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1.
Brain Res ; 1723: 146425, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31473223

RESUMO

Cocaine and ethanol are two commonly co-abused substances; however, the neuropathology following chronic dual consumption is poorly understood. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that are integral to brain maintenance and repair making them an appealing target to reverse neurodegeneration associated with abused substances. Yet, knowledge about NSC response to chronic poly-drug administration of ethanol and cocaine is minimal. Here, we developed a novel chronic poly-drug administration paradigm of ethanol and cocaine using a transgenic mouse model to trace endogenous NSC survival and differentiation in three brain regions from both male and female mice. We report significant and distinct patterns of NSC survival and differentiation among brain regions, as well as between sexes. Additionally, poly-drug administration had synergistic effects on NSC survival. Altered cognitive and hedonic behaviors were also observed, however the extent of these behavioral changes was not proportional to the NSC changes. With this mouse model we can effectively examine cognitive and behavioral changes and correlate them with pathological changes in the brain in response to chronic poly-drug administration, which is of great value in understanding the progression of neurodegeneration in polysubstance use disorders and evaluation potential therapeutics on neuroregeneration.


Assuntos
Cocaína/efeitos adversos , Etanol/efeitos adversos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Adultas/efeitos dos fármacos , Fatores Etários , Animais , Encéfalo/patologia , Diferenciação Celular/efeitos dos fármacos , Cocaína/metabolismo , Cocaína/farmacologia , Modelos Animais de Doenças , Etanol/metabolismo , Etanol/farmacologia , Feminino , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regeneração Nervosa/efeitos dos fármacos , Neurogênese/fisiologia , Fatores Sexuais
2.
Neurochem Int ; 120: 21-32, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30041015

RESUMO

Human neural stem cells (hNSCs) can differentiate into an oligodendrocyte lineage to facilitate remyelination in patients. Molecular mechanisms underlying oligodendrocyte fate specification remains unknown, hindering the development of efficient methods to generate oligodendrocytes from hNSCs. We have found that Neurobasal-A medium (NB) is capable of inducing hNSCs to oligodendrocyte progenitor cells (OPCs). We identified several signaling molecules are altered after cultivation in NB medium, including Akt, ERK1/2 and c-Src. While sustained activation of Akt and ERK1/2 during both NB induction and subsequent differentiation was required for OPC differentiation, c-Src phosphorylation was increased temporally during the period of NB induction. Both pharmacological inhibition and RNA interference confirmed that a transient elevation of phospho-c-Src is critical for OPC induction. Furthermore, inactivation of c-Src inhibited phosphorylation of Akt and ERK1/2. In summary, we identified a novel and critical role of c-Src in guiding hNSC differentiation to an oligodendrocyte lineage.


Assuntos
Diferenciação Celular/fisiologia , Células-Tronco Neurais/citologia , Oligodendroglia/citologia , Quinases da Família src/metabolismo , Proteína Tirosina Quinase CSK , Linhagem da Célula/fisiologia , Humanos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Bainha de Mielina/metabolismo , Neurogênese/fisiologia
3.
J Vis Exp ; (132)2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29443111

RESUMO

Human fetal brain neural stem cells are a unique non-genetically modified model system to study the impact of various stimuli on human developmental neurobiology. Rather than use an animal model or genetically modified induced pluripotent cells, human neural stem cells provide an effective in vitro system to examine the effects of treatments, screen drugs, or examine individual differences. Here, we provide the detailed protocols for methods used to expand human fetal brain neural stem cells in culture with serum-free media, to differentiate them into various neuronal subtypes and astrocytes via different priming procedures, and to freeze and recover these cells. Furthermore, we describe a procedure of using human fetal brain neural stem cells to study Zika virus infection.


Assuntos
Imuno-Histoquímica/métodos , Células-Tronco Neurais/metabolismo , Infecção por Zika virus/imunologia , Zika virus/patogenicidade , Animais , Diferenciação Celular , Humanos , Células-Tronco Neurais/citologia
4.
Stem Cell Reports ; 9(6): 1916-1930, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29129682

RESUMO

Chronic alcohol abuse results in alcohol-related neurodegeneration, and critical gaps in our knowledge hinder therapeutic development. Neural stem cells (NSCs) are a subpopulation of cells within the adult brain that contribute to brain maintenance and recovery. While it is known that alcohol alters NSCs, little is known about how NSC response to alcohol is related to sex, brain region, and stage of differentiation. Understanding these relationships will aid in therapeutic development. Here, we used an inducible transgenic mouse model to track the stages of differentiation of adult endogenous NSCs and observed distinct NSC behaviors in three brain regions (subventricular zone, subgranular zone, and tanycyte layer) after long-term alcohol consumption. Particularly, chronic alcohol consumption profoundly affected the survival of NSCs in the subventricular zone and altered NSC differentiation in all three regions. Significant differences between male and female mice were further discovered.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Ventrículos Laterais/fisiopatologia , Degeneração Neural/fisiopatologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Adultas/efeitos dos fármacos , Consumo de Bebidas Alcoólicas/genética , Álcoois/toxicidade , Animais , Mapeamento Encefálico , Diferenciação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Ventrículos Laterais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Degeneração Neural/induzido quimicamente , Degeneração Neural/genética , Células-Tronco Neurais/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia
5.
Stem Cell Reports ; 8(3): 715-727, 2017 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-28216147

