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1.
Cell ; 187(20): 5679-5697.e23, 2024 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-39178853

RESUMO

Animals adapt to environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here, we find that thyroid hormone-a regulator of metabolism in many peripheral organs-directly activates cell-type-specific transcriptional programs in the frontal cortex of adult male mice. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulatory genes in both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread plasticity of cortical circuits. Indeed, whole-cell electrophysiology revealed that thyroid hormone alters excitatory and inhibitory synaptic transmission, an effect that requires thyroid hormone-induced gene regulatory programs in presynaptic neurons. Furthermore, thyroid hormone action in the frontal cortex regulates innate exploratory behaviors and causally promotes exploratory decision-making. Thus, thyroid hormone acts directly on the cerebral cortex in males to coordinate exploratory behaviors with whole-body metabolic state.


Assuntos
Hormônios Tireóideos , Animais , Masculino , Camundongos , Hormônios Tireóideos/metabolismo , Neurônios/metabolismo , Transmissão Sináptica , Córtex Cerebral/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Lobo Frontal/metabolismo , Lobo Frontal/efeitos dos fármacos , Astrócitos/metabolismo , Oligodendroglia/metabolismo
2.
Cell ; 186(6): 1179-1194.e15, 2023 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-36931245

RESUMO

The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24-THY1-/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1-/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA- bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.


Assuntos
Células-Tronco Neurais , Camundongos , Animais , Humanos , Células-Tronco Neurais/metabolismo , Neurônios , Diferenciação Celular/fisiologia , Neuroglia/metabolismo , Encéfalo , Astrócitos
3.
Cell ; 185(16): 2899-2917.e31, 2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35914528

RESUMO

Glioblastomas are incurable tumors infiltrating the brain. A subpopulation of glioblastoma cells forms a functional and therapy-resistant tumor cell network interconnected by tumor microtubes (TMs). Other subpopulations appear unconnected, and their biological role remains unclear. Here, we demonstrate that whole-brain colonization is fueled by glioblastoma cells that lack connections with other tumor cells and astrocytes yet receive synaptic input from neurons. This subpopulation corresponds to neuronal and neural-progenitor-like tumor cell states, as defined by single-cell transcriptomics, both in mouse models and in the human disease. Tumor cell invasion resembled neuronal migration mechanisms and adopted a Lévy-like movement pattern of probing the environment. Neuronal activity induced complex calcium signals in glioblastoma cells followed by the de novo formation of TMs and increased invasion speed. Collectively, superimposing molecular and functional single-cell data revealed that neuronal mechanisms govern glioblastoma cell invasion on multiple levels. This explains how glioblastoma's dissemination and cellular heterogeneity are closely interlinked.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Animais , Astrócitos/patologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Invasividade Neoplásica , Neurônios/fisiologia
4.
Cell ; 185(13): 2213-2233.e25, 2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35750033

RESUMO

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice. Population and isogenic models demonstrate that APOE4 local haplotype, rather than a single risk allele, contributes to risk. Global transcriptomic analyses reveal human-specific, APOE4-driven lipid metabolic dysregulation in astrocytes and microglia. APOE4 enhances de novo cholesterol synthesis despite elevated intracellular cholesterol due to lysosomal cholesterol sequestration in astrocytes. Further, matrisome dysregulation is associated with upregulated chemotaxis, glial activation, and lipid biosynthesis in astrocytes co-cultured with neurons, which recapitulates altered astrocyte matrisome signaling in human brain. Thus, APOE4 initiates glia-specific cell and non-cell autonomous dysregulation that may contribute to increased AD risk.


Assuntos
Doença de Alzheimer , Células-Tronco Pluripotentes Induzidas , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Animais , Apolipoproteína E3/genética , Apolipoproteína E3/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Astrócitos/metabolismo , Colesterol/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Microglia/metabolismo
5.
Nat Immunol ; 25(3): 432-447, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38409259

RESUMO

Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.


