Search Results (3,515)

Pinealectomy leads to melatonin deficiency, which is known to disrupt circadian clock regulation and may increase vulnerability of the hippocampus to oxidative stress and neuroinflammatory processes. The objective of this study was to examine the gene expression levels of circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period circadian regulator 1 (PER1), cryptochrome circadian regulator 1 (CRY1), brain-derived neurotrophic factor (BDNF), and interleukin-6 (IL-6) in the hippocampus to elucidate the impact of pinealectomy-induced circadian dysregulation on these gene expressions and to assess its association with hippocampal alterations. A total of 30 Wistar rats were randomly divided into three groups: Control, Sham, and Pinealectomy (PNX) (n = 10 per group). Gene expression levels were analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). Immunohistochemical analysis was performed to assess caspase-3 and glial fibrillary acidic protein (GFAP) immunoreactivity. In addition, oxidative stress parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), as well as the inflammatory marker tumor necrosis factor-alpha (TNF-α), were measured. The pinealectomy group showed a significant downregulation of BMAL1, BDNF, CLOCK, CRY1, and PER1 gene expression levels, with decreases ranging from approximately 60% to 83% compared with the sham and control groups, whereas IL-6 expression was significantly increased by approximately 185% (p < 0.05). Immunohistochemical analysis demonstrated significantly increased caspase-3 and GFAP immunoreactivity in the PNX group. Furthermore, pinealectomy resulted in a significant increase in MDA and TNF-α levels, accompanied by marked decreases in SOD, CAT, and GSH levels (p < 0.05). In conclusion, pinealectomy is associated with significant disruption of hippocampal circadian clock gene expression, accompanied by oxidative stress, neuroinflammation, and histopathological alterations. These findings highlight the critical role of circadian regulation in maintaining hippocampal cellular integrity. Full article

Background/Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental condition increasingly associated with dysregulated neuroimmune signaling and altered neurotrophic homeostasis. Tumor necrosis factor-alpha (TNF-α) has been implicated in ASD pathophysiology; however, the downstream effects of TNF-α blockade on cytokine–neurotrophin interactions during neurodevelopment remain insufficiently characterized. In this study, we evaluated the effects of infliximab (IFX), a monoclonal anti-TNF-α antibody, on behavioral performance, neuroinflammatory cytokine profiles, glial activation, and brain-derived neurotrophic factor (BDNF) signaling in a propionic acid (PPA)-induced experimental ASD rat model. Methods: Experimental ASD was induced by propionic acid administration in rats. Animals were divided into control and treatment groups. Behavioral performance was assessed using the Morris Water Maze, direct social interaction, and three-chamber sociability tests. Levels of TNF-α, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and BDNF were measured in serum, hippocampal, and cerebellar tissues. Microglial and astrocytic activation were evaluated using CD11 and GFAP immunohistochemistry. Results: PPA administration resulted in pronounced impairments in learning, memory, and social behaviors, accompanied by elevated proinflammatory cytokine levels, increased BDNF expression, and marked glial activation in the hippocampus and cerebellum. Although IFX treatment significantly reduced TNF-α levels in central tissues, it did not improve behavioral deficits and was associated with persistently elevated IL-1β and IL-6 levels, sustained glial reactivity, and further alterations in BDNF levels. Conclusions: These findings suggest that TNF-α suppression alone does not normalize the disrupted cytokine–neurotrophin axis and may differentially modulate BDNF-related neuroplastic signaling during development. In conclusion, this study indicates that non-selective TNF-α blockade during neurodevelopment fails to confer behavioral benefit in experimental ASD and highlights the importance of considering cytokine–BDNF pathway interactions when designing immunomodulatory strategies for neurodevelopmental disorders. Full article

Background/Objectives: Phthalates are a group of organic compounds widely used for enhancement in flexibility and transparency of polyvinyl chloride (PVC) products. Exposure to phthalate-containing substances has been shown to affect brain function, particularly in learning and memory processes. Quercetin is a plant-derived flavonoid with remarkable anti-oxidant and anti-inflammatory potential. This study investigated the possible protective effects of quercetin on spatial learning and memory, histomorphometric changes, and hippocampal expression of inflammatory cytokines (TNF-α and IL-6) in male mice exposed to di(2-ethylhexyl) phthalate (DEHP). Methods: A total of 42 male mice were divided into seven groups. Quercetin was administered orally at doses of 25 and 50 mg/kg/day, either alone or in combination with DEHP (200 mg/kg/day). Following the final day of the treatment, spatial learning and memory were assessed by the Morris Water Maze test. Hippocampal tissues were sampled for Nissl, H&E, and immunofluorescence staining. Quantitative real-time PCR was used to measure the expression of TNF-α and IL-6. Results: The DEHP group exhibited significant impairments in learning and memory, neuronal damage, and cellular disorganization in the hippocampus, along with increased astrocyte activation and elevated expression of TNF-α and IL-6. On the other hand, quercetin supplementation significantly reduced these inflammatory markers and histological damages and also improved spatial learning and memory. Conclusions: Overall, quercetin improves cognitive function that is associated with attenuating astrocyte activation and inflammation. Full article

