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1.
Biol Sex Differ ; 15(1): 39, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715106

RESUMO

BACKGROUND: Early life adversity impairs hippocampal development and function across diverse species. While initial evidence indicated potential variations between males and females, further research is required to validate these observations and better understand the underlying mechanisms contributing to these sex differences. Furthermore, most of the preclinical work in rodents was performed in adult males, with only few studies examining sex differences during adolescence when such differences appear more pronounced. To address these concerns, we investigated the impact of limited bedding (LB), a mouse model of early adversity, on hippocampal development in prepubescent and adolescent male and female mice. METHODS: RNA sequencing, confocal microscopy, and electron microscopy were used to evaluate the impact of LB and sex on hippocampal development in prepubescent postnatal day 17 (P17) mice. Additional studies were conducted on adolescent mice aged P29-36, which included contextual fear conditioning, retrograde tracing, and ex vivo diffusion magnetic resonance imaging (dMRI). RESULTS: More severe deficits in axonal innervation and myelination were found in the perforant pathway of prepubescent and adolescent LB males compared to LB female littermates. These sex differences were due to a failure of reelin-positive neurons located in the lateral entorhinal cortex (LEC) to innervate the dorsal hippocampus via the perforant pathway in males, but not LB females, and were strongly correlated with deficits in contextual fear conditioning. CONCLUSIONS: LB impairs the capacity of reelin-positive cells located in the LEC to project and innervate the dorsal hippocampus in LB males but not female LB littermates. Given the critical role that these projections play in supporting normal hippocampal function, a failure to establish proper connectivity between the LEC and the dorsal hippocampus provides a compelling and novel mechanism to explain the more severe deficits in myelination and contextual freezing found in adolescent LB males.


Childhood adversity, such as severe deprivation and neglect, leads to structural changes in human brain development that are associated with learning deficits and behavioral difficulties. Some of the most consistent findings in individuals exposed to childhood adversity are reduced hippocampal volume and abnormal hippocampal function. This is important because the hippocampus is necessary for learning and memory, and it plays a crucial role in depression and anxiety. Although initial studies suggested more pronounced hippocampal deficits in men, additional research is needed to confirm these findings and to elucidate the mechanisms responsible for these sex differences. We found that male and female mice exposed to early impoverishment and deprivation exhibit similar structural changes to those observed in deprived children. Interestingly, adolescent male mice, but not females, display severe deficits in their ability to freeze when placed back in a box where they were previously shocked. The ability to associate "shock/danger" with a "box/place" is referred to as contextual fear conditioning and requires normal connections between the entorhinal cortex and the hippocampus. We found that these connections did not form properly in male mice exposed to impoverished conditions, but they were only minimally affected in females. These findings appear to explain why exposure to impoverished conditions impairs contextual fear conditioning in male mice but not in female mice. Additional work is needed to determine whether similar sex-specific changes in these connections are also observed in adolescents exposed to neglect and deprivation.


Assuntos
Hipocampo , Memória , Camundongos Endogâmicos C57BL , Via Perfurante , Proteína Reelina , Caracteres Sexuais , Animais , Masculino , Feminino , Hipocampo/metabolismo , Medo , Camundongos , Estresse Psicológico
2.
Nat Commun ; 15(1): 3872, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719797

RESUMO

The gut microbiota and microglia play critical roles in Alzheimer's disease (AD), and elevated Bacteroides is correlated with cerebrospinal fluid amyloid-ß (Aß) and tau levels in AD. We hypothesize that Bacteroides contributes to AD by modulating microglia. Here we show that administering Bacteroides fragilis to APP/PS1-21 mice increases Aß plaques in females, modulates cortical amyloid processing gene expression, and down regulates phagocytosis and protein degradation microglial gene expression. We further show that administering Bacteroides fragilis to aged wild-type male and female mice suppresses microglial uptake of Aß1-42 injected into the hippocampus. Depleting murine Bacteroidota with metronidazole decreases amyloid load in aged 5xFAD mice, and activates microglial pathways related to phagocytosis, cytokine signaling, and lysosomal degradation. Taken together, our study demonstrates that members of the Bacteroidota phylum contribute to AD pathogenesis by suppressing microglia phagocytic function, which leads to impaired Aß clearance and accumulation of amyloid plaques.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Modelos Animais de Doenças , Camundongos Transgênicos , Microglia , Fagocitose , Placa Amiloide , Animais , Microglia/metabolismo , Microglia/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Doença de Alzheimer/microbiologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Placa Amiloide/metabolismo , Feminino , Camundongos , Masculino , Bacteroides fragilis/metabolismo , Microbioma Gastrointestinal , Humanos , Camundongos Endogâmicos C57BL , Hipocampo/metabolismo , Hipocampo/patologia
3.
ACS Chem Neurosci ; 15(10): 1951-1966, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38696478

