Sleep deprivation (SD) is a prevalent health risk factor in modern society. It can lead to gut microbiota dysbiosis and related cognitive impairment, so natural intervention strategies targeting the microbiota-gut-brain axis have significant research significance. As the main active components in oolong tea, Oolong Tea Polyphenols (OTPs) possess neuroprotective potential and gut microbiota-regulating potential. However, their role and mechanism in cognitive impairment induced by SD remain unclear. In this study, a mouse model of sleep deprivation was established using the modified multiple platform water environment method. Through techniques including behavioral experiments, 16S rRNA sequencing and other methods, the intrinsic mechanism by which OTPs ameliorate cognitive impairment induced by sleep deprivation was systematically evaluated. The results showed that OTP supplementation significantly improved various behavioral indicators of sleep-deprived mice, reversed the dysbiosis of the microbiota structure, increased the abundance of beneficial bacteria such as Lactobacillus, reduced the abundance of harmful bacteria such as Desulfovibrio and thus promoted the production of short-chain fatty acids. Meanwhile, OTPs improved intestinal barrier function, reduced the levels of serum lipopolysaccharide and inflammatory factors, protected the integrity of the blood-brain barrier (BBB), inhibited the excessive activation of neuroglial cells in the hippocampal region, downregulated the activity of the TLR4/NF-κB signaling pathway and restored the balance of neurotransmitters in the hippocampus. In conclusion, OTPs significantly alleviate SD-induced cognitive impairment via the microbiota-gut-brain axis, which provides a theoretical basis for their application as a food-derived intervention strategy.

Significant efforts have harvested a sophisticated understanding of Alzheimer's disease (AD) including amyloid beta (Aβ) cascade mechanisms, although effective treatment for reversing or stopping AD progression is not available. This study reports that ferul enanthate (SL), a novel derivative of active agents targeting brain microvessels, oxidative phosphorylation, and ATP generation can reverse the hippocampus-dependent spatial memory defects and reduce Aβ plaques in AD model mice (APP/PS1) at advanced stages. Spatial transcriptomics discovers that SL endows a cluster of genes expressing in Aging-AD-Rescue (AAR) pattern, which is prominent in hippocampal dendritic region where Aβ plaques are densely deposited. Furthermore, this AAR rule covers hippocampal Glut1 (glucose transporter 1) expression and ATP generation, which are further confirmed by immunoblotting or immunofluorescence studies. Our data demonstrate that SL can still reverse memory defects at advanced stages of AD mice by modifying aging-dependent multiple pathologies of AD, particularly promoting Glut1 expression and ATP generation.

Seizure susceptibility relates to microglial TREM2 expression and morphology in a multiple repeated low-dose kainic acid model.

Sepsis-associated encephalopathy (SAE) constitutes a major determinant of sepsis-related mortality across acute and survivorship phases. While molecular hydrogen (H₂) exhibits neuroprotective capacities in SAE, its precise mechanistic underpinnings remain unresolved. This study investigates the protection of SAE by H2 through regulating SIRT1-mediated mitophagy. SAE was modeled in mice via cecal ligation and puncture (CLP). The cognitive abilities of mice were evaluated via behavioral tests (Morris water maze), observation of the pathological morphology of brain tissues (HE staining), and observation of neuronal cell structure (Nissl staining). Proteomics was employed to explore the specific mechanism by which hydrogen regulates mitophagy. Western blotting, immunofluorescence, and electron microscopy were used to quantify the dynamic changes of sirtuin 1 (SIRT1) and mitophagy during SAE. In addition, an SIRT1 inhibitor (EX527) was utilized to observe its effects on hydrogen treatment and mitophagy. Inhalation of 2% hydrogen significantly enhanced the 7-day survival rate of septic mice (from 50 to 75%, P < 0.01) and improved cognitive performance in the Morris water maze, as evidenced by increased platform crossings (P < 0.05) and reduced escape latency. Hydrogen treatment upregulated SIRT1 expression and promoted PINK1/Parkin-mediated mitophagy, leading to reduced phosphorylation of STING, decreased levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), and suppressed neuronal apoptosis in the hippocampal CA1 region. These protective effects were reversed by the SIRT1 inhibitor EX527. This study demonstrates that inhalation of 2% H2 exerts significant protective effects against SAE, in which SIRT1 plays a pivotal role by modulating PINK1-dependent mitophagy, thereby ameliorating neuroinflammation and neuronal apoptosis. By rescuing mitophagy deficits, SIRT1 targeting merits clinical exploration for SAE. Not applicable.

