Search Results (163)

Cancer-related cognitive impairment (CRCI)—encompassing anxiety, depression, and memory deficits—significantly diminishes the quality of life in patients with cancer, yet remains underrecognized in clinical practice. In this study, we investigated the therapeutic potential of tabernanthalog (TBG), a non-hallucinogenic analog of psychedelic compounds, as a novel intervention for CRCI using a Lewis lung carcinoma (3LL) mouse model. Behavioral assessments revealed heightened anxiety-like behavior and memory impairment following 3LL cell transplantation. Biochemical analysis revealed reduced tryptophan levels in both blood and hippocampal tissue, accompanied by the downregulation of serotonergic receptor genes and upregulation of pro-inflammatory cytokine genes in the hippocampus of tumor-bearing mice. Additionally, microglial density and morphological activation were markedly elevated. TBG treatment reversed these behavioral deficits, improving both anxiety-related behavior and memory performance. These effects were associated with the normalization of microglial density and morphology, as well as the restoration of serotonergic receptor and cytokine gene expression. In vitro, TBG partially suppressed neuroinflammatory gene expression in BV-2 microglial cells exposed to conditioned medium from 3LL cells. Collectively, these findings suggest that TBG alleviates CRCI-like symptoms by modulating neuroinflammation and microglial activation. This study highlights TBG as a promising therapeutic candidate for improving cognitive and emotional functioning in patients with cancer. Full article

Background/Objectives: The hippocampus is an essential part of the central nervous system (CNS); it plays a significant role in social–cognitive memory processing. Prenatal exposure to valproic acid (VPA) can lead to impaired hippocampal functions. In this study, we evaluated the effect of plumbagin (PLB) as a natural product on spatial learning and memory, neuro-morphological changes, and inflammation levels in a VPA-induced autism model during adolescence. Methods: Pregnant Wistar rats received a single intraperitoneal (i.p.) injection of VPA (600 mg/kg) or saline on gestational day 12.5. The male offspring were then categorized and assigned to five groups: Saline+DMSO-, VPA+DMSO-, and VPA+PLB-treated groups at doses of 0.25, 0.5, or 1 mg/kg. Spatial learning and memory were evaluated using the Morris water maze. Histopathological evaluations of the hippocampus were performed using Nissl and hematoxylin–eosin staining, as well as immunofluorescence. The pro-inflammatory cytokine levels were also quantified by quantitative real-time PCR. Results: The findings revealed that a VPA injection on gestational day 12.5 is associated with cognitive impairments in male pups, including a longer escape latency and traveled distance, as well as decreased time spent in the target quadrant. Treatment with PLB significantly enhanced the cognitive function, reduced dark cells, and ameliorated neuronal–morphological alterations in the hippocampus of VPA-exposed rats. Moreover, PLB was found to reduce astrocyte activation and the expression levels of pro-inflammatory cytokines. Conclusions: These findings suggest that PLB partly mitigates VPA-induced cognitive deficits by ameliorating hippocampal inflammation levels. Full article

Memory is a fundamental neurological function, essential for animal survival. Over the course of vertebrate evolution, elaborations in the forebrain telencephalon create new memory mechanisms, meaning basal vertebrates such as amphibians must have a less sophisticated system of memory acquisition, storage, and retrieval than the well-known hippocampal-based circuitry of mammals. Personality also appears to be a fundamental vertebrate trait and is generally defined as consistent individual behavior over time and across life history stages. In anuran amphibians (frogs), personality studies generally ask whether adult frogs retain the personality of their tadpole stage or whether personality shifts with metamorphosis, an idea behavioral ecologists term adaptive decoupling. Using a multidisciplinary perspective and recognizing there are ~7843 species of frogs, each with some molecular, morphological, physiological, or behavioral feature that makes it unique, we review, clarify, and provide perspective on what we collectively know about memory and personality and their mechanisms in anuran amphibians. We propose four working hypotheses: (1) as tadpoles grow, new telencephalic neurons become integrated into functional networks, producing behaviors that become more sophisticated with age; (2) since carnivores tend to be more bold/aggressive than herbivores, carnivorous anuran adults will be more aggressive than herbivorous tadpoles; (3) each amphibian species, and perhaps life history stage, will have a set point on the Shy–Bold Continuum; and (4) around this set point there will be a range of individual responses. We also suggest that several factors are slowing our understanding of the variety and depth of memory and personality possibilities in anurans. These include the scala natura approach to comparative studies (i.e., the idea that one frog represents all frogs); the assumption that amphibians are no more than simple reflex machines; that study species tend to be chosen more for convenience than taxonomic representation; and that studies are designed to prove or disprove a construct. This latter factor is a particular hindrance because what we are really seeking as scientists is not the confirmation or refutation of ideas, but rather what those ideas are intended to produce, which is understanding. Full article

