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1.
Nat Commun ; 12(1): 1142, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602941

RESUMO

Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H1 receptor (H1R) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H1R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H1R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H1R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.


Assuntos
Neurônios Colinérgicos/metabolismo , Receptores Histamínicos H1/metabolismo , Filtro Sensorial , Comportamento Social , Anedonia/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Disfunção Cognitiva/complicações , Maleato de Dizocilpina/farmacologia , Feminino , Integrases/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia
2.
Nat Neurosci ; 24(2): 176-185, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33432195

RESUMO

We characterize the landscape of somatic mutations-mutations occurring after fertilization-in the human brain using ultra-deep (~250×) whole-genome sequencing of prefrontal cortex from 59 donors with autism spectrum disorder (ASD) and 15 control donors. We observe a mean of 26 somatic single-nucleotide variants per brain present in ≥4% of cells, with enrichment of mutations in coding and putative regulatory regions. Our analysis reveals that the first cell division after fertilization produces ~3.4 mutations, followed by 2-3 mutations in subsequent generations. This suggests that a typical individual possesses ~80 somatic single-nucleotide variants present in ≥2% of cells-comparable to the number of de novo germline mutations per generation-with about half of individuals having at least one potentially function-altering somatic mutation somewhere in the cortex. ASD brains show an excess of somatic mutations in neural enhancer sequences compared with controls, suggesting that mosaic enhancer mutations may contribute to ASD risk.


Assuntos
Transtorno do Espectro Autista/patologia , Córtex Pré-Frontal/patologia , Divisão Celular/genética , Cromatina/genética , Desenvolvimento Embrionário/genética , Epigênese Genética , Éxons , Feminino , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Genoma Humano/genética , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Sequenciamento Completo do Genoma
3.
PLoS One ; 15(12): e0243857, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33332381

RESUMO

Chronic alcohol abuse has been linked to the disruption of executive function and allostatic conditioning of reward response dysregulation in the mesocorticolimbic pathway (MCL). Here, we analyzed genome-wide mRNA and miRNA expression from matched cases with alcohol dependence (AD) and controls (n = 35) via gene network analysis to identify unique and shared biological processes dysregulated in the prefrontal cortex (PFC) and nucleus accumbens (NAc). We further investigated potential mRNA/miRNA interactions at the network and individual gene expression levels to identify the neurobiological mechanisms underlying AD in the brain. By using genotyped and imputed SNP data, we identified expression quantitative trait loci (eQTL) uncovering potential genetic regulatory elements for gene networks associated with AD. At a Bonferroni corrected p≤0.05, we identified significant mRNA (NAc = 6; PFC = 3) and miRNA (NAc = 3; PFC = 2) AD modules. The gene-set enrichment analyses revealed modules preserved between PFC and NAc to be enriched for immune response processes, whereas genes involved in cellular morphogenesis/localization and cilia-based cell projection were enriched in NAc modules only. At a Bonferroni corrected p≤0.05, we identified significant mRNA/miRNA network module correlations (NAc = 6; PFC = 4), which at an individual transcript level implicated miR-449a/b as potential regulators for cellular morphogenesis/localization in NAc. Finally, we identified eQTLs (NAc: mRNA = 37, miRNA = 9; PFC: mRNA = 17, miRNA = 16) which potentially mediate alcohol's effect in a brain region-specific manner. Our study highlights the neurotoxic effects of chronic alcohol abuse as well as brain region specific molecular changes that may impact the development of alcohol addiction.


Assuntos
Alcoolismo/genética , Redes Reguladoras de Genes , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Doença Crônica , Análise por Conglomerados , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Metalotioneína/genética , Metalotioneína/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Núcleo Accumbens/patologia , Córtex Pré-Frontal/patologia , Locos de Características Quantitativas/genética
4.
Nat Commun ; 11(1): 5781, 2020 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188183

RESUMO

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10-5), Aß (CERAD score, P = 1.8 × 10-5), and cognitive diagnosis (P = 3.5 × 10-7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data.