The hippocampus (HPC), a central hub for memory and cognition, exhibits unique metabolic resilience during ageing despite widespread brain glucose hypometabolism. Here, we report that aged humans and macaques paradoxically display elevated HPC glucose uptake [18F-fluorodeoxyglucose (FDG) PET standardized uptake value ratio] alongside strengthened connectivity to sensory-motor and limbic networks-an adaptive rewiring revealed by graph-theoretical metabolic network analysis. Integrated multi-omics profiling identified STT3A (oligosaccharyltransferase) and ALG5 (dolichyl-phosphate β-glucosyltransferase) as key regulators of age-related HPC adaptation, with their upregulation in aged macaque hippocampi driving N-glycosylation-dependent metabolic reprogramming. Mechanistically, STT3A/ALG5 silencing in aged rats reduced insulin receptor/AKT1/AS160 phosphorylation, impairing GLUT4 membrane trafficking, while enhancing GLUT3 glycosylation and neuronal glucose uptake. This dual regulation preserved synaptic integrity and spatial memory retrieval despite reduced hippocampal FDG metabolism. Behavioural assays further demonstrated STT3A knockdown-induced motor coordination improvements through GLUT3-mediated metabolic rebalancing. Our findings establish STT3A-ALG5 as a glycosylation checkpoint that sustains HPC energy homeostasis via GLUT4-to-GLUT3 substrate switching, positioning 18F-FDG PET as a dynamic biomarker for monitoring HPC ageing and these glycosyltransferases as therapeutic targets against cognitive decline.

Perfluorooctanoic acid is a perfluoroalkyl substance that finds many applications across numerous industrial and household products. Environmental persistence and capacity to accumulate in biological systems are well documented. Increasing evidence links PFOA exposure to neurotoxicity, though its underlying mechanisms remain unclear. The purpose of this research was to assess the neurotoxic implications of PFOA in male Wistar rats by investigating oxidative stress, mitochondrial function, histopathological changes, and glial activation in the hippocampus of the forebrain. Animals received oral doses of PFOA (48 mg/kg and 96 mg/kg) over 30, 60, and 90 days. Brain tissues were examined for lipid peroxidation levels, antioxidant enzyme activity (SOD, CAT, GPx, GST), reduced glutathione levels, mitochondrial membrane potential, and acetylcholinesterase activity. Histological analysis was performed using H&E staining, while glial response was assessed via GFAP immunohistochemistry. The outcomes indicated a marked (p < 0.05), dose- and time-dependent elevation in oxidative stress, evidenced by elevated lipid peroxidation and diminished antioxidant enzyme activity. Mitochondrial dysfunction was confirmed by a disrupted membrane potential, and reduced acetylcholinesterase activity indicated a cholinergic imbalance. Histological analysis showed pronounced neuronal degeneration, cytoplasmic vacuolation, reactive gliosis, and structural disorganization across brain tissues, with detailed microscopic evaluation focused primarily on the hippocampal region along with other affected areas. GFAP upregulation indicated astrogliosis and neuroinflammation. In conclusion, PFOA exposure induces neurotoxicity through oxidative imbalance, mitochondrial disruption, glial activation, and impaired neurotransmission. These findings highlight the neurological risks associated with prolonged PFOA exposure and reinforce the need for regulatory measures and further toxicological evaluation.