Assuntos
Astrócitos , Esclerose Múltipla , Animais , Humanos , Camundongos , Anti-Inflamatórios , Modelos Animais de Doenças , Epigênese Genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Inflamação , Proteômica
6.
Cell ; 184(19): 5053-5069.e23, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34390642

RESUMO

Genetic perturbations of cortical development can lead to neurodevelopmental disease, including autism spectrum disorder (ASD). To identify genomic regions crucial to corticogenesis, we mapped the activity of gene-regulatory elements generating a single-cell atlas of gene expression and chromatin accessibility both independently and jointly. This revealed waves of gene regulation by key transcription factors (TFs) across a nearly continuous differentiation trajectory, distinguished the expression programs of glial lineages, and identified lineage-determining TFs that exhibited strong correlation between linked gene-regulatory elements and expression levels. These highly connected genes adopted an active chromatin state in early differentiating cells, consistent with lineage commitment. Base-pair-resolution neural network models identified strong cell-type-specific enrichment of noncoding mutations predicted to be disruptive in a cohort of ASD individuals and identified frequently disrupted TF binding sites. This approach illustrates how cell-type-specific mapping can provide insights into the programs governing human development and disease.


Assuntos
Córtex Cerebral/embriologia , Cromatina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Análise de Célula Única , Astrócitos/citologia , Diferenciação Celular , Linhagem da Célula/genética , Análise por Conglomerados , Aprendizado Profundo , Epigênese Genética , Lógica Fuzzy , Glutamatos/metabolismo , Humanos , Mutação/genética , Neurônios/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética
7.
Cell ; 184(21): 5465-5481.e16, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34582787

RESUMO

In vivo cell fate conversions have emerged as potential regeneration-based therapeutics for injury and disease. Recent studies reported that ectopic expression or knockdown of certain factors can convert resident astrocytes into functional neurons with high efficiency, region specificity, and precise connectivity. However, using stringent lineage tracing in the mouse brain, we show that the presumed astrocyte-converted neurons are actually endogenous neurons. AAV-mediated co-expression of NEUROD1 and a reporter specifically and efficiently induces reporter-labeled neurons. However, these neurons cannot be traced retrospectively to quiescent or reactive astrocytes using lineage-mapping strategies. Instead, through a retrograde labeling approach, our results reveal that endogenous neurons are the source for these viral-reporter-labeled neurons. Similarly, despite efficient knockdown of PTBP1 in vivo, genetically traced resident astrocytes were not converted into neurons. Together, our results highlight the requirement of lineage-tracing strategies, which should be broadly applied to studies of cell fate conversions in vivo.


Assuntos
Astrócitos/citologia , Diferenciação Celular , Linhagem da Célula , Neurônios/citologia , Animais , Astrócitos/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Encéfalo/patologia , Lesões Encefálicas/patologia , Linhagem Celular Tumoral , Reprogramação Celular , Dependovirus/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica , Genes Reporter , Proteína Glial Fibrilar Ácida/genética , Ribonucleoproteínas Nucleares Heterogêneas/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Integrases/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo
8.
Cell ; 184(3): 709-722.e13, 2021 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-33482084

RESUMO

Neural stem cells (NSCs) in the adult brain transit from the quiescent state to proliferation to produce new neurons. The mechanisms regulating this transition in freely behaving animals are, however, poorly understood. We customized in vivo imaging protocols to follow NSCs for several days up to months, observing their activation kinetics in freely behaving mice. Strikingly, NSC division is more frequent during daylight and is inhibited by darkness-induced melatonin signaling. The inhibition of melatonin receptors affected intracellular Ca2+ dynamics and promoted NSC activation. We further discovered a Ca2+ signature of quiescent versus activated NSCs and showed that several microenvironmental signals converge on intracellular Ca2+ pathways to regulate NSC quiescence and activation. In vivo NSC-specific optogenetic modulation of Ca2+ fluxes to mimic quiescent-state-like Ca2+ dynamics in freely behaving mice blocked NSC activation and maintained their quiescence, pointing to the regulatory mechanisms mediating NSC activation in freely behaving animals.


Assuntos
Células-Tronco Adultas/metabolismo , Cálcio/metabolismo , Ritmo Circadiano , Espaço Intracelular/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Comportamento Animal/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Citosol/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Melatonina/metabolismo , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Optogenética , Transdução de Sinais/efeitos dos fármacos , Triptaminas/farmacologia
9.
Cell ; 183(6): 1617-1633.e22, 2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33259802

RESUMO

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Assuntos
Neoplasias Encefálicas/genética , Carcinogênese/genética , Glioma/genética , Histonas/genética , Interneurônios/metabolismo , Mutação/genética , Células-Tronco Neurais/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Neoplasias Encefálicas/patologia , Carcinogênese/patologia , Linhagem da Célula , Reprogramação Celular/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Glioma/patologia , Histonas/metabolismo , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Modelos Biológicos , Gradação de Tumores , Oligodendroglia/metabolismo , Regiões Promotoras Genéticas/genética , Prosencéfalo/embriologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transcrição Gênica , Transcriptoma/genética
10.
Cell ; 181(4): 784-799.e19, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32413299

RESUMO

Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies.


