoneal administration of semaglutide (0.1 mg/kg, every other day), and were euthanized 60 days after discontinuation of semaglutide administration. Immunomorphological methods were used to detect neuronal, astrocytic and microglial alterations. A novel object recognition test was performed to assess behavioral effects. Results: STZ-treated animals demonstrated cognitive impairments, ventriculomegaly, a significant increase in p-tau protein fluorescence intensity (p = 0.02), a decrease in CA1–CA3 field area (by 23%, p = 0.008), and reduced hippocampal neuronal density. Decreases in TOMM20 (mitochondrial marker) and synaptophysin levels were accompanied by significant glial activation in the hippocampal CA3 field. Semaglutide administration significantly reduced the enlarged ventricular lumen (by 43.5%), decreased p-tau fluorescence intensity, reduced vimentin-positive reactive astrocytes (by 68.4%), and increased synaptophysin fluorescence intensity. Furthermore, it reduced microglial activation (decreasing IBA1 cell density and elongation) and alleviated the disrupted AQP4 distribution. However, semaglutide did not completely halt the neurodegenerative process and showed no effect on the number of doublecortin-positive cells in the dentate gyrus. Conclusions: Hippocampal changes assessment revealed that course administration of semaglutide exerts prolonged effects, attenuating the severity of pathomorphological alterations and behavioral changes in a sporadic AD model after drug discontinuation. Full article

Viral infections of the central nervous system produce memory impairment through mechanisms that extend beyond acute neuronal injury. Herpes simplex virus type 1, human immunodeficiency virus, varicella zoster virus, cytomegalovirus, Epstein–Barr virus, influenza, SARS-CoV-2, West Nile virus, and Zika virus each enter or engage the brain through distinct routes, yet converge on four shared molecular pathways that selectively damage hippocampal circuits: mitochondria-associated membrane (MAM) dysfunction, chronic neuroinflammation, blood–brain barrier (BBB) disruption, and impaired CREB-BDNF signaling. These pathways specifically compromise the dentate gyrus, CA3, and CA1 subfields, producing predictable deficits in pattern separation, associative retrieval, and temporal memory binding. Antiretroviral and antiviral therapies suppress viral replication but fail to reverse organelle-level dysfunction, leaving most hippocampal injury unaddressed. Emerging plasma biomarkers, p-tau217, neurofilament light chain, and GFAP, combined with hippocampal subfield MRI, now enable mechanistic stratification before irreversible circuit loss occurs. This review proposes, as a unifying hypothesis, that virus-associated memory impairment represents a convergent hippocampal syndrome driven by shared downstream pathways, and that combination therapies targeting these pathways simultaneously offer greater therapeutic promise than pathogen-specific approaches alone. The evidentiary basis for this framework varies across pathogens and conditions; direct mechanistic evidence, mechanistic analogy, and preclinical data are distinguished throughout. Full article

Prenatal exposure to ionizing radiation is a known risk factor for neurodevelopmental deficits; however, the molecular mechanisms linking chronic embryonic insult to abnormal brain development remain poorly understood. This study investigated the long-term consequences of chronic prenatal gamma irradiation throughout gestation in C57BL/6 mice. Behavioural analysis of adult offspring revealed a specific increase in depression-like behaviours, with no significant alterations in anxiety or general exploratory activity. Immunohistochemical assessment demonstrated a significant reduction in adult hippocampal neurogenesis, marked by decreased doublecortin (DCX)-positive newborn neurons in the subgranular zone and fewer NeuN-positive mature neurons in the dentate gyrus hilus. Integrated RNA-seq, qPCR, and Western blot analyses implicated the upregulation of the Mef2c/Egr1 signalling pathway in this neurogenic deficit. Furthermore, miRNA sequencing identified a pronounced decrease in miR-1843a-3p, which was subsequently validated to directly target Mef2c. Collectively, these findings suggest that prenatal gamma irradiation disrupts neurogenic processes and adult brain function, leading to specific behavioral abnormalities. This long-term impairment is associated with, and may be at least partially mediated by, dysregulation of the miR-1843a-3p/Mef2c/Egr1 pathway. Full article

Fragile X Syndrome (FXS) is an inherited cause of intellectual disability and autism, arising from silencing of the Fmr1 gene and loss of Fragile X Messenger Ribonucleoprotein 1 (FMRP). FMRP is an RNA-binding protein critically involved in neurodevelopmental processes, including neurogenesis. We examined the proliferation and maturation of adult-born dentate granule cells (abDGCs) and glial populations in Fmr1 knockout (KO) and wild-type (WT) mice at 4, 12, and 24 weeks of age under control and early-life stress (ELS) conditions. Based on prior findings, we hypothesized that KO mice would exhibit increased neurogenesis and atypical responses to ELS compared with WT mice. Using immunohistochemistry, we quantified multiple stages of neurogenesis in the dentate gyrus, including proliferating (Ki67+), immature (doublecortin [DCX]+), and apoptotic (cleaved caspase-3 [CC3]+) cells. We also assessed glia using Iba1 (microglia) and GFAP (astrocytes) immunoreactivity. KO mice displayed significantly increased Ki67+ proliferating and reduced CC3+ apoptotic cells across ages, accompanied by increased Iba1+ and GFAP+ glial densities. However, KO mice exhibited fewer DCX+ neuroblasts at later time points. When reared in ELS conditions, KO mice show blunted or no changes in neurogenesis and glial populations relative to WT mice reared in ELS conditions or KO mice in control conditions. These results indicate that FMRP loss disrupts hippocampal neurogenesis by increasing cell proliferation while limiting neuronal maturation and expanding glial populations. Moreover, the absence of neurogenic and glial responses to ELS in KO mice highlights a gene–environment interaction that may influence FXS-related neuropathology by limiting the adaptive capacity of the hippocampal neurogenic niche. Full article

Serotonin (5–HT) in the brain is involved in the regulation of various emotional states and behaviors. Most serotonergic neurons are located in the raphe nuclei. The raphe magnus (RMg) is one of the raphe nuclei and belongs to the caudal raphe complex. The primary goal of our research was to examine the effects of chronic, repeated electrical stimulation of the RMg on rats’ motility over a period of 15 days. During the research, 35 rats were used; 21 rats underwent electrical stimulation of the RMg (RMg-ST), while 14 rats were included in the control group (RMg-Sham). In addition, we aimed to evaluate the effects of electrical stimulation in the RMg-ST group as well as the naïve procedure in the RMg-Sham group on anxiety-related behaviors and spatial memory on selected days 30 min after the end of stimulation. We found that rats in the RMg-ST group were characterized by considerably higher locomotor activity than animals in the RMg-Sham group over a 15-day stimulation period. Stimulated animals were less anxious during the elevated plus maze on the 4th and 5th days of stimulation and demonstrated improved memory performance during the Morris water maze conducted between the 9th and 12th days of stimulation in comparison to the control animals. Furthermore, in both behavioral tests, rats’ motility when subjected to the RMg electrical stimulation was much higher than in control rats. On the last day of the 15-day stimulation period, rats were sacrificed, and their brains were collected. Brain immunofluorescent analysis revealed an increase in the number of 5–HT-positive cells in the RMg-ST group and altered activity of c-Fos-positive cells in selected brain structures connected with locomotion (secondary motor cortex), anxiety (arcuate nucleus of the hypothalamus), and spatial memory (dentate gyrus) after stimulation in comparison to the results in the RMg-Sham group. These findings suggest that locomotion may be strictly dependent on the RMg neuronal projections, and electrical stimulation of the structure influences cognitive behaviors. Full article