RESUMO

Zika virus (ZIKV) infection causes microcephaly in a subset of infants born to infected pregnant mothers. It is unknown whether human individual differences contribute to differential susceptibility of ZIKV-related neuropathology. Here, we use an Asian-lineage ZIKV strain, isolated from the 2015 Mexican outbreak (Mex1-7), to infect primary human neural stem cells (hNSCs) originally derived from three individual fetal brains. All three strains of hNSCs exhibited similar rates of Mex1-7 infection and reduced proliferation. However, Mex1-7 decreased neuronal differentiation in only two of the three stem cell strains. Correspondingly, ZIKA-mediated transcriptome alterations were similar in these two strains but significantly different from that of the third strain with no ZIKV-induced neuronal reduction. This study thus confirms that an Asian-lineage ZIKV strain infects primary hNSCs and demonstrates a cell-strain-dependent response of hNSCs to ZIKV infection.


Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/virologia , Infecção por Zika virus/virologia , Zika virus/fisiologia , Animais , Astrócitos , Encéfalo/imunologia , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Chlorocebus aethiops , Análise por Conglomerados , Feto , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Masculino , Camundongos , Células-Tronco Neurais/citologia , Neurogênese/genética , Neurônios , Transcriptoma , Células Vero , Zika virus/classificação , Infecção por Zika virus/genética , Infecção por Zika virus/imunologia , Infecção por Zika virus/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-36438593

RESUMO

Zika virus is a flavivirus known to cause microcephaly during development. The mechanism underlying Zika virus-induced neuropathogenesis is still poorly understood. Recent studies have utilized the cutting edge cell culture and animal model technologies to elucidate factors contributing to Zika virus-associated microcephaly. While future work is needed, current studies have suggested three main factors that contribute to Zika virus pathology: viral lineage, host immunity, and pregnancy stages. This mini review will focus on some of the recent findings that advanced our knowledge in Zika virus-associated microcephaly.

7.
Behav Brain Res ; 322(Pt B): 212-222, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-27765672

RESUMO

A major aspect of mammalian aging is the decline in functional competence of many self-renewing cell types, including adult-born neuronal precursors. Since age-related senescence of self-renewal occurs simultaneously with chronic up-regulation of the p38MAPKalpha (p38α) signaling pathway, we used the dominant negative mouse model for attenuated p38α activity (DN-p38αAF/+) in which Thr180 and Tyr182 are mutated (T→A/Y→F) to prevent phosphorylation activation (DN-p38αAF/+) and kinase activity. As a result, aged DN-p38αAF/+ mice are resistant to age-dependent decline in proliferation and regeneration of several peripheral tissue progenitors when compared to wild-type littermates. Aging is the major risk factor for non-inherited forms of Alzheimer's disease (AD); environmental and genetic risk factors that accelerate the senescence phenotype are thought to contribute to an individual's relative risk. In the present study, we evaluated aged DN-p38αAF/+ and wildtype littermates in a series of behavioral paradigms to test if p38α mutant mice exhibit altered baseline abnormalities in neurological reflexes, locomotion, anxiety-like behavior, and age-dependent cognitive decline. While aged DN-p38αAF/+ and wildtype littermates appear equal in all tested baseline neurological and behavioral parameters, DN-p38αAF/+ exhibit superior context discrimination fear conditioning. Context discrimination is a cognitive task that is supported by proliferation and differentiation of adult-born neurons in the dentate gyrus of the hippocampus. Consistent with enhanced context discrimination in aged DN-p38αAF/+, we discovered enhanced production of adult-born neurons in the dentate gyrus of DN-p38αAF/+ mice compared to wildtype littermates. Our findings support the notion that p38α inhibition has therapeutic utility in aging diseases that affect cognition, such as AD.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/psicologia , Discriminação Psicológica/fisiologia , Medo/fisiologia , Proteína Quinase 14 Ativada por Mitógeno/deficiência , Neurogênese/fisiologia , Envelhecimento/patologia , Análise de Variância , Animais , Ansiedade/enzimologia , Ansiedade/patologia , Condicionamento Psicológico/fisiologia , Eletrochoque , Comportamento Exploratório/fisiologia , Medo/psicologia , Feminino , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/enzimologia , Hipocampo/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Quinase 14 Ativada por Mitógeno/genética , Neurônios/enzimologia , Neurônios/patologia , Testes Psicológicos
8.
Cell Host Microbe ; 20(2): 259-70, 2016 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-27476412

RESUMO

Currently there are no approved vaccines or specific therapies to prevent or treat Zika virus (ZIKV) infection. We interrogated a library of FDA-approved drugs for their ability to block infection of human HuH-7 cells by a newly isolated ZIKV strain (ZIKV MEX_I_7). More than 20 out of 774 tested compounds decreased ZIKV infection in our in vitro screening assay. Selected compounds were further validated for inhibition of ZIKV infection in human cervical, placental, and neural stem cell lines, as well as primary human amnion cells. Established anti-flaviviral drugs (e.g., bortezomib and mycophenolic acid) and others that had no previously known antiviral activity (e.g., daptomycin) were identified as inhibitors of ZIKV infection. Several drugs reduced ZIKV infection across multiple cell types. This study identifies drugs that could be tested in clinical studies of ZIKV infection and provides a resource of small molecules to study ZIKV pathogenesis.


Assuntos
Antivirais/isolamento & purificação , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Zika virus/efeitos dos fármacos , Células Cultivadas , Humanos , Zika virus/crescimento & desenvolvimento
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