Background: Wolfram syndrome (WFS) is a rare neurodegenerative disease that is genetically determined and inherited in an autosomal recessive manner. Although the first clinical symptom appearing in early childhood is diabetes mellitus, subsequent symptoms are associated with optic nerve atrophy, followed by central nervous system atrophy. Methods: The aim of the study was to analyse magnetic resonance images (MRI) of the brain in combination with single-voxel magnetic resonance spectroscopy (MRS) and to assess the copy number of mitochondrial DNA (mtDNA-CN) in 10 patients with WFS compared with a control group of 17 healthy individuals. Results: A significant decrease in the amount of selected metabolites was observed in WFS patients compared to controls in all assessed brain regions (pons, cerebellum, white matter, thalamus, and hippocampus). For three metabolites, Glutamate (Glu), Glutamate + Glutamine (Glx) and total N-acetylaspartate (TNAA), significant differences in concentrations were found between the study groups in almost all matrices evaluating specific areas of the brain (p < 0.011), with the exception of a trend toward reduced TNAA in the hippocampus (p = 0.065). In addition, patients with WFS had a significant decrease in the mitochondrial-to-nuclear DNA ratio compared to controls (p < 0.0003). Some metabolites, such as N-acetylaspartate and total N-acetylaspartate, showed strong correlations with specific regions of the visual pathway on MRI scans in patients with WFS. Conclusions: Selected brain metabolites and mtDNA-CN may become potential markers of WFS, and the results of this study may be used to define indicators for future therapeutic strategies. Full article

Mushroom use dates back to ancient times, and it currently remains significant among indigenous and urban populations as a medicinal option. Psilocybe species are suggested to modify emotions when administered in macro- or microdose form for the treatment of anxiety and depression, both often affected by a delayed onset and adverse effects of current pharmacological therapy. The objective of this study was to evaluate the anxiolytic and/or antidepressant-like effects of P. cubensis mushroom aqueous extract (PcAE) microdosing in mice using open-field and rota-rod tests, followed by plus-maze or forced swimming tests. We also evaluated changes in neuronal activity and dendritic maturation using electrocorticography (ECoG) and immunohistochemical techniques. The outcomes were compared with an effective macrodose of PcAE and antidepressant fluoxetine (FLX). For this study, mice were grouped as follows: (1) vehicle, (2) acute, and (3) repeated (10 days) PcAE microdosing (1 µg/kg); (4) single PcAE macrodose (1 g/kg); and (5) acute and (6) repeated reference drug fluoxetine (FLX, 10 mg/kg).The anxiolytic and antidepressant-like effects using microdosing were similar to those observed with macrodoses of PcAE and FLX; significant dose- and/or time-dependent changes in the ECoG and dendritic maturation of hippocampus neurons were also observed, in addition to altered corticosterone levels. To conclude, P. cubensis mushroom promotes brain effects in mice after micro- and macrodosing, supporting its potential as a therapeutic alternative for mental health. Full article

Opioid analgesics are essential in the management of severe and chronic pain; however, their prolonged use is limited by the onset of analgesic tolerance and opioid-induced hyperalgesia (OIH). Recent studies increasingly implicate both synaptic functional and structural plasticity within nociceptive pathways as crucial mechanisms in OIH and tolerance. This review integrates current mechanistic understanding of how opioids alter synaptic transmission throughout the dorsal root ganglia (DRG), spinal dorsal horn, and supraspinal nociceptive networks. Peripherally, μ-opioid receptor (MOR) activation on TRPV1-positive nociceptors initiates presynaptic long-term potentiation (LTP), forming an early substrate for central sensitization. In the spinal dorsal horn, chronic opioid exposure drives NMDAR-dependent LTP, TRPC-mediated calcium influx, and actin cytoskeleton remodeling, leading to persistent increases in synaptic strength and excitatory connectivity. In supraspinal regions—including the ventral hippocampus, prefrontal cortex, and amygdala—opioids promote experience-dependent plasticity and predictive coding, which link environmental cues to reduced analgesic effectiveness. In addition to synaptic functional plasticity, opioid-induced synaptic structural plasticity within nociceptive pathways has been shown to underlie the long-term nature of opioid analgesic tolerance. Collectively, these data define a distributed network of opioid-responsive synapses whose pathological potentiation underpins the development of tolerance and hyperalgesia. Elucidating these mechanisms underlying OIH and tolerance paves the way for targeted therapeutic strategies that maintain analgesic efficacy while minimizing adverse synaptic remodeling and negative outcomes. Full article