Background/Objectives: Depression is frequently comorbid with obesity. We previously showed that astrocyte-mediated hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behaviors in obese murine models. However, it remains unclear if the metabolic disorder-induced depressive phenotypes and astrocytic maladaptation in the ventral hippocampus (vHPC) could be reversed following the amelioration of key metabolic impairments such as insulin resistance and dyslipidemia. Method: Male mice were fed a high-fat diet (HFD) for 12 weeks, followed by either continued HFD feeding (HFD/HFD group) or a switch to a standard diet for 4 weeks (HFD/SD group). Results: Results showed that HFD/HFD mice displayed not only glucose/lipid metabolic dysfunction, but also depression-like behaviors. In contrast, HFD/SD mice showed improvements in metabolic disorders and depressive phenotypes. Mechanistically, dietary fat reduction restored astrocyte morphology and glutamate transporter expression (GLT-1, GLAST) in the vHPC and suppressed neuroinflammatory signaling, as evidenced by reduced levels of phospho-IKK, TNF-α, IL-1β, and IL-6 in the vHPC. Conclusions: These findings suggest that dietary fat reduction reverses obesity-induced depressive phenotypes, astrocytic deficits, at least in part via suppression of neuroinflammation through the NF-κB signaling pathway. Full article

Cognitive impairment in subjects with Alzheimer’s disease correlates well with the loss of synaptic plasticity. This results from mitochondrial dysfunction and production of reactive oxygen species, which damage nerve terminals causing them to release ATP and adenosine. These purines activate receptors on microglia resulting in a change in morphology and release proinflammatory cytokines that exacerbate neuronal damage. The review describes retrospective studies with naturally occurring antioxidants, vitamin E, resveratrol, Ginkgo biloba and others that suggested they reduce the incidence of Alzheimer’s disease. They have antioxidant activity in cellular systems and rodent models, but most of them failed in clinical trials, probably because they were not absorbed after oral administration or, like anti-inflammatory drugs, were not given at the right time or for long enough to detect an effect on disease progression. Ladostigil is an aminoindan derivative that is well absorbed after oral administration. It has antioxidant effects in cells and prevents cytokine release from activated microglia. In a phase 2 trial in subjects with mild cognitive impairment, ladostigil significantly reduced number of converters to Alzheimer’s disease in ApoE4-ve subjects and delayed the decline in whole brain and hippocampal volumes without causing adverse effects related to drug intake. Full article

Parvalbumin (PV) neurons in the basal forebrain (BF) orchestrate cognitive functions via extensive brain-wide projections. However, the age-related cognitive decline of their anatomical circuits remains poorly understood. Here, we employed viral tracing and fluorescence micro-optical sectioning tomography (fMOST) to reveal the vulnerability of the BF-PV circuits during aging. Quantitative whole-brain fluorescence intensity analysis revealed that BF-PV neurons projecting to the medial mammillary nucleus (MM) exhibited pronounced age-dependent neurodegeneration, characterized by 81.1% fiber loss and axonal swelling, while those innervating hippocampal CA1 showed a 70.3% reduction in fiber density. Optogenetic interventions demonstrated that selective activation of the BF^PV-MM circuit can ameliorate cognitive deficits in old mice, significantly improving the novel object recognition index and its change rate. In contrast, modulation of the BF^PV-CA1 circuit showed no significant effects. Moreover, with the whole-brain dataset, we reconstructed the morphology of individual neurons, revealing structural divergence between MM- and CA1-projecting PV neurons. Taken together, our results delineate the optogenetic-targeted activation of the BF^PV-MM circuit, which can ameliorate age-related cognitive decline and provide both theoretical and therapeutic foundations for targeting neurodegenerative disorders. Full article