RESUMO

Aims: the study aimed to (i) use adeno-associated virus technology to modulate parvalbumin (PV) gene expression, both through overexpression and silencing, within the hippocampus of male mice and (ii) assess the impact of PV on the metabolic pathway of glutamate and γ-aminobutyric acid (GABA). Methods: a status epilepticus (SE) mouse model was established by injecting kainic acid into the hippocampus of transgenic mice. When the seizures of mice reached SE, the mice were killed at that time point and 30 min after the onset of SE. Hippocampal tissues were extracted and the mRNA and protein levels of PV and the 65 kDa (GAD65) and 67 kDa (GAD67) isoforms of glutamate decarboxylase were assessed using real-time quantitative polymerase chain reaction and Western blot, respectively. The concentrations of glutamate and GABA were detected with high-performance liquid chromatography (HPLC), and the intracellular calcium concentration was detected using flow cytometry. Results: we demonstrate that the expression of PV is associated with GAD65 and GAD67 and that PV regulates the levels of GAD65 and GAD67. PV was correlated with calcium concentration and GAD expression. Interestingly, PV overexpression resulted in a reduction in calcium ion concentration, upregulation of GAD65 and GAD67, elevation of GABA concentration, reduction in glutamate concentration, and an extension of seizure latency. Conversely, PV silencing induced the opposite effects. Conclusion: parvalbumin may affect the expression of GAD65 and GAD67 by regulating calcium ion concentration, thereby affecting the metabolic pathways associated with glutamate and GABA. In turn, this contributes to the regulation of seizure activity.


Assuntos
Cálcio , Glutamato Descarboxilase , Ácido Glutâmico , Ácido Caínico , Camundongos Transgênicos , Parvalbuminas , Estado Epiléptico , Ácido gama-Aminobutírico , Animais , Parvalbuminas/metabolismo , Glutamato Descarboxilase/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/induzido quimicamente , Ácido gama-Aminobutírico/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Cálcio/metabolismo , Camundongos , Hipocampo/metabolismo , Modelos Animais de Doenças
4.
Pak J Pharm Sci ; 37(2): 349-356, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38767102

RESUMO

Evidence suggests that surgical procedures can effect the central nervous system and lead to changes in mood and behavior, rarely understood about the role of acute inflammation in promoting acute anxiety postoperatively. This study was designed to explore the possible mechanism of dexmedetomidine (DEX, a2-adrenergic receptor agonist) for reducing acute postoperative anxiety, which may be related to the activation of nuclear factor kappa B (NF-κB) and downstream signal pathway in the hippocampus. Experiments were conducted with rat, the elevated plus-maze and open field test were performed to evaluate anxiety-like behavior. Inhibit DEX with Atipamezole (AT, α2-adrenergic receptor antagonist) and inhibit NF-κB with Pyrrolidinedithiocarbamate (PDTC, inhibit phosphorylation of IκB, prevent the activation of NF-κB), the level of interleukin-6 (IL-6), IL-1ß, IL-10 and Tumor necrosis factor-α (TNF-α); the nuclear translocation of NF-κB in the hippocampus and anxiety-like behavior were measured. Rats exhibited anxiety-like behavior at 6h and 12h after surgery. Preoperative administration of DEX significantly alleviated postoperative anxiety-like behavior. DEX premedication inhibited the nuclear translocation of NF-κB alleviate acute postoperative anxiety. These findings are the first to show that acute postoperative anxiety may be related to NF-κB nuclear translocation in the hippocampus in rats, which can be alleviated by DEX premedication.


Assuntos
Ansiedade , Dexmedetomidina , Hipocampo , NF-kappa B , Ratos Sprague-Dawley , Transdução de Sinais , Animais , Dexmedetomidina/farmacologia , NF-kappa B/metabolismo , Masculino , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Transdução de Sinais/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ratos , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Comportamento Animal/efeitos dos fármacos , Ansiolíticos/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Imidazóis
5.
Methods Mol Biol ; 2799: 29-46, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38727901

RESUMO

The expression and activity of ionotropic glutamate receptors control signal transduction at the excitatory synapses in the CNS. The NMDAR comprises two obligatory GluN1 subunits and two GluN2 or GluN3 subunits in different combinations. Each GluN subunit consists of four domains: the extracellular amino-terminal and agonist-binding domains, the transmembrane domain, and the intracellular C-terminal domain (CTD). The CTD interaction with various classes of intracellular proteins is critical for trafficking and synaptic localization of NMDARs. Amino acid mutations or the inclusion of premature stop codons in the CTD could contribute to the emergence of neurodevelopmental and neuropsychiatric disorders. Here, we describe the method of preparing primary hippocampal neurons and lentiviral particles expressing GluN subunits that can be used as a model to study cell surface expression and synaptic localization of NMDARs. We also show a simple method of fluorescence immunostaining of eGFP-tagged GluN2 subunits and subsequent microscopy technique and image analysis to study the effects of disease-associated mutations in the CTDs of GluN2A and GluN2B subunits.