The Fukushima nuclear accident highlighted that evacuation-related psychosocial harm can outweigh direct radiation risks, underscoring the need to define the health impacts of chronic low-dose-rate (LDR) radiation and evidence-based thresholds for intervention. This study investigated the effects of continuous, postnatal LDR gamma irradiation (1.2 mGy/h, cumulative dose: 5 Gy) in male mice. While no changes in body weight, hippocampal neurogenesis, or major glial and neuronal populations were observed, persistent DNA damage (γ-H2AX foci) in dentate gyrus granule cells occurred in both irradiated male and female mice. Irradiated male mice developed anxiety-like behaviour, a phenotype not observed in a previously published study of female mice subjected to an identical irradiation protocol. Molecular profiling revealed two novel, dysregulated miRNA/mRNA axes in the hippocampus linking DNA damage to behaviour: a maladaptive miR-466i-5p/Tfcp2l1 pathway associated with genomic instability, and a potentially adaptive miR-101a-5p/BMP6 pathway promoting neuronal survival. Venn analysis further identified miR-124b-3p and novel-miR489-3p as conserved exposure biomarkers, altered in both the hippocampus and blood of irradiated animals. Our results show that a high cumulative dose of chronic LDR induces markedly less severe hippocampal pathology than has been reported for equivalent acute doses. These findings support the concept of dose-rate-dependent threshold dose and contribute to the evidence base for developing countermeasures following nuclear incidents or other radiation exposures. Full article

Various neuromodulatory benefits of the ketogenic diet (KD) have been demonstrated, yet its influence on reward learning and underlying mechanisms remain poorly defined. This study combined proteomics and metabolomics to identify key molecular changes in the hippocampus of KD-fed mice. Our analysis revealed significant upregulation of the “dopaminergic synapse” pathway, with CAMK2A emerging as a central regulator. In vitro, treatment of the hippocampal neuronal cell line HT22 with β-hydroxybutyrate (BHB), a primary KD metabolite, increased the protein expression of CAMK2A and increased the phosphorylation of its downstream target, GluA1. Crucially, Camk2a knockdown completely blocked BHB-induced p-GluA1 enhancement. To determine the behavioral relevance, we stereotaxically delivered AAV-shCamk2a into the hippocampus of KD-fed mice. Knockdown of Camk2a reversed the pro-reward effects of KD, as measured by the sucrose preference test and conditioned place preference test, without impairing general locomotor activity in the open field test. Together, these results suggest a novel BHB–CAMK2A–dopaminergic signaling axis through which KD enhances reward learning, thus bridging systemic metabolism with cognitive function and expanding our understanding of KD-mediated neuromodulation. Full article

Alzheimer’s disease (AD) is a neurodegenerative disorder for which no effective treatments are currently available. PANoptosis is a coordinated cell death pathway involving pyroptosis, apoptosis, and necroptosis. Astragaloside IV (AS-IV) is a bioactive saponin derived from Astragalus membranaceus. Behavioral performance was evaluated using the Morris water maze and open field tests, while neuronal damage was assessed by Nissl staining. The expression levels of Aβ, IL-18, and PANoptosis-related proteins were analyzed by Western blot. Immunofluorescence was performed to assess the co-localization of PANoptosis-associated proteins with neurons in the hippocampal region. In addition, the effects of AS-IV on the expression of PANoptosis-related proteins were examined in Aβ-induced HT22 cells. AS-IV improved spatial memory performance and alleviated anxiety-like behaviors in AD mice. Furthermore, AS-IV treatment significantly reduced Aβ protein levels and attenuated neuronal loss in the hippocampus. Key markers of PANoptosis were downregulated following AS-IV treatment. Immunofluorescence revealed strong co-localization between PANoptosis-associated proteins and neurons. In vitro, AS-IV also inhibited the Aβ-induced upregulation of PANoptosis-related proteins in HT22 cells. Collectively, these results indicate that AS-IV exerts neuroprotective effects in AD models, which may be associated with reduced Aβ protein deposition, attenuated neuronal loss, and the regulation of PANoptosis-related proteins in the hippocampus. Full article