Assuntos
Encéfalo/patologia , Degeneração Neural/patologia , Algoritmos , Doença de Alzheimer/patologia , Progressão da Doença , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Degeneração Neural/genética , Córtex Pré-Frontal/patologia , Fatores de Tempo , Aprendizado de Máquina não Supervisionado
5.
Croat Med J ; 61(4): 354-365, 2020 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-32881434

RESUMO

AIM: To analyze axon morphology on rapid Golgi impregnated pyramidal neurons in the dorsolateral prefrontal cortex in schizophrenia. METHODS: Postmortem brain tissue from five subjects diagnosed with schizophrenia and five control subjects without neuropathological findings was processed with the rapid Golgi method. Layer III and layer V pyramidal neurons from Brodmann area 9 were chosen in each brain for reconstruction with Neurolucida software. The axons and cell bodies of 136 neurons from subjects with schizophrenia and of 165 neurons from control subjects were traced. The data obtained by quantitative analysis were compared between the schizophrenia and control group with the t test. RESULTS: Axon impregnation length was consistently greater in the schizophrenia group. The axon main trunk length was significantly greater in the schizophrenia than in the control group (93.7 ± 36.6 µm vs 49.8 ± 9.9 µm, P = 0.032). Furthermore, in the schizophrenia group more axons had visibly stained collaterals (14.7% vs 5.5%). CONCLUSION: Axon rapid Golgi impregnation stops at the beginning of the myelin sheath. The increased axonal staining in the schizophrenia group could, therefore, be explained by reduced axon myelination. Such a decrease in axon myelination is in line with both the disconnection hypothesis and the two-hit model of schizophrenia as a neurodevelopmental disease. Our results support that the cortical circuitry disorganization in schizophrenia might be caused by functional alterations of two major classes of principal neurons due to altered oligodendrocyte development.


Assuntos
Axônios/patologia , Córtex Pré-Frontal/patologia , Células Piramidais/patologia , Esquizofrenia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Complexo de Golgi/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Coloração e Rotulagem/métodos
6.
PLoS One ; 15(8): e0237015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760098

RESUMO

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1ß, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-ß stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1ß, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1ß-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-ß-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.


Assuntos
Oftalmopatia de Graves/enzimologia , Oftalmopatia de Graves/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Adulto , Animais , Apoptose , Bovinos , Sobrevivência Celular , Citocinas/biossíntese , Estresse do Retículo Endoplasmático , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Inativação Gênica , Oftalmopatia de Graves/patologia , Humanos , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
7.
Proc Natl Acad Sci U S A ; 117(29): 17278-17287, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32631999

RESUMO

The prefrontal cortex (PFC) plays a critical role in curbing impulsive behavior, but the underlying circuit mechanism remains incompletely understood. Here we show that a subset of dorsomedial PFC (dmPFC) layer 5 pyramidal neurons, which project to the subthalamic nucleus (STN) of the basal ganglia, play a key role in inhibiting impulsive responses in a go/no-go task. Projection-specific labeling and calcium imaging showed that the great majority of STN-projecting neurons were preferentially active in no-go trials when the mouse successfully withheld licking responses, but lateral hypothalamus (LH)-projecting neurons were more active in go trials with licking; visual cortex (V1)-projecting neurons showed only weak task-related activity. Optogenetic activation and inactivation of STN-projecting neurons reduced and increased inappropriate licking, respectively, partly through their direct innervation of the STN, but manipulating LH-projecting neurons had the opposite effects. These results identify a projection-defined subtype of PFC pyramidal neurons as key mediators of impulse control.


Assuntos
Comportamento Impulsivo/fisiologia , Inibição Psicológica , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Animais , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Interneurônios/fisiologia , Camundongos , Neurônios/fisiologia , Optogenética , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Células Piramidais/patologia , Núcleo Subtalâmico/diagnóstico por imagem , Núcleo Subtalâmico/fisiologia , Córtex Visual
8.
Life Sci ; 258: 118099, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682917