Assuntos
Hipocampo , Neurônios , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Hipocampo/metabolismo , Hipocampo/citologia , Neurônios/metabolismo , Animais , Subunidades Proteicas/metabolismo , Subunidades Proteicas/genética , Células Cultivadas , Ratos , Humanos , Lentivirus/genética , Cultura Primária de Células/métodos , Expressão Gênica
6.
Methods Mol Biol ; 2799: 107-138, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38727905

RESUMO

NMDAR-dependent forms of synaptic plasticity in brain regions like the hippocampus are widely believed to provide the neural substrate for long-term associative memory formation. However, the experimental data are equivocal at best and may suggest a more nuanced role for NMDARs and synaptic plasticity in memory. Much of the experimental data available comes from studies in genetically modified mice in which NMDAR subunits have been deleted or mutated in order to disrupt NMDAR function. Behavioral assessment of long-term memory in these mice has involved tests like the Morris watermaze and the radial arm maze. Here we describe these behavioral tests and some of the different testing protocols that can be used to assess memory performance. We discuss the importance of distinguishing selective effects on learning and memory processes from nonspecific effects on sensorimotor or motivational aspects of performance.


Assuntos
Aprendizagem em Labirinto , Memória de Longo Prazo , Receptores de N-Metil-D-Aspartato , Memória Espacial , Animais , Receptores de N-Metil-D-Aspartato/metabolismo , Camundongos , Memória de Longo Prazo/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória Espacial/fisiologia , Hipocampo/fisiologia , Hipocampo/metabolismo , Comportamento Animal/fisiologia , Plasticidade Neuronal/fisiologia
7.
CNS Neurosci Ther ; 30(5): e14716, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38698533

RESUMO

BACKGROUND: Sevoflurane is a superior agent for maintaining anesthesia during surgical procedures. However, the neurotoxic mechanisms of clinical concentration remain poorly understood. Sevoflurane can interfere with the normal function of neurons and synapses and impair cognitive function by acting on α5-GABAAR. METHODS: Using MWM test, we evaluated cognitive abilities in mice following 1 h of anesthesia with 2.7%-3% sevoflurane. Based on hippocampal transcriptome analysis, we analyzed the differential genes and IL-6 24 h post-anesthesia. Western blot and RT-PCR were performed to measure the levels of α5-GABAAR, Radixin, P-ERM, P-Radixin, Gephyrin, IL-6, and ROCK. The spatial distribution and expression of α5-GABAAR on neuronal somata were analyzed using histological and three-dimensional imaging techniques. RESULTS: MWM test indicated that partial long-term learning and memory impairment. Combining molecular biology and histological analysis, our studies have demonstrated that sevoflurane induces immunosuppression, characterized by reduced IL-6 expression levels, and that enhanced Radixin dephosphorylation undermines the microstructural stability of α5-GABAAR, leading to its dissociation from synaptic exterior and resulting in a disordered distribution in α5-GABAAR expression within neuronal cell bodies. On the synaptic cleft, the expression level of α5-GABAAR remained unchanged, the spatial distribution became more compact, with an increased fluorescence intensity per voxel. On the extra-synaptic space, the expression level of α5-GABAAR decreased within unchanged spatial distribution, accompanied by an increased fluorescence intensity per voxel. CONCLUSION: Dysregulated α5-GABAAR expression and distribution contributes to sevoflurane-induced partial long-term learning and memory impairment, which lays the foundation for elucidating the underlying mechanisms in future studies.


Assuntos
Anestésicos Inalatórios , Hipocampo , Transtornos da Memória , Receptores de GABA-A , Sevoflurano , Sevoflurano/toxicidade , Animais , Camundongos , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Anestésicos Inalatórios/toxicidade , Receptores de GABA-A/metabolismo , Receptores de GABA-A/biossíntese , Receptores de GABA-A/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia
8.
CNS Neurosci Ther ; 30(5): e14740, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38715318