Brain asymmetry is a fundamental feature of neural organization. However, the molecular basis of hippocampal lateralization in response to environmental stimuli remains poorly understood. Here, we examined the transcriptomic profiles of the left and right hippocampal CA1 regions in rats reared under isolated or enriched housing conditions to elucidate hemisphere-specific responses and shared molecular adaptations. RNA-sequencing analysis revealed lateralized differences in the number and identity of differentially expressed genes, accompanied by distinct biological themes, as indicated by overrepresentation and gene set enrichment analysis. The left CA1 region was prominently engaged in pathways related to synaptic organization and mitochondrial function, whereas the right CA1 region exhibited enrichment in transcriptional regulation and RNA metabolic processes. Despite these asymmetries, co-expression and protein–protein interaction network analyses revealed shared molecular architectures. Immediate early genes formed consistent central hubs across both hemispheres, and a common Mecp2–Grin2b–Cdkl5–Tet3 protein interaction cluster was identified as a potential integrative regulatory module. Additional enrichment analysis of differentially expressed genes shared between hemispheres further highlighted conserved responses, particularly in synaptic plasticity and cell–cell communication. Together, these findings demonstrate that the left and right CA1 regions employ distinct yet partially convergent transcriptional programs to adapt to environmental stimuli. This coordinated molecular asymmetry provides novel insights into hippocampal lateralization and its role in experience-dependent brain plasticity.

Brain asymmetry is a fundamental feature of neural organization. However, the molecular basis of hippocampal lateralization in response to environmental stimuli remains poorly understood. Here, we examined the transcriptomic profiles of the left and right hippocampal CA1 regions in rats reared under isolated or enriched housing conditions to elucidate hemisphere-specific responses and shared molecular adaptations. RNA-sequencing analysis revealed lateralized differences in the number and identity of differentially expressed genes, accompanied by distinct biological themes, as indicated by overrepresentation and gene set enrichment analysis. The left CA1 region was prominently engaged in pathways related to synaptic organization and mitochondrial function, whereas the right CA1 region exhibited enrichment in transcriptional regulation and RNA metabolic processes. Despite these asymmetries, co-expression and protein-protein interaction network analyses revealed shared molecular architectures. Immediate early genes formed consistent central hubs across both hemispheres, and a common Mecp2-Grin2b-Cdkl5-Tet3 protein interaction cluster was identified as a potential integrative regulatory module. Additional enrichment analysis of differentially expressed genes shared between hemispheres further highlighted conserved responses, particularly in synaptic plasticity and cell-cell communication. Together, these findings demonstrate that the left and right CA1 regions employ distinct yet partially convergent transcriptional programs to adapt to environmental stimuli. This coordinated molecular asymmetry provides novel insights into hippocampal lateralization and its role in experience-dependent brain plasticity.

Agomelatine normalizes region-specific, diurnal mGluR5 dysregulation in a chronic mild stress rat model of depression.

Polysaccharide from Schisandra chinensis (SPJ) can attenuate the progression of Alzheimer's disease (AD) by regulating changes in gut microbiota and its metabolites, but the mechanism of action is unclear. This study aimed to investigate the anti-AD effects and regulatory mechanisms of SPJ in an Aβ25-35-induced AD model from the perspective of the 'microbe-gut-brain' axis. The results showed that SPJ improved spatial learning memory ability, pathological changes in the hippocampal CA1 region and intestinal barrier integrity, and modulated the composition and abundance of gut microbiota in AD rats. Meanwhile, SPJ also regulated phenylalanine, tyrosine, and tryptophan biosynthesis, and linoleic acid, α-linolenic acid, phenylalanine, and arachidonic acid metabolism in AD rats. Furthermore, correlation analysis revealed a correlation between gut microbes and metabolites. In short, via the 'microbe-gut-brain' axis, SPJ ameliorates cognitive deficits, spatial memory loss, and neuroinflammation in AD rats. © 2025 Society of Chemical Industry.