RESUMO

Although emerging evidence has highlighted the heterogeneities of astrocytes under physiological versus pathological conditions, little is known regarding these processes in different brain regions during stress. Thus, the present study established a mouse model of chronic social defeat stress (CSDS) and isolated astrocytes from the medial prefrontal cortex (mPFC) and hippocampus. The results revealed dramatic A1-specific (neurotoxic phenotype) astrocytic responses, depressive-like behaviors, and significant inhibition of neuronal activities in both the mPFC and hippocampus according to electrophysiological data. Subsequently, astrocytes in the mPFC and hippocampus of CSDS mice were suppressed and this reversed the astrocytic responses and rescued depressive-like behaviors. Furthermore, when astrocytes were activated in the mPFC and hippocampus in healthy mice, there was a non-specific phenotypic activation of astrocytes in the absence of depressive-like behaviors. Next, microglia were depleted and the mice subsequently performed in the CSDS model; this reduced astrocyte responses and restored depressive-like behaviors. On the other hand, when microglia were depleted but astrocytes were activated in CSDS mice, this abolished the restoration of microglia depletion-induced depressive-like behaviors. Taken together, these results indicate that neuronal inhibition by astrocytes in the mPFC and hippocampus contributed to depressive-like behaviors mediated by activated microglia. This study provides evidence regarding the interaction of microglia and astrocytes during stress and how that relationship can trigger depressive-like behaviors.


Assuntos
Astrócitos/patologia , Comportamento Animal , Depressão/psicologia , Neurônios/patologia , Estresse Psicológico/patologia , Animais , Doença Crônica , Hipocampo/patologia , Locomoção , Masculino , Camundongos , Inibição Neural , Neuroglia/metabolismo , Córtex Pré-Frontal/patologia
9.
J Clin Neurosci ; 78: 376-386, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32376157

RESUMO

The insular gliomas were classified based on their locations and extensions to the adjacent areas. The insular and orbitofrontal cortices with underlying fiber tracts were studied on ten (20 sides) human cadaveric brains and two heads. Twenty patients with insular gliomas with the orbitofrontal or septal region extensions were studied on preoperative magnetic resonance imaging (MRI). Insular gliomas can extend to the orbitofrontal area dorsolaterally and/or ventromedially through the subdivision of the uncinate fasciculus. The dorsolateral part of the uncinate fasciculus interconnects the temporopolar area to the lateral orbitofrontal cortex through insula, and the ventromedial part of the uncinate fasciculus interconnects the temporopolar area to the medial orbital cortex, gyrus rectus, and septal region. The gyrus rectus infiltration on MRI indicates a ventromedial involvement by passing through the ventromedial part of the uncinate fasciculus. Diffusion tensor imaging (DTI) MRI demonstration of the UF is difficult due to the interruption of the fiber tracts by tumor. Tumor infiltration extending to the gyrus rectus requires a 15° lateral tilting with vertex toward contralateral side, as well as 70° head rotation to the contralateral side of lesion, for exposure of frontal base, septal region, and lateral border of the anterior perforating substance at the same time with the exposure of whole sylvian fissure via transsylvian approach of the insular tumors. An understanding of the orbitofrontal extension of the insular tumor based on the subdivisions of UF is useful in preoperative surgical planning and can assist for gross total resection.


Assuntos
Glioma/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Invasividade Neoplásica/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Substância Branca/diagnóstico por imagem , Adulto , Córtex Cerebral/cirurgia , Imagem de Tensor de Difusão/métodos , Feminino , Glioma/cirurgia , Humanos , Masculino , Fibras Nervosas , Córtex Pré-Frontal/diagnóstico por imagem
10.
Nat Commun ; 11(1): 2301, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385265

RESUMO

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (ß: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (ß: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.


Assuntos
Depressão/genética , Córtex Pré-Frontal/metabolismo , Idoso , Bancos de Espécimes Biológicos , Depressão/metabolismo , Depressão/patologia , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neuroimagem/métodos , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/patologia , Fatores de Risco
11.
Psychiatry Res Neuroimaging ; 301: 111089, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32442837