Oxidative stress and membrane damage are believed to be principally involved in the pathogenesis of epilepsy. This study aimed to assess the effects of phenosanic acid (PA), an antioxidant and membrane protector, in acute pentylenetetrazole and chronic lithium–pilocarpine seizure models in male Wistar rats. PA was administered acutely (ip, 120 mg/kg BW ip, or 240 mg/kg BW per os) or chronically (80 mg/kg BW/day per os). Indices of free radical oxidation, the hypothalamo–pituitary–adrenocortical axis, and the nitrergic system were assessed in blood and brain regions. Morphological analysis of the hippocampus was performed in the lithium–pilocarpine model. PA exerted an acute anti-seizure effect in the pentylenetetrazole model. In the lithium–pilocarpine model, acute PA treatment decreased the death rate and corticosterone levels in the neocortex and brainstem. In contrast, the level of free radical oxidation products reacting with thiobarbituric acid declined in the brain stem in response to chronic PA treatment. In the lithium–pilocarpine model, the neuronal density in the dentate gyrus was elevated, and the proliferating cell nuclear antigen positive (PCNA+) cell counts in the subgranular zone did not differ between groups. Doublecortin positive (DCX+) cell count was significantly increased after chronic PA treatment. PA-induced reduction in mortality in the lithium–pilocarpine epilepsy model may be partially mediated by decreasing the lipid peroxidation and corticosterone levels in different brain regions. Chronic PA treatment may affect adult hippocampal neurogenesis by either prolonging the action of factors that increase neurogenesis after status epilepticus or by slowing down the neuronal differentiation rate. These data suggest that PA may be a disease-modifying AED able to hamper epileptogenesis. Full article

To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer’s disease (AD), we challenged primary neurons with amyloid-β (Aβ). Both the naturally secreted or synthetic Aβ oligomers (AβOs) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature excitatory neurons (CaMKIIα-high) via a Ca²⁺-dependent calcineurin-coupled NFAT transcriptionally and calpain-mediated protein degradation, respectively. The TRPC3 expression was also found to be upregulated in pyramidal neurons of human AD brains. The selective downregulation of the Trpc6 gene induced synaptotoxicity, while no significant effect was observed from the Trpc3-targeting siRNA, suggesting potentially differential roles of TRPC3 and 6 in modulating the synaptic morphology and functions. Electrophysiological recordings of mouse hippocampal slices overexpressing TRPC3 revealed increased neuronal hyperactivity upon the TRPC3 channel activation by its agonist. Furthermore, the AβO-mediated synaptotoxicity appeared to be positively correlated with the degrees of the induced dendritic Ca²⁺ flux in neurons, which was completely prevented by the co-treatment with two pyrazole-based TRPC3-selective antagonists Pyr3 or Pyr10. Taken together, our findings suggest that the aberrantly upregulated TRPC3 is another ion channel critically contributing to the process of AβO-induced Ca²⁺ overload, neuronal hyperexcitation, and synaptotoxicity, thus representing a potential therapeutic target of AD. Full article

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder, with lead (Pb) exposure increasingly linked to its risk. However, the molecular mechanisms linking Pb to ASD remain poorly understood. This study established a postnatal Pb-exposed mouse model and employed the three-chamber social test and the marble-burying test to assess ASD-like behavioral phenotypes. The Pb levels in both blood and the hippocampus were quantified, and hippocampal neurons were assessed for morphological alterations. Moreover, a Tandem Mass Tag (TMT)-based quantitative proteomics approach was applied to elucidate the underlying mechanisms. Neurobehavioral experiments revealed Pb-exposed C57BL/6 offspring exhibited reduced social interaction and novelty preference along with increased repetitive marble-burying behavior. The Pb levels in both the blood and hippocampus of Pb-treated mice were significantly elevated compared with those of control animals. Postnatal Pb exposure resulted in a reduction in the neuronal numbers and disorganized neuronal arrangement in the hippocampus. A total of 66 proteins were identified as being differentially expressed after postnatal Pb exposure. Among them, 34 differentially expressed proteins were common in both Pb exposure groups, with 33 downregulated and 1 upregulated. Bioinformatic analysis revealed multi-pathway regulation involved in Pb-induced neurodevelopmental disorders, including dysregulation of synaptic signaling, abnormal activation of neuron apoptosis, and neuroinflammation. Notably, the SYT10/IGF-1 signaling pathway may play a potential key role. These findings enhance understanding of Pb-induced autism-like behaviors, providing novel proteomic insights into the etiology of ASD. Full article