Assuntos
Aquaporina 4/metabolismo , Edema/metabolismo , Edema/terapia , Animais , Aquaporina 4/fisiologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Edema Encefálico/metabolismo , Calmodulina/metabolismo , Sistema Nervoso Central/metabolismo , Edema/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Trifluoperazina/farmacologia
11.
Cell ; 180(3): 502-520.e19, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31983537

RESUMO

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.


Assuntos
Astrócitos/metabolismo , Carcinogênese/metabolismo , Transdiferenciação Celular , Neoplasias Cerebelares/metabolismo , Meduloblastoma/metabolismo , Comunicação Parácrina , Animais , Linhagem da Célula , Neoplasias Cerebelares/patologia , Modelos Animais de Doenças , Feminino , Proteínas Hedgehog/metabolismo , Xenoenxertos , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Microambiente Tumoral
12.
Nat Immunol ; 23(6): 878-891, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35618831

RESUMO

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.


Assuntos
Astrócitos , Produtos Biológicos , Animais , Encéfalo , Humanos , Interleucina-2/genética , Interleucinas , Camundongos , Doenças Neuroinflamatórias , Linfócitos T Reguladores
13.
Cell ; 176(3): 416-418, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30682369

RESUMO

By in vivo screening in zebrafish larvae, Wheeler et al. identify environmental agents that directly modulate transcriptional programs of astrocytes. The herbicide linuron exploits the unfolded protein response pathway to induce a pro-inflammatory program in reactive astrocytes that potentiates inflammatory tissue damage in the CNS.


Assuntos
Astrócitos , Sinais (Psicologia) , Animais , Inflamação , Peixe-Zebra
14.
Cell ; 177(5): 1091-1093, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31100265

RESUMO

Are neurons solely responsible for determining behavioral output, or can other brain cells modulate behavior? In this issue of Cell, Nagai et al. demonstrate that striatal astrocytes, through GABAB receptor signaling, regulate behaviors including hyperactivity and attention by inducing new synapse formation between neurons.


Assuntos
Astrócitos , Sinais (Psicologia) , Atenção , Neurônios , Receptores de GABA-B
15.
Cell ; 177(6): 1522-1535.e14, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31130380

RESUMO

Metabolic coordination between neurons and astrocytes is critical for the health of the brain. However, neuron-astrocyte coupling of lipid metabolism, particularly in response to neural activity, remains largely uncharacterized. Here, we demonstrate that toxic fatty acids (FAs) produced in hyperactive neurons are transferred to astrocytic lipid droplets by ApoE-positive lipid particles. Astrocytes consume the FAs stored in lipid droplets via mitochondrial ß-oxidation in response to neuronal activity and turn on a detoxification gene expression program. Our findings reveal that FA metabolism is coupled in neurons and astrocytes to protect neurons from FA toxicity during periods of enhanced activity. This coordinated mechanism for metabolizing FAs could underlie both homeostasis and a variety of disease states of the brain.


Assuntos
Astrócitos/metabolismo , Ácidos Graxos/metabolismo , Neurônios/metabolismo , Animais , Apolipoproteínas E/metabolismo , Apolipoproteínas E/fisiologia , Astrócitos/fisiologia , Encéfalo/metabolismo , Ácidos Graxos/toxicidade , Homeostase , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução , Ratos , Ratos Sprague-Dawley
16.
Cell ; 179(7): 1483-1498.e22, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31813625

RESUMO

Metabolism has been shown to control peripheral immunity, but little is known about its role in central nervous system (CNS) inflammation. Through a combination of proteomic, metabolomic, transcriptomic, and perturbation studies, we found that sphingolipid metabolism in astrocytes triggers the interaction of the C2 domain in cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrial antiviral signaling protein (MAVS), boosting NF-κB-driven transcriptional programs that promote CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitment to MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HK enzymatic activity and the production of lactate involved in the metabolic support of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pick disease, suppresses astrocyte pathogenic activities and ameliorates EAE. Collectively, these findings define a novel immunometabolic mechanism that drives pro-inflammatory astrocyte activities, outlines a new role for MAVS in CNS inflammation, and identifies candidate targets for therapeutic intervention.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Fosfolipases A2 Secretórias/metabolismo , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/farmacologia , 1-Desoxinojirimicina/uso terapêutico , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Hexoquinase/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Fosfolipases A2 Secretórias/genética
17.
Cell ; 177(5): 1280-1292.e20, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31031006