RESUMO

It is thought that altered connectivity between the striatum and the cortex could contribute to psychosis. However, whether psychosis risk is associated with altered white matter connectivity between the striatum and any cortical region is still unclear. Further, no previous study has directly examined whether psychosis risk is associated with altered striatal connectivity with specific cortical networks. The current study examined the integrity of corticostriatal white matter tracts in psychosis risk (n=18) and in non-psychosis risk comparison participants (n=19). We used probabilistic tractography to identify white matter tracts connecting each of four different striatal subregions with their most functionally connected cortical network: limbic, default mode, frontoparietal, and motor networks. We then compared groups on fractional anisotropy in these four tracts. Psychosis risk was associated with decreased fractional anisotropy in white matter tracts connecting the limbic striatum with the limbic cortical network, especially in an anterior right external capsule segment and in tracts specifically connected to the right prefrontal cortex. In contrast, psychosis risk was not associated with decreased white matter integrity in other corticostriatal tracts. Hence, the current research suggests that psychosis risk is especially associated with decreased corticostriatal white matter integrity involved in processing emotional and personally relevant information.


Assuntos
Corpo Estriado/diagnóstico por imagem , Imagem de Tensor de Difusão , Sistema Límbico/diagnóstico por imagem , Córtex Pré-Frontal/diagnóstico por imagem , Transtornos Psicóticos/etiologia , Substância Branca/diagnóstico por imagem , Adolescente , Anisotropia , Estudos de Casos e Controles , Corpo Estriado/patologia , Feminino , Humanos , Sistema Límbico/patologia , Masculino , Córtex Pré-Frontal/patologia , Medição de Risco , Fatores de Risco , Substância Branca/patologia , Adulto Jovem
12.
Am J Psychiatry ; 177(9): 844-854, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32375536

RESUMO

OBJECTIVE: The dual-pathway model has been proposed to explain the heterogeneity in symptoms of attention deficit hyperactivity disorder (ADHD) by two independent psychological pathways based on distinct brain circuits. The authors sought to test whether the hypothesized cognitive and motivational pathways have separable neural correlates. METHODS: In a longitudinal community-based cohort of 1,963 adolescents, the neuroanatomical correlates of ADHD were identified by a voxel-wise association analysis and then validated using an independent clinical sample (99 never-medicated patients with ADHD, 56 medicated patients with ADHD, and 267 healthy control subjects). The cognitive and motivational pathways were assessed by neuropsychological tests of working memory, intrasubject variability, stop-signal reaction time, and delay discounting. The associations were tested between the identified neuroanatomical correlates and both ADHD symptoms 2 years later and the polygenic risk score for ADHD. RESULTS: Gray matter volumes of both a prefrontal cluster and a posterior occipital cluster were negatively associated with inattention. Compared with healthy control subjects, never-medicated patients, but not medicated patients, had significantly lower gray matter volumes in these two clusters. Working memory and intrasubject variability were associated with the posterior occipital cluster, and delay discounting was independently associated with both clusters. The baseline gray matter volume of the posterior occipital cluster predicted the inattention symptoms in a 2-year follow-up and was associated with the genetic risk for ADHD. CONCLUSIONS: The dual-pathway model has both shared and separable neuroanatomical correlates, and the shared correlate in the occipital cortex has the potential to serve as an imaging trait marker of ADHD, especially the inattention symptom domain.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Sintomas Comportamentais , Cognição/fisiologia , Técnicas de Rastreamento Neuroanatômico/métodos , Lobo Occipital , Córtex Pré-Frontal , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Sintomas Comportamentais/diagnóstico , Sintomas Comportamentais/fisiopatologia , Ciências Biocomportamentais , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Estudos Longitudinais , Masculino , Motivação/fisiologia , Neuroimagem/métodos , Testes Neuropsicológicos , Lobo Occipital/diagnóstico por imagem , Lobo Occipital/patologia , Tamanho do Órgão , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/patologia , Medição de Risco/métodos
13.
Sci Rep ; 10(1): 6884, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327679