RESUMO

AIMS: γ-aminobutyric acid (GABA) from reactive astrocytes is critical for the dysregulation of neuronal activity in various neuroinflammatory conditions. While Scutellaria baicalensis Georgi (S. baicalensis) is known for its efficacy in addressing neurological symptoms, its potential to reduce GABA synthesis in reactive astrocytes and the associated neuronal suppression remains unclear. This study focuses on the inhibitory action of monoamine oxidase B (MAO-B), the key enzyme for astrocytic GABA synthesis. METHODS: Using a lipopolysaccharide (LPS)-induced neuroinflammation mouse model, we conducted immunohistochemistry to assess the effect of S. baicalensis on astrocyte reactivity and its GABA synthesis. High-performance liquid chromatography was performed to reveal the major compounds of S. baicalensis, the effects of which on MAO-B inhibition, astrocyte reactivity, and tonic inhibition in hippocampal neurons were validated by MAO-B activity assay, qRT-PCR, and whole-cell patch-clamp. RESULTS: The ethanolic extract of S. baicalensis ameliorated astrocyte reactivity and reduced excessive astrocytic GABA content in the CA1 hippocampus. Baicalin and baicalein exhibited significant MAO-B inhibition potential. These two compounds downregulate the mRNA levels of genes associated with reactive astrogliosis or astrocytic GABA synthesis. Additionally, LPS-induced aberrant tonic inhibition was reversed by both S. baicalensis extract and its key compounds. CONCLUSIONS: In summary, baicalin and baicalein isolated from S. baicalensis reduce astrocyte reactivity and alleviate aberrant tonic inhibition of hippocampal neurons during neuroinflammation.


Assuntos
Astrócitos , Flavanonas , Flavonoides , Lipopolissacarídeos , Neurônios , Extratos Vegetais , Scutellaria baicalensis , Ácido gama-Aminobutírico , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Flavanonas/farmacologia , Scutellaria baicalensis/química , Camundongos , Ácido gama-Aminobutírico/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Flavonoides/farmacologia , Extratos Vegetais/farmacologia , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Inibição Neural/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo
9.
Nat Commun ; 15(1): 3980, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730231

RESUMO

Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.


Assuntos
Núcleo Caudado , Córtex Pré-Frontal Dorsolateral , Hipocampo , Locos de Características Quantitativas , Esquizofrenia , Caracteres Sexuais , Humanos , Esquizofrenia/genética , Esquizofrenia/metabolismo , Feminino , Masculino , Hipocampo/metabolismo , Núcleo Caudado/metabolismo , Córtex Pré-Frontal Dorsolateral/metabolismo , Adulto , Transcriptoma , Perfilação da Expressão Gênica , Fatores Sexuais , Cromossomos Humanos X/genética , Córtex Pré-Frontal/metabolismo
10.
Sci Rep ; 14(1): 10773, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730262

RESUMO

The developing brain is vulnerable to maternal bacterial and viral infections which induce strong inflammatory responses in the mother that are mimicked in the offspring brain, resulting in irreversible neurodevelopmental defects, and associated cognitive and behavioural impairments. In contrast, infection during pregnancy and lactation with the immunoregulatory murine intestinal nematode, Heligmosomoides bakeri, upregulates expression of genes associated with long-term potentiation (LTP) of synaptic networks in the brain of neonatal uninfected offspring, and enhances spatial memory in uninfected juvenile offspring. As the hippocampus is involved in spatial navigation and sensitive to immune events during development, here we assessed hippocampal gene expression, LTP, and neuroimmunity in 3-week-old uninfected offspring born to H. bakeri infected mothers. Further, as maternal immunity shapes the developing immune system, we assessed the impact of maternal H. bakeri infection on the ability of offspring to resist direct infection. In response to maternal infection, we found an enhanced propensity to induce LTP at Schaffer collateral synapses, consistent with RNA-seq data indicating accelerated development of glutamatergic synapses in uninfected offspring, relative to those from uninfected mothers. Hippocampal RNA-seq analysis of offspring of infected mothers revealed increased expression of genes associated with neurogenesis, gliogenesis, and myelination. Furthermore, maternal infection improved resistance to direct infection of H. bakeri in offspring, correlated with transfer of parasite-specific IgG1 to their serum. Hippocampal immunohistochemistry and gene expression suggest Th2/Treg biased neuroimmunity in offspring, recapitulating peripheral immunoregulation of H. bakeri infected mothers. These findings indicate maternal H. bakeri infection during pregnancy and lactation alters peripheral and neural immunity in uninfected offspring, in a manner that accelerates neural maturation to promote hippocampal LTP, and upregulates the expression of genes associated with neurogenesis, gliogenesis, and myelination.


Assuntos
Hipocampo , Plasticidade Neuronal , Animais , Feminino , Hipocampo/metabolismo , Hipocampo/parasitologia , Gravidez , Camundongos , Infecções por Nematoides/imunologia , Infecções por Nematoides/parasitologia , Potenciação de Longa Duração , Efeitos Tardios da Exposição Pré-Natal/imunologia , Infecções por Strongylida/imunologia , Infecções por Strongylida/parasitologia , Masculino , Neuroimunomodulação
11.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731870