Microglia, the central nervous system's resident macrophages, are critical for immune defense, protecting neurons during infection. Their role in postnatal brain development, particularly after injury, remains unclear. Nucling, a protein up-regulated during cardiac muscle differentiation, regulates NF-κB, influencing apoptosis and cell proliferation. In this study, we examined the role of Nucling in microglial activation using wild-type (WT) and Nucling-knockout (KO) neonatal mice subjected to poly(I:C), a viral mimic. Poly(I:C) treatment increased Iba1-positive microglia in both genotypes; however, KO mice showed a significantly exaggerated response in both cortical and hippocampal regions. Furthermore, while proinflammatory M1 markers (iNOS, CD86, TNFα, IL-6) were upregulated in both WT and KO mice, the anti-inflammatory M2 marker Arginase 1 (Arg1) was induced in WT but significantly suppressed in KO mice, indicating impaired M2 polarization. These findings suggest that Nucling is essential for maintaining microglial polarization, supporting immunological processes against pathogens and aiding central nervous system development.

Transcranial alternating current stimulation (tACS) and temporal interference stimulation (TIS) as electrical neuromodulation therapy have shown promising applications in cognitive impairments. Meanwhile, the TIS technique is more novel, with deep and non-invasive brain stimulation. At present, the therapeutic or neuromodulation differences between TIS and tACS on post-stroke cognitive dysfunction(PSCI) are still unclear. Here, we aim to compare and analyze the neuromodulation model and clinical performances of TIS and tACS. The prospective, single-blind and randomized controlled trial will be conducted over a 2-week period. Through precise statistical sample size calculation,thirty-six eligible participants with mild PSCI will be recruited and randomly allocated to either the tACS or the TIS group. Participants in the TIS group will receive stimulation at frequencies of 2005Hz and 2010Hz targeting the hippocampal region. Those in the tACS group will undergo 5Hz stimulation of the dorsolateral prefrontal cortex (DLPFC). The intervention will last for 2weeks, with each participant receiving 25-min stimulation sessions once a day, five times per week. The primary outcome measure will be the Montreal Cognitive Assessment (MoCA), while secondary outcomes will include performance on the N-back task, digital span test (DST), shape trails test (STT) and functional near-infrared spectroscopy (fNIRS). All clinical assessments will be collected at two time points: pre-intervention (T1) and post-intervention (T2). The trial protocol is registered with www.chictr.org.cn under protocol registration number ChiCTR2400081207. Registered on February 26, 2024.

The potential of taVNS in attenuating blood-brain barrier damage, promoting angiogenesis and improving impaired cognitive function in a rat model of vascular cognitive impairment and dementia by activating the Wnt7/β-catenin signaling pathway.

Humans and other primates can robustly report whether they've seen specific images before, even when those images are extremely similar to ones they've previously seen. Multiple lines of evidence suggest that pattern separation computations in the hippocampus (HC) contribute to this behavior by shaping the fidelity of visual memory. However, unclear is whether HC uniquely determines memory fidelity or whether computations in other brain areas also contribute. To investigate, we recorded neural signals from inferotemporal cortex (ITC) and HC of two rhesus monkeys (1 male, 1 female) as they performed a memory task in which they judged whether images were novel or exactly repeated in the presence of visually similar lure images with a range of visual similarities. We found behavioral evidence for sharpening, reflected as memory performance that was nonlinearly transformed relative to a benchmark defined by visual representations in ITC. As expected, we found that behavioral sharpening aligned with visual memory representations in HC. Surprisingly, and unaccounted for by HC pattern separation proposals, we also found neural correlates of behavioral sharpening reflected in ITC. These results, coupled with further analysis of the data, suggest that ITC contributes to shaping the fidelity of visual memory in the transformation from visual processing to memory storage and signaling.Significance Statement Visual recognition memories are stored with remarkable visual fidelity, allowing humans and other primates to distinguish images they have encountered from visually similar images they have not. This fidelity has long been attributed to computations in the hippocampus that sharpen visual representations before memory storage ("pattern separation"). Unclear is how this proposal aligns with other evidence that visual memories are stored within high-level visual cortex itself, before signals reach the hippocampus. Here we demonstrate that, like the hippocampus, inferotemporal cortex also reflects sharpened visual memory representations, suggesting that visual cortex contributes to shaping the visual fidelity of visual memory.

Double dissociation between the involvement of Gadd45α and Gadd45β/γ in the perirhinal cortex and hippocampus of male rats for object memory.