As the global elderly population is rising, concerns about cognitive decline and memory loss are becoming urgent. This study evaluated the potential of sea cucumber hydrolysates (SCH) from Stichopus japonicus in alleviating cognitive deficits using a D-galactose-induced murine aging model. The effects of SCH on behavior, hippocampal morphology, gut microbiota, hippocampal cholinergic system, brain-derived neurotrophic factor (BDNF) signaling, and neuroinflammatory pathways were investigated. Results showed that SCH ameliorated learning and memory deficits and reduced neuronal damage in aging mice. SCH also modulated gut microbiota, along with increased fecal short-chain fatty acids levels. Functional prediction revealed that alterations in gut microbiota were related to signal transduction. Further, SCH enhanced hippocampal cholinergic function through elevating acetylcholine (ACh) levels and inhibiting acetylcholinesterase (AChE) activity and activated BDNF signaling, consistent with predictions of gut microbiota function. Restoration of cholinergic homeostasis and transmission of the BDNF pathway might contribute to the inhibition of hippocampal neuroinflammation via suppressing microglial activation and the nuclear factor kappa-B (NF-κB) pathway. In summary, SCH attenuated cognitive deficits through suppressing neuroinflammation, which might be correlated with the signal transduction caused by regulating gut microbiota. Further validation will be conducted through microbiota depletion and fecal microbiota transplantation. These findings suggest that SCH is a promising functional component for counteracting aging-related cognitive deficits. Full article

Background/Objectives: High-altitude environments have a significant detrimental impact on the cognitive functions of the brain. Qi Jing Wan (QJW), a traditional herbal formula composed of Angelica sinensis, Astragalus membranaceus, and Rhizoma Polygonati Odorati, has demonstrated potential efficacy in treating cognitive disorders. However, its effects on cognitive dysfunction in plateau hypoxic environments remain unclear. Methods: In this study, acute and chronic plateau cognitive impairment mouse models were constructed to investigate the preventive and therapeutic effects of QJW and its significant active ingredient, diosgenin (Dio). Behavioral experiments were conducted to assess learning and memory in mice. Morphological changes in hippocampal neurons and synapses were assessed, and microglial activation and inflammatory factor levels were measured to evaluate brain damage. Potential active ingredients capable of crossing the blood–brain barrier were identified through chemical composition analysis and network database screening, followed by validation in animal and brain organoid experiments. Transcriptomics analysis, immunofluorescence staining, and molecular docking techniques were employed to explore the underlying mechanisms. Results: QJW significantly enhanced learning and memory abilities in plateau model mice, reduced structural damage to hippocampal neurons, restored NeuN expression, inhibited inflammatory factor levels and microglial activation, and improved hippocampal synaptic damage. Transcriptomics analysis revealed that Dio alleviated hypoxic brain damage and protected cognitive function by regulating the expression of PDE4C. Conclusions: These findings indicate that QJW and its significant active ingredient Dio effectively mitigate hypoxic brain injury and prevent cognitive impairment in high-altitude environments. Full article

Background/Objectives: Diabetes frequently leads to cognitive impairment, encompassing issues with memory and executive function, as well as depression and anxiety. This study examines the impact of high-intensity interval exercise (HIIE) alongside glucagon-like peptide-1 receptor agonist (GLP-1 RA) semaglutide on cognitive dysfunction associated with diabetes. Methods: Db/db mice were divided into a control group, semaglutide group, HIIE group, and semaglutide combined with HIIE group to study metabolic and neurobehavioral effects. Cognitive and behavioral tests, hippocampal morphology, and molecular analyses (APP, BDNF, Aβ, p-Tau, PKA, AMPK) were performed. HT22 cells under high glucose were treated with semaglutide, L-lactate, PKA inhibitor H89, and AMPK inhibitor Compound C to validate mechanisms. Results: Over 8 weeks, both HIIE and semaglutide improved neuronal morphology and cognitive performance while reducing depression in db/db mice. However, the current study observed no synergistic effects. Both therapies decreased Aβ and p-Tau protein levels and increased BDNF levels in the hippocampus, likely through the AMPK and PKA signaling pathways, respectively. In vitro, HT22 cells under high glucose conditions exhibited elevated APP and p-Tau expression and reduced BDNF levels, which could be altered by L-lactate and semaglutide. The AMPK inhibitor Compound C and the PKA inhibitor H89 attenuated the increase in BDNF levels induced by L-lactate and semaglutide, but their combination mitigated this inhibitory effect. This study suggests that while HIIE and semaglutide improve cognitive function and reduce depression via BDNF, their combined use did not show the anticipated synergistic benefits due to potential antagonism between the AMPK and PKA pathways. Conclusions: This has important implications for designing exercise prescriptions for cognitive impairment in diabetics. Full article