RESUMO

Transcranial magneto-acoustic stimulation (TMAS), which is characterized by high spatiotemporal resolution and high penetrability, is a non-invasive neuromodulation technology based on the magnetic-acoustic coupling effect. To reveal the effects of TMAS treatment on amyloid-beta (Aß) plaque and synaptic plasticity in Alzheimer's disease, we conducted a comparative analysis of TMAS and transcranial ultrasound stimulation (TUS) based on acoustic effects in 5xFAD mice and BV2 microglia cells. We found that the TMAS-TUS treatment effectively reduced amyloid plaque loads and plaque-associated neurotoxicity. Additionally, TMAS-TUS treatment ameliorated impairments in long-term memory formation and long-term potentiation. Moreover, TMAS-TUS treatment stimulated microglial proliferation and migration while enhancing the phagocytosis and clearance of Aß. In 5xFAD mice with induced microglial exhaustion, TMAS-TUS treatment-mediated Aß plaque reduction, synaptic rehabilitation improvement, and the increase in phospho-AKT levels were diminished. Overall, our study highlights that stimulation of hippocampal microglia by TMAS treatment can induce anti-cognitive impairment effects via PI3K-AKT signaling, providing hope for the development of new strategies for an adjuvant therapy for Alzheimer's disease.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Microglia , Placa Amiloide , Animais , Microglia/metabolismo , Camundongos , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Estimulação Magnética Transcraniana/métodos , Estimulação Acústica , Camundongos Transgênicos , Modelos Animais de Doenças , Sinapses/metabolismo , Hipocampo/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Plasticidade Neuronal , Potenciação de Longa Duração , Transdução de Sinais
12.
Int Immunopharmacol ; 133: 112158, 2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38691917

RESUMO

BACKGROUND: The prevalence of depression is higher in patients with inflammatory bowel disease (IBD) than in the general population. Inflammatory cytokines and the kynurenine pathway (KP) play important roles in IBD and associated depression. Aripiprazole (ARP), an atypical antipsychotic, shows various anti-inflammatory properties and may be useful in treating major depressive disorder. This study aimed to evaluate the protective effects of ARP on TNBS-induced colitis and subsequent depression in rats, highlighting the role of the KP. MATERIAL AND METHODS: Fifty-six male Wistar rats were used, and all groups except for the normal and sham groups received a single dose of intra-rectal TNBS. Three different doses of ARP and dexamethasone were injected intraperitoneally for two weeks in treatment groups. On the 15th day, behavioral tests were performed to evaluate depressive-like behaviors. Colon ulcer index and histological changes were assessed. The tissue levels of inflammatory cytokines, KP markers, lipopolysaccharide (LPS), nuclear factor-kappa-B (NF-κB), and zonula occludens (ZO-1) were evaluated in the colon and hippocampus. RESULTS: TNBS effectively induced intestinal damages and subsequent depressive-like symptoms in rats. TNBS treatment significantly elevated the intestinal content of inflammatory cytokines and NF-κB expression, dysregulated the KP markers balance in both colon and hippocampus tissues, and increased the serum levels of LPS. However, treatment with ARP for 14 days successfully reversed these alterations, particularly at higher doses. CONCLUSION: ARP could alleviate IBD-induced colon damage and associated depressive-like behaviors mainly via suppressing inflammatory cytokines activity, serum LPS concentration, and affecting the NF-κB/kynurenine pathway.


Assuntos
Anti-Inflamatórios , Aripiprazol , Colite , Citocinas , Depressão , Cinurenina , NF-kappa B , Ratos Wistar , Ácido Trinitrobenzenossulfônico , Animais , Masculino , Cinurenina/metabolismo , Cinurenina/sangue , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/farmacologia , Aripiprazol/uso terapêutico , Aripiprazol/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/metabolismo , Ratos , NF-kappa B/metabolismo , Citocinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Colo/patologia , Colo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Modelos Animais de Doenças , Humanos
13.
Sci Rep ; 14(1): 11557, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773352

RESUMO

Juvenile loneliness is a risk factor for psychopathology in later life. Deprivation of early social experience due to peer rejection has a detrimental impact on emotional and cognitive brain function in adulthood. Accumulating evidence indicates that soy peptides have many positive effects on higher brain function in rodents and humans. However, the effects of soy peptide use on juvenile social isolation are unknown. Here, we demonstrated that soy peptides reduced the deterioration of behavioral and cellular functions resulting from juvenile socially-isolated rearing. We found that prolonged social isolation post-weaning in male C57BL/6J mice resulted in higher aggression and impulsivity and fear memory deficits at 7 weeks of age, and that these behavioral abnormalities, except impulsivity, were mitigated by ingestion of soy peptides. Furthermore, we found that daily intake of soy peptides caused upregulation of postsynaptic density 95 in the medial prefrontal cortex and phosphorylation of the cyclic adenosine monophosphate response element binding protein in the hippocampus of socially isolated mice, increased phosphorylation of the adenosine monophosphate-activated protein kinase in the hippocampus, and altered the microbiota composition. These results suggest that soy peptides have protective effects against juvenile social isolation-induced behavioral deficits via synaptic maturation and cellular functionalization.