Propofol, an anesthetic known for its safety, efficacy and neuroprotective properties, has potential novel antidepressant effects. However, its specific mechanisms still require further elucidation. Presently, we established a learned helplessness (LH) depression model to investigate the effects of propofol treatment on depression-like impairment. Thirty adult male C57BL/6j mice were randomly divided into three groups: control group (CON), model group (LH), and propofol group (PRO), with 10 mice per group. Behavioral analyses were conducted using weight measurement, sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and Morris water maze test (MWM). Subsequently, HE staining was performed to examine pathological changes in the hippocampal region. Western blotting was conducted to assess changes in Notch signaling pathway components, synaptic plasticity-related proteins, and proteins in the glutamate system. Immunofluorescence was used to detect expression changes of NICD, SYP, and DCX. Hippocampal glutamate concentration was determined using a glutamate assay kit. Consequently, stressed mice exhibited pronounced depressive behaviors and decreased spatial learning and memory, accompanied by significant neuronal death in the dentate gyrus of the hippocampal region and reduced levels of neuronal regeneration as well as synaptic plasticity. Additionally, glutamate reuptake function was impaired in depression, manifested specifically as increased glutamate concentrations in the hippocampal region and neuronal glutamate transmission levels. Meaningfully, propofol upregulated Notch signaling pathway activity and improved glutamate reuptake function significantly resulting in enhanced adult hippocampal neurogenesis and synaptic plasticity. These findings demonstrated the effectiveness of propofol as a potential antidepressant and contributed to discovering novel antidepressant drugs.

Sepsis‑induced abnormalities in brain function or sepsis‑associated encephalopathy (SAE) can manifest as cognitive dysfunction and other neuropsychiatric symptoms; however, the underlying mechanisms remain unclear. The aim of the present study was to elucidate the possible effects and mechanism of capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, on the pathological features of SAE. A model of SAE in C57BL/6 mice was generated using cecal ligation and puncture (CLP). Capsaicin (1 mg/kg) was injected subcutaneously before surgery. Cognitive function in mice was evaluated using the novel object recognition test (NORT) and Morris water maze (MWM). Immunofluorescence staining, ELISA, western blotting and transmission electron microscopy were performed to detect the degree of microglial activation (ionized calcium‑binding adapter molecule 1), proinflammatory cytokine levels (TNF‑α), autophagy and apoptosis‑related protein expression, and autophagosomes. Autophagic flux was monitored using the LC3‑GFP‑mCherry fluorescent reporter. Compared with that in the sham group mice, the expression levels of TRPV1 were significantly reduced in the hippocampal tissue of mice with sepsis. Mice with sepsis also exhibited cognitive dysfunction. Notably, a single administration of capsaicin reduced the mortality rate, but did not improve cognitive function in mice with sepsis. Furthermore, repeated administration of capsaicin was revealed to enhance the recognition index of novel objects among mice with sepsis, to reduce the latency to locate the platform and to augment the duration of mouse platform quadrant movements, according to the NORT and MWM tasks. Increased microglial activation, release of proinflammatory cytokines and expression levels of apoptosis‑related proteins were all observed in mice with CLP‑induced sepsis, as was brain tissue destruction in the hippocampal regions. By contrast, capsaicin treatment ameliorated CLP‑induced microglial activation, inflammation, neuronal apoptosis (cleaved caspase 3 expression increased) and brain tissue destruction. Furthermore, application of capsaicin increased the expression levels of LC3, reduced the expression of p62 and elevated autophagic flux compared with those in the CLP group. Finally, treatment with capsaicin effectively enhanced the levels of Bcl‑2‑interacting protein 3 (BNIP3) and BNIP3‑like (NIX) expression. These findings suggested that capsaicin may be considered a potential drug for the treatment of SAE, and BNIP3/NIX‑mediated mitophagy may be involved in this process.

Distinct hippocampus codes for contextual cueing: learning contexts and their predictive associations with targets in visual search.

Aging-related adaptations of metabotropic glutamate receptors within the CA3 region of the rat hippocampus.

Spautin-1 alleviates depression-like behaviors in mice after traumatic brain injury by inhibiting MMP3 expression in microglia in the Hippocampal CA1 region.