Background. Microglia, accounting for 5–15% of total brain cells, represent an essential population of glial cells in the cultures used for modeling neuroinflammation in vitro. However, microglia proliferation is poor in neuron–glial cultures. Here, we studied the population composition of rat hippocampal neuron–glial cell cultures prepared utilizing papain (PAP cultures) and trypsin (TRY cultures) as proteolytic enzymes for cell isolation. Methods. To evaluate the percentage and morphology of microglia in TRY and PAP cultures and cultures incubated in the presence of TGFβ+MCSF+cholesterol, which should enhance microglia proliferation, we used an immunostaining and calcium imaging approach in combination with staining using the recently developed vital microglia fluorescent probe CDr20. Results. We have shown that the microglia percentage in PAP cultures was higher than in TRY cultures. Microglia in PAP cultures are predominantly polarized, while bushy morphology was more characteristic of TRY cultures. We have also demonstrated that the TGFβ+MCSF+cholesterol combination increases the microglia number both in PAP and TRY cultures (up to 25–30%) and promotes the appearance of ameboid microglia characterized by high mobility. However, the significant appearance of ameboid microglia was observed already at the early stages of cultivation (2 DIV) in TRY cultures, while in PAP cultures, the described transformation was observed at 7 DIV. Based on the absence of the ATP-induced Ca²⁺ response, round shape, significant proliferation, and high mobility, we have suggested that ameboid microglia are reactive. Conclusions. Thus, our results demonstrate that papain is a more suitable proteolytic enzyme for preparing mixed hippocampal neuron–glial cultures with a higher percentage of heterogeneous microglia and functional neurons and astrocytes (tricultures). Full article

Background and Objectives: Schizophrenia is a chronic psychiatric disorder affecting approximately 24 million people worldwide, characterized by structural and functional brain abnormalities. Despite its prevalence, automated segmentation tools like Vol2Brain have been underutilized in large-sample studies examining limbic system anatomical volumes in patients with schizophrenia. This study aimed to assess volume differences in all major limbic system structures between schizophrenia patients and healthy controls using Vol2Brain. Method: This retrospective study included 68 schizophrenia patients and 68 healthy controls, with MRI scans obtained from OpenNeuro. Limbic system volumetric and cortical thickness measurements were conducted using Vol2Brain, an automated segmentation platform. Results: Schizophrenia patients exhibited significantly reduced volumes in the amygdala, hippocampus, anterior cingulate gyrus, posterior cingulate gyrus, and middle cingulate gyrus compared to controls. However, the left amygdala volume was larger in schizophrenia patients. A cortical thickness analysis revealed that schizophrenia patients had thinner limbic cortices, particularly in the anterior and posterior cingulate gyri and the right parahippocampal gyrus. In contrast, the right anterior cingulate gyrus was thicker in schizophrenia patients. The differences in total and left parahippocampal gyrus volumes and cortical thickness did not reach statistical significance. Conclusions: These findings reinforce previous evidence of limbic system abnormalities in patients with schizophrenia, which may contribute to cognitive and emotional dysregulation. The study also highlights Vol2Brain’s potential as a rapid, cost-free, and reliable alternative for brain volume analysis, facilitating more standardized and reproducible neuroimaging assessments in psychiatric research. Full article

As the global population ages, the mechanisms underlying age-related susceptibility to delirium have attracted attention. Given the central role of microglia in the pathogenesis of inflammation-related delirium, we investigated the temporal dynamics of neurobehavioral changes and microglial responses, following lipopolysaccharide (LPS, 200 μg/kg) administration in young and old male C57BL/6 mice. Although a similar illness trajectory across 48 h post-treatment (HPT) was observed in both age groups, old-LPS mice exhibited worsened delirium-like behavior. At 48 HPT, in old but not young mice, significantly decreased hippocampal neuronal activity coincided with microglial overactivation. Widespread hippocampal microglial activation was present at 3 HPT but subsided by 12 HPT in young but not old mice, indicating a generally retarded but prolonged microglial response to LPS challenge in old mice. However, for both age groups, at 3 HPT, p16^INK4a-negative microglia (with low abundance in the aged brain) exhibited comparable morphological activation, which was not observed for p16^INK4a-positive microglia (highly abundant in the aged brain). These results suggest that age-related susceptibility to LPS-induced delirium-like behavior accompanied by different patterns of microglial response might implicate microglial composition shifts and that optimizing microglial composition represents a promising approach to reduce vulnerability to inflammatory challenge. Full article