RESUMO

Hyperactivity and disturbances of attention are common behavioral disorders whose underlying cellular and neural circuit causes are not understood. We report the discovery that striatal astrocytes drive such phenotypes through a hitherto unknown synaptic mechanism. We found that striatal medium spiny neurons (MSNs) triggered astrocyte signaling via γ-aminobutyric acid B (GABAB) receptors. Selective chemogenetic activation of this pathway in striatal astrocytes in vivo resulted in acute behavioral hyperactivity and disrupted attention. Such responses also resulted in upregulation of the synaptogenic cue thrombospondin-1 (TSP1) in astrocytes, increased excitatory synapses, enhanced corticostriatal synaptic transmission, and increased MSN action potential firing in vivo. All of these changes were reversed by blocking TSP1 effects. Our data identify a form of bidirectional neuron-astrocyte communication and demonstrate that acute reactivation of a single latent astrocyte synaptogenic cue alters striatal circuits controlling behavior, revealing astrocytes and the TSP1 pathway as therapeutic targets in hyperactivity, attention deficit, and related psychiatric disorders.


Assuntos
Astrócitos/metabolismo , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Comportamento Animal , Comunicação Celular , Neurônios/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Animais , Astrócitos/patologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Sinapses/genética , Trombospondina 1/genética , Trombospondina 1/metabolismo , Ácido gama-Aminobutírico/genética , Ácido gama-Aminobutírico/metabolismo
18.
Cell ; 178(1): 27-43.e19, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31230713

RESUMO

When a behavior repeatedly fails to achieve its goal, animals often give up and become passive, which can be strategic for preserving energy or regrouping between attempts. It is unknown how the brain identifies behavioral failures and mediates this behavioral-state switch. In larval zebrafish swimming in virtual reality, visual feedback can be withheld so that swim attempts fail to trigger expected visual flow. After tens of seconds of such motor futility, animals became passive for similar durations. Whole-brain calcium imaging revealed noradrenergic neurons that responded specifically to failed swim attempts and radial astrocytes whose calcium levels accumulated with increasing numbers of failed attempts. Using cell ablation and optogenetic or chemogenetic activation, we found that noradrenergic neurons progressively activated brainstem radial astrocytes, which then suppressed swimming. Thus, radial astrocytes perform a computation critical for behavior: they accumulate evidence that current actions are ineffective and consequently drive changes in behavioral states. VIDEO ABSTRACT.


Assuntos
Astrócitos/metabolismo , Comportamento Animal/fisiologia , Larva/fisiologia , Peixe-Zebra/fisiologia , Neurônios Adrenérgicos/metabolismo , Animais , Animais Geneticamente Modificados/fisiologia , Astrócitos/citologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Mapeamento Encefálico , Cálcio/metabolismo , Comunicação Celular/fisiologia , Retroalimentação Sensorial/fisiologia , Neurônios GABAérgicos/metabolismo , Potenciais da Membrana/fisiologia , Optogenética , Natação/fisiologia
19.
Cell ; 176(3): 581-596.e18, 2019 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-30661753

RESUMO

Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.


Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Animais , Sistema Nervoso Central/imunologia , Biologia Computacional/métodos , Encefalomielite Autoimune Experimental/imunologia , Endorribonucleases/metabolismo , Meio Ambiente , Exposição Ambiental/efeitos adversos , Genoma , Genômica , Humanos , Inflamação/metabolismo , Linurona/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Receptores sigma/efeitos dos fármacos , Receptores sigma/metabolismo , Transdução de Sinais , Proteína 1 de Ligação a X-Box/metabolismo , Peixe-Zebra
20.
Immunity ; 57(5): 938-940, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38749396

RESUMO

Astrocytes respond to all forms of central nervous system maladies. In a recent issue of Nature, Lee et al. demonstrate that astrocytes encode inflammatory stimuli as epigenetic memory, which strengthens responses to subsequent stimuli and exacerbates pathology in disease models.


Assuntos
Astrócitos , Inflamação , Astrócitos/imunologia , Inflamação/imunologia , Humanos