Assuntos
Agressão , Suplementos Nutricionais , Medo , Hipocampo , Camundongos Endogâmicos C57BL , Isolamento Social , Animais , Isolamento Social/psicologia , Masculino , Medo/efeitos dos fármacos , Agressão/efeitos dos fármacos , Camundongos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Proteínas de Soja/farmacologia , Memória/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteína 4 Homóloga a Disks-Large/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
14.
BMC Res Notes ; 17(1): 143, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773625

RESUMO

OBJECTIVES: The G72 mouse model of schizophrenia represents a well-known model that was generated to meet the main translational criteria of isomorphism, homology and predictability of schizophrenia to a maximum extent. In order to get a more detailed view of the complex etiopathogenesis of schizophrenia, whole genome transcriptome studies turn out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cortex, hippocampus and thalamus of G72 transgenic and wild-type control mice. Experimental animals were age-matched and importantly, both sexes were considered separately. DATA DESCRIPTION: The isolated RNA from all three brain regions was purified, quantified und quality controlled before initiation of the hybridization procedure with SurePrint G3 Mouse Gene Expression v2 8  ×  60 K microarrays. Following immunofluorescent measurement und preprocessing of image data, raw transcriptome data from G72 mice and control animals were extracted and uploaded in a public database. Our data allow insight into significant alterations in gene transcript levels in G72 mice and enable the reader/user to perform further complex analyses to identify potential age-, sex- and brain-region-specific alterations in transcription profiles and related pathways. The latter could facilitate biomarker identification and drug research and development in schizophrenia research.


Assuntos
Córtex Cerebral , Modelos Animais de Doenças , Hipocampo , Esquizofrenia , Tálamo , Transcriptoma , Animais , Esquizofrenia/genética , Esquizofrenia/metabolismo , Hipocampo/metabolismo , Masculino , Feminino , Camundongos , Transcriptoma/genética , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Tálamo/metabolismo , Camundongos Transgênicos , Perfilação da Expressão Gênica/métodos , Fatores Sexuais
15.
Alzheimers Res Ther ; 16(1): 116, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773640

RESUMO

Systemic inflammation and neuroinflammation affect the natural course of the sporadic form of Alzheimer's disease (AD), as supported by epidemiological and preclinical data, and several epidemiological studies indicate a higher prevalence of AD in patients with inflammatory bowel disease. In this study, we explored whether colitis induced by dextran sulfate sodium (DSS) in young, presymptomatic/preplaque mice worsens and/or anticipates age-dependent cognitive impairment in Tg2576, a widely used mouse model of AD. We demonstrated that DSS colitis induced in young Tg2576 mice anticipates the onset age of learning and memory deficit in the Morris water maze test. To explore potential mechanisms behind the acceleration of cognitive decline in Tg2576 mice by DSS colitis, we focused on gut microbiota, systemic inflammation and neuroinflammation markers. We observed a Firmicutes/Bacteroidetes ratio change in Tg2576 DSS animals comparable to that of elderly Tg2576 mice, suggesting accelerated microbiota aging in Tg2576 DSS mice, a change not observed in C57BL6 DSS mice. We also observed substantial differences between Tg2576 and WT mice in several inflammation and neuroinflammation-related parameters as early as 3 months of age, well before plaque deposition, a picture which evolved rapidly (between 3 and 5.5 months of age) in contrast to Tg2576 and WT littermates not treated with DSS. In detail, following induction of DSS colitis, WT and Tg2576 mice exhibited contrasting features in the expression level of inflammation-evoked astrocyte-associated genes in the hippocampus. No changes in microglial features occurred in the hippocampus between the experimental groups, whereas a reduced glial fibrillary acidic protein immunoreactivity was observed in Tg2576 vs. WT mice. This finding may reflect an atrophic, "loss-of-function" profile, further exacerbated by DSS where a decreased of GFAP mRNA expression level was detected. In conclusion, we suggest that as-yet unidentified peripheral mediators evoked by DSS colitis and involving the gut-brain axis emphasize an astrocyte "loss-of-function" profile present in young Tg2576 mice, leading to impaired synaptic morphological and functional integrity as a very early sign of AD.


Assuntos
Doença de Alzheimer , Colite , Sulfato de Dextrana , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Animais , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Camundongos , Colite/induzido quimicamente , Colite/patologia , Sulfato de Dextrana/toxicidade , Microbioma Gastrointestinal , Fenótipo , Masculino , Hipocampo/patologia , Hipocampo/metabolismo , Feminino , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologia
16.
Brain Behav ; 14(5): e3503, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38775292