RESUMO

Tremendous individual differences exist in stress responsivity and social defeat stress is a key approach for identifying cellular mechanisms of stress susceptibility and resilience. Syrian hamsters show reliable territorial aggression, but after social defeat they exhibit a conditioned defeat (CD) response characterized by increased submission and an absence of aggression in future social interactions. Hamsters that achieve social dominance prior to social defeat exhibit greater defeat-induced neural activity in infralimbic (IL) cortex neurons that project to the basolateral amygdala (BLA) and reduced CD response compared to subordinate hamsters. Here, we hypothesize that chemogenetic activation of an IL-to-BLA neural projection during acute social defeat will reduce the CD response in subordinate hamsters and thereby produce dominant-like behavior. We confirmed that clozapine-N-oxide (CNO) itself did not alter the CD response and validated a dual-virus, Cre-dependent, chemogenetic approach by showing that CNO treatment increased c-Fos expression in the IL and decreased it in the BLA. We found that CNO treatment during social defeat reduced the acquisition of CD in subordinate, but not dominant, hamsters. This project extends our understanding of the neural circuits underlying resistance to acute social stress, which is an important step toward delineating circuit-based approaches for the treatment of stress-related psychopathologies.


Assuntos
Tonsila do Cerebelo/patologia , Complexo Nuclear Basolateral da Amígdala/patologia , Comportamento Social , Estresse Psicológico/patologia , Agressão , Animais , Clozapina/análogos & derivados , Condicionamento Clássico , Cricetinae , Vetores Genéticos/metabolismo , Masculino , Córtex Pré-Frontal/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo
14.
Am J Chin Med ; 48(3): 559-577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345030

RESUMO

Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1ß, RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1ß. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.


Assuntos
Cicloparafinas/administração & dosagem , Cicloparafinas/farmacologia , Depressão/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Cervos , Depressão/induzido quimicamente , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
15.
Neurology ; 94(19): e2005-e2013, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32277059

RESUMO

OBJECTIVE: To determine if survival and cognitive profile is affected by initial presentation in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) (motor vs cognitive), we compared survival patterns in ALS-FTD based on initial phenotypic presentation and their cognitive profile compared to behavioral variant FTD (bvFTD). METHODS: Cognitive/behavioral profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD). The initial presentation of ALS-FTD was categorized into either motor or cognitive. Survival was calculated from initial symptom onset. MRI brain atrophy patterns were examined using a validated visual rating scale. RESULTS: In the ALS-FTD group, 41 (69%) patients were categorized as having an initial cognitive presentation and 18 (31%) a motor presentation. Patients with motor presentation experienced a significantly shorter median survival of 2.7 years compared to 4.4 years (p < 0.001) in those with a cognitive presentation. No differences between motor vs cognitive onset ALS-FTD were found on cognitive testing. When compared to bvFTD, ALS-FTD-cognitive presentation was characterized by reduced language function (p < 0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both motor and cognitive onset ALS-FTD showed reduced emotion processing (p = 0.01) and exhibited greater motor cortex and dorsal lateral prefrontal cortex atrophy than bvFTD. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival. CONCLUSIONS: Initial motor presentation in ALS-FTD leads to faster progression than in those with a cognitive presentation, despite similar overall cognitive deficits. These findings suggest that disease progression in ALS-FTD may be critically linked to physiologic and motor changes.


Assuntos
Esclerose Amiotrófica Lateral/psicologia , Variação Biológica da População , Transtornos Cognitivos/diagnóstico , Demência Frontotemporal/psicologia , Análise de Sobrevida , Esclerose Amiotrófica Lateral/complicações , Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/patologia , Atrofia/complicações , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Feminino , Demência Frontotemporal/complicações , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/patologia , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Motor/patologia , Neuroimagem , Testes Neuropsicológicos , Córtex Pré-Frontal/patologia
16.
Chem Biol Interact ; 323: 109076, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32240654

RESUMO

A growing body of evidence indicates that exposure to nonylphenol (NP), a typical persistent organic pollutant (POP), in early life results in the impairment of the central nervous system (CNS), but the underlying mechanism still remains to be elucidated. High levels of pro-inflammatory cytokines in the brain have been implicated in the CNS damages. The animal model of exposure to NP in early life was established by maternal gavage during the pregnancy and lactation in the present study. We found that exposure to NP in early life increased the levels of pro-inflammatory cytokines in the rat prefrontal cortex. Interestingly, the levels of pro-inflammatory cytokines in the intestine as well as in the serum were also increased by NP exposure. Furthermore, the increased permeability of intestinal barrier and blood-brain barrier (BBB), two critical barriers in the gut to brain communication, was observed in the rats exposed to NP in early lives. The decreased expression of zonula occludens-1 (ZO-1) and claudin-1 (CLDN-1), tight junction proteins (TJs) that responsible for maintaining the permeability of intestinal barrier and BBB, was found, which may underlie these increases in permeability. Taken together, these results suggested that the disturbed gut-brain communication may contribute to the increased levels of pro-inflammatory cytokines in the prefrontal cortex caused by NP exposure in early life.


Assuntos
Citocinas/metabolismo , Trato Gastrointestinal/patologia , Mediadores da Inflamação/metabolismo , Fenóis/toxicidade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Líquido Cefalorraquidiano/metabolismo , Claudina-1/metabolismo , Citocinas/sangue , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Mediadores da Inflamação/sangue , Intestinos/efeitos dos fármacos , Intestinos/patologia , Exposição Materna , Permeabilidade , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1/metabolismo
17.
Toxicol Appl Pharmacol ; 395: 114980, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234516

RESUMO

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.


Assuntos
Anti-Inflamatórios/administração & dosagem , Transtornos da Memória/prevenção & controle , Minociclina/administração & dosagem , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Tolueno/toxicidade , Administração por Inalação , Animais , Expressão Gênica/efeitos dos fármacos , Abuso de Inalantes , Interleucina-1beta/genética , Masculino , Transtornos da Memória/induzido quimicamente , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/antagonistas & inibidores , Tolueno/administração & dosagem , Fator de Crescimento Transformador beta/genética
19.
Int Rev Neurobiol ; 150: 129-153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32204829

RESUMO

Stress alters both cognitive and emotional function, and increases risk for a variety of psychological disorders, such as depression and posttraumatic stress disorder. The prefrontal cortex is critical for executive function and emotion regulation, is a target for stress hormones, and is implicated in many stress-influenced psychological disorders. Therefore, understanding how stress-induced changes in the structure and function of the prefrontal cortex are related to stress-induced changes in behavior may elucidate some of the mechanisms contributing to stress-sensitive disorders. This review focuses on data from rodent models to describe the effects of chronic stress on behaviors mediated by the medial prefrontal cortex, the effects of chronic stress on the morphology and physiology of the medial prefrontal cortex, mechanisms that may mediate these effects, and evidence for sex differences in the effects of stress on the prefrontal cortex. Understanding how stress influences prefrontal cortex and behaviors mediated by it, as well as sex differences in this effect, will elucidate potential avenues for novel interventions for stress-sensitive disorders characterized by deficits in executive function and emotion regulation.


Assuntos
Comportamento Animal/fisiologia , Córtex Pré-Frontal/patologia , Córtex Pré-Frontal/fisiopatologia , Caracteres Sexuais , Estresse Psicológico/fisiopatologia , Animais
20.
Dalton Trans ; 49(14): 4559-4569, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32202264

RESUMO

Two tridentate ligand systems bearing N-heterocyclic carbene (NHC), amine and carboxylate donor groups coupled to benzothiazole- or stilbene-based amyloid binding moieties were synthesised. Reaction of the imidazolium salt containing pro-ligands with Re(CO)5Cl yielded the corresponding rhenium metal complexes which were characterised by NMR, and X-ray crystallography. These ligands are of interest for the potential preparation of technetium-99m imaging agents for Alzheimer's disease and the capacity of these rhenium complexes bind to amyloid fibrils composed of amyloid-ß peptide and amyloid plaques in human frontal cortex brain tissue was evaluated using fluorescence microscopy. These studies show that the complexes bound efficiently to amyloid-ß fibrils and some evidence of binding to amyloid-ß plaques.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/química , Complexos de Coordenação/química , Compostos de Organotecnécio/química , Aminas/química , Benzotiazóis/química , Sítios de Ligação , Ácidos Carboxílicos/química , Complexos de Coordenação/síntese química , Humanos , Ligantes , Estrutura Molecular , Compostos de Organotecnécio/síntese química , Córtex Pré-Frontal/patologia , Rênio/química , Estilbenos/química
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