Fetal hypoxia and maternal stress during pregnancy are major risk factors for neurological disorders. The effects of maternal hypoxia may be transmitted to the next generation through persistent alterations in maternal endocrine and metabolic regulation. In this study, using immunohistochemistry, quantitative RT-PCR, and Western blotting, we assessed morphological features and HIF1-dependent processes in the fetal and adult brains of progeny of female rats exposed to maternal hypoxia (PMH). We identified a delay in progenitor cell differentiation into neurons at embryonic day 14, a decreased number of neurons in the hippocampus, an increased number of astrocytes in the prefrontal cortex, and a decreased number of astrocytes in the raphe nuclei of the PMH rats. However, no significant changes were observed in HIF1α protein levels or in the protein levels of HIF1-dependent gene products in the examined brain structures. Thus, the transgenerational effect of maternal hypoxia is manifested as structural disturbances of brain development but is not accompanied by changes in HIF1-dependent metabolism. Full article

Estrogen deficiency is an established risk factor for menopausal brain dysfunctions in women. Urgent exploration of drugs is needed to improve estrogen deficiency-related brain dysfunctions without the side effects of estrogen supplements. Three-month-old rats had bilateral ovariectomy (OVX) performed and were treated with emodin (EMO, 80 mg/kg/day) and 17 β-estradiol (EST, 0.5 mg/kg/day). Brain functions were evaluated by cognition and emotion-related behavioral tests. Levels of glucagon-like peptide-1 (GLP-1) and estrogen in blood, mRNA levels of estrogen receptor (ER) α, ERβ, GLP-1 receptor (GLP-1R), proprotein convertase subtilisin/kexin type 1 (PCSK1) and proglucagon (proGCG) in intestinal segments, and brain ERα and GLP-1R levels were evaluated. Contractions of isolated intestinal segments were recorded. Additionally, an ERβ antagonist, PHTPP (200 μg/kg/day), was used to clarify the role of ERβ. EST and EMO significantly ameliorated cognition deficit and depressive behaviors in OVX rats, and reduced neuronal loss and synaptic abnormalities in the hippocampus and prefrontal cortex. The blood GLP-1 levels of sham operation rats (sham, 3.09 pg/mL), EMO-treated (2.57 pg/mL) and EST-treated OVX rats (2.64 pg/mL), were higher than that of OVX rats (1.03 pg/mL). EMO had no effect on the blood estrogen level. Furthermore, EMO up-regulated mRNA levels of ERβ in ileum, colon, and cerebral GLP-1R level, while EST increased mRNA levels of ERβ in colon and cerebral ERα level. In vitro intestinal segment spontaneous contraction tests revealed that EMO reduced contraction amplitudes in isolated intestinal segments from OVX rats, with the ileum and proximal colon showing greater sensitivity to EMO. The ileum and colon segments from OVX rats were less sensitive to EST as compared to those of normal rats. Upon PHTPP intervention, the up-regulated intestinal mRNA levels of ERβ, PCSK1, proGCG, blood GLP-1 level by EMO, and the beneficial effects of EMO in abnormal behaviors of OVX rats were significantly inhibited. Overall, it was found that EMO up-regulated blood GLP-1 level via intestinal Erβ-dependent mechanism and increased brain GLP-1R level, which may be involved in the neuroprotection of EMO in OVX animals. Full article

Chronic social isolation (CSIS) is a form of psychosocial stressor strongly associated with the development of depression. Preclinical studies demonstrated that CSIS induces behavioral phenotypes resembling human depression, including anhedonia, behavioral despair and anxiety. This review summarizes proteomic-driven discoveries characterizing hippocampal non-synaptic mitochondria (NSM) and synaptosomal fractions containing synaptic mitochondria from adult male rats exposed to six weeks of CSIS, an animal model of depression, compared to controls. The compartment-specific proteomic alterations reveal mechanisms underlying mitochondrial dysregulation, providing molecular insights into the depression-like phenotype. Hippocampal NSM exhibit changes in energy metabolism-related proteins, including components of the tricarboxylic acid cycle and oxidative phosphorylation, as well as mitochondrial transport proteins and alterations in chaperones, structural and translational proteins, and monoamine oxidase, further elucidating how these proteomic changes contribute to mitochondrial dysregulation. In contrast, synaptosomal proteomics reveal predominantly increased protein abundance associated with energy metabolism, signaling, cytoskeletal organization, protein quality control, and vesicle trafficking, suggesting compensatory adaptations. Together, these findings highlight compartment-specific mitochondrial proteomic changes that may underlie depression-like behaviors and represent potential targets for therapeutic intervention. Full article

Astrocytes undergo pronounced reactivity during traumatic brain injury (TBI); however, the temporal dynamics of this response and the signaling mechanisms regulating astrocyte proliferation remain incompletely defined. In this study, we characterized the spatiotemporal profile of astrocyte reactivity and proliferation in the hippocampus during TBI and investigated the involvement of mammalian target of rapamycin complex 1 (mTORC1) signaling in these processes. Using a mouse model of TBI, we found that injury triggered a rapid astrocytic response in the hippocampus, characterized by increased glial fibrillary acidic protein (GFAP) expression and morphological hypertrophy as early as 4 h post-injury. Astrocyte proliferation emerged subsequently, peaked during the acute phase (48 and 72 h), and declined to baseline levels at 7 days post-trauma, indicating a transient proliferative response during TBI. Concurrently, mTORC1 signaling was robustly activated in reactive astrocytes in the hippocampus and was specifically associated with proliferative reactive astrocytes during injury. Pharmacological inhibition of mTORC1 signaling with rapamycin significantly reduced reactive astrocyte proliferation during TBI without altering astrocytic hypertrophy. Together, these findings demonstrate that TBI induces a rapid but transient astrocyte activation and proliferation response in the hippocampus and that mTORC1 activation is required for the proliferation, but not the hypertrophic activation, of reactive astrocytes during traumatic brain injury. Full article

Background/Objectives: Migraine with aura (MwA) is a heterogeneous disorder comprising pure visual aura (MwAv) and more complex phenotypes with additional somatosensory and/or dysphasic symptoms (MwAvsd). Previous structural magnetic resonance imaging (MRI) studies have demonstrated hippocampal subfield volume reductions associated with aura complexity, suggesting a role for the hippocampus in MwA pathophysiology. However, functional network mechanisms underlying these structural differences remain unclear. This study aimed to investigate hippocampal resting-state functional connectivity (FC) in MwA subtypes and healthy controls (HCs), and to determine whether hippocampal connectivity patterns differ according to aura complexity. Methods: In this comparative cross-sectional study, 27 patients with MwAvsd, 18 with MwAv, and 29 age- and sex-matched HCs underwent resting-state functional MRI on a 3T scanner. Seed-based FC analyses were performed using both hippocampi as regions of interest. Results: MwAvsd patients demonstrated significantly increased FC between the right hippocampus and the left dorsal parietal cortex and right sensory association cortex compared with MwAv patients. In contrast, MwAv patients showed increased FC between the left hippocampus and the right dorsolateral prefrontal cortex compared with MwAvsd patients. Additionally, MwAv patients exhibited stronger FC between the left hippocampus and bilateral anterior prefrontal cortices and the left angular cortex compared with HCs. No other significant hippocampal FC differences were observed. Conclusions: Hippocampal FC is altered in MwA and varies according to aura phenotype. Complex aura is characterized by enhanced hippocampal coupling with multisensory integration regions and reduced connectivity with executive control areas, whereas pure visual aura demonstrates increased hippocampal–prefrontal and hippocampal–parietal associative connectivity compared with HCs. These findings suggest that the hippocampus might serve as a target for future neuromodulatory and therapeutic investigations in MwA patients. Full article

Background: Scientific interest has grown in naturally derived compounds capable of supporting or enhancing cognitive performance. Tanacetum vulgare L. is an abundant source of secondary metabolites and has been associated with a broad range of biological activities; however, its potential influence on cognitive function remains largely unexplored. Methods: The present study explored the effects of T. vulgare essential oil (EO) on cognitive performance, hippocampal brain-derived neurotrophic factor (BDNF) expression, and histomorphological alterations in a rat model. Animals were administered T. vulgare EO at doses of 0.5 and 1.5 mL/kg for 28 days and were subjected to a series of behavioral tests after one week of pretreatment. Results: Both doses of EO facilitated the formation of short- and long-term memory traces in the inhibitory avoidance tasks, with a more pronounced effect observed at the lower dose, whereas improvement in passive learning was evident only at the higher dose. Spatial and recognition memory were enhanced at both doses. EO treatment significantly increased hippocampal BDNF expression without inducing pathological alterations. Conclusions: These findings suggest that T. vulgare EO may improve specific hippocampal-dependent cognitive functions, with upregulation of hippocampal BDNF representing a potential underlying mechanism. Full article