RESUMO

BACKGROUND: Crocin has a good prospect in the treatment of Alzheimer's disease (AD), but the mechanisms underlying its neuroprotective effects remain elusive. This study aimed to investigate the neuroprotective effects of Crocin and its underlying mechanisms in AD. METHODS: AD mice were set up by injecting Aß25-35 solution into the hippocampus. Then, the AD mice were injected intraperitoneally with 40 mg/kg/day of Crocin for 14 days. Following the completion of Crocin treatment, an open-field test, Y-maze test and Morris water maze test were conducted to evaluate the impact of Crocin on spatial learning and memory deficiency in mice. The effects of Crocin on hippocampal neuron injury, proinflammatory cytokine expressions (IL-1ß, IL-6, and TNF-α), and PI3K/AKT signaling-related protein expressions were measured using hematoxylin and eosin staining, Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR) experiments, respectively. RESULTS: Crocin attenuated Aß25-35-induced spatial learning and memory deficiency and hippocampal neuron injury. Furthermore, the Western blot and qRT-PCR results showed that Crocin effectively suppressed inflammation and activated the PI3K/AKT pathway in Aß25-35-induced mice. CONCLUSION: Crocin restrained neuroinflammation via the activation of the PI3K/AKT pathway, thereby ameliorating the cognitive dysfunction of AD mice.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Carotenoides , Disfunção Cognitiva , Hipocampo , Doenças Neuroinflamatórias , Fármacos Neuroprotetores , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Carotenoides/farmacologia , Carotenoides/administração & dosagem , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Modelos Animais de Doenças , Fragmentos de Peptídeos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem Espacial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo
17.
PLoS Biol ; 22(5): e3002596, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38718086

RESUMO

Autism spectrum disorders (ASD) frequently accompany macrocephaly, which often involves hydrocephalic enlargement of brain ventricles. Katnal2 is a microtubule-regulatory protein strongly linked to ASD, but it remains unclear whether Katnal2 knockout (KO) in mice leads to microtubule- and ASD-related molecular, synaptic, brain, and behavioral phenotypes. We found that Katnal2-KO mice display ASD-like social communication deficits and age-dependent progressive ventricular enlargements. The latter involves increased length and beating frequency of motile cilia on ependymal cells lining ventricles. Katnal2-KO hippocampal neurons surrounded by enlarged lateral ventricles show progressive synaptic deficits that correlate with ASD-like transcriptomic changes involving synaptic gene down-regulation. Importantly, early postnatal Katnal2 re-expression prevents ciliary, ventricular, and behavioral phenotypes in Katnal2-KO adults, suggesting a causal relationship and a potential treatment. Therefore, Katnal2 negatively regulates ependymal ciliary function and its deletion in mice leads to ependymal ciliary hyperfunction and hydrocephalus accompanying ASD-related behavioral, synaptic, and transcriptomic changes.


Assuntos
Transtorno do Espectro Autista , Cílios , Epêndima , Camundongos Knockout , Fenótipo , Animais , Cílios/metabolismo , Epêndima/metabolismo , Camundongos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Hidrocefalia/genética , Hidrocefalia/metabolismo , Hidrocefalia/patologia , Hidrocefalia/fisiopatologia , Hipocampo/metabolismo , Masculino , Neurônios/metabolismo , Camundongos Endogâmicos C57BL , Sinapses/metabolismo , Comportamento Animal , Katanina/metabolismo , Katanina/genética , Transcriptoma/genética , Modelos Animais de Doenças
18.
J Neuroimmune Pharmacol ; 19(1): 23, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38775885

RESUMO

Hyperbilirubinemia is one of the most common occurrence in newborns and is toxic to the brain, resulting in neurological sequelae such as auditory impairment, with potential to evolve to chronic bilirubin encephalopathy and long-term cognitive impairment in adults. In the early postnatal period, neurogenesis is rigorous and neuroinflammation is detrimental to the brain. What are the alterations in neurogenesis and the underlying mechanisms of bilirubin encephalopathy during the early postnatal period? This study found that, there were a reduction in the number of neuronal stem/progenitor cells, an increase in microglia in the dentate gyrus (DG) and an inflammatory state in the hippocampus, characterized by increased levels of IL-6, TNF-α, and IL-1ß, as well as a decreased level of IL-10 in a rat model of bilirubin encephalopathy (BE). Furthermore, there was a significant decrease in the number of newborn neurons and the expression of neuronal differentiation-associated genes (NeuroD and Ascl1) in the BE group. Additionally, cognitive impairment was observed in this group. The administration of minocycline, an inhibitor of microglial activation, resulted in a reduction of inflammation in the hippocampus, an enhancement of neurogenesis, an increase in the expression of neuron-related genes (NeuroD and Ascl1), and an improvement in cognitive function in the BE group. These results demonstrate that microglia play a critical role in reduced neurogenesis and impaired brain function resulting from bilirubin encephalopathy model, which could inspire the development of novel pharmaceutical and therapeutic strategies.


Assuntos
Hipocampo , Kernicterus , Microglia , Minociclina , Neurogênese , Animais , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Microglia/efeitos dos fármacos , Microglia/metabolismo , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Minociclina/farmacologia , Modelos Animais de Doenças , Ratos Sprague-Dawley , Inflamação/metabolismo , Inflamação/patologia , Doenças Neuroinflamatórias/tratamento farmacológico
19.
Cell Commun Signal ; 22(1): 269, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745240

RESUMO

BACKGROUND: The pathway involving PTEN-induced putative kinase 1 (PINK1) and PARKIN plays a crucial role in mitophagy, a process activated by artesunate (ART). We propose that patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis exhibit insufficient mitophagy, and ART enhances mitophagy via the PINK1/PARKIN pathway, thereby providing neuroprotection. METHODS: Adult female mice aged 8-10 weeks were selected to create a passive transfer model of anti-NMDAR encephalitis. We conducted behavioral tests on these mice within a set timeframe. Techniques such as immunohistochemistry, immunofluorescence, and western blotting were employed to assess markers including PINK1, PARKIN, LC3B, p62, caspase3, and cleaved caspase3. The TUNEL assay was utilized to detect neuronal apoptosis, while transmission electron microscopy (TEM) was used to examine mitochondrial autophagosomes. Primary hippocampal neurons were cultured, treated, and then analyzed through immunofluorescence for mtDNA, mtROS, TMRM. RESULTS: In comparison to the control group, mitophagy levels in the experimental group were not significantly altered, yet there was a notable increase in apoptotic neurons. Furthermore, markers indicative of mitochondrial leakage and damage were found to be elevated in the experimental group compared to the control group, but these markers showed improvement following ART treatment. ART was effective in activating the PINK1/PARKIN pathway, enhancing mitophagy, and diminishing neuronal apoptosis. Behavioral assessments revealed that ART ameliorated symptoms in mice with anti-NMDAR encephalitis in the passive transfer model (PTM). The knockdown of PINK1 led to a reduction in mitophagy levels, and subsequent ART intervention did not alleviate symptoms in the anti-NMDAR encephalitis PTM mice, indicating that ART's therapeutic efficacy is mediated through the activation of the PINK1/PARKIN pathway. CONCLUSIONS: At the onset of anti-NMDAR encephalitis, mitochondrial damage is observed; however, this damage is mitigated by the activation of mitophagy via the PINK1/PARKIN pathway. This regulatory feedback mechanism facilitates the removal of damaged mitochondria, prevents neuronal apoptosis, and consequently safeguards neural tissue. ART activates the PINK1/PARKIN pathway to enhance mitophagy, thereby exerting neuroprotective effects and may achieve therapeutic goals in treating anti-NMDAR encephalitis.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato , Artesunato , Modelos Animais de Doenças , Fármacos Neuroprotetores , Proteínas Quinases , Animais , Artesunato/farmacologia , Artesunato/uso terapêutico , Camundongos , Feminino , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Encefalite Antirreceptor de N-Metil-D-Aspartato/patologia , Encefalite Antirreceptor de N-Metil-D-Aspartato/tratamento farmacológico , Proteínas Quinases/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Microscopia Eletrônica de Transmissão , Mitofagia/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Hipocampo/patologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo
20.
Nat Commun ; 15(1): 4047, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38744873

RESUMO

Human hippocampal organoids (hHOs) derived from human induced pluripotent stem cells (hiPSCs) have emerged as promising models for investigating neurodegenerative disorders, such as schizophrenia and Alzheimer's disease. However, obtaining the electrical information of these free-floating organoids in a noninvasive manner remains a challenge using commercial multi-electrode arrays (MEAs). The three-dimensional (3D) MEAs developed recently acquired only a few neural signals due to limited channel numbers. Here, we report a hippocampal cyborg organoid (cyb-organoid) platform coupling a liquid metal-polymer conductor (MPC)-based mesh neuro-interface with hHOs. The mesh MPC (mMPC) integrates 128-channel multielectrode arrays distributed on a small surface area (~2*2 mm). Stretchability (up to 500%) and flexibility of the mMPC enable its attachment to hHOs. Furthermore, we show that under Wnt3a and SHH activator induction, hHOs produce HOPX+ and PAX6+ progenitors and ZBTB20+PROX1+ dentate gyrus (DG) granule neurons. The transcriptomic signatures of hHOs reveal high similarity to the developing human hippocampus. We successfully detect neural activities from hHOs via the mMPC from this cyb-organoid. Compared with traditional planar devices, our non-invasive coupling offers an adaptor for recording neural signals from 3D models.


Assuntos
Hipocampo , Células-Tronco Pluripotentes Induzidas , Organoides , Humanos , Organoides/metabolismo , Organoides/citologia , Hipocampo/citologia , Hipocampo/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neurônios/metabolismo , Neurônios/citologia , Metais/química , Transcriptoma , Giro Denteado/citologia , Giro Denteado/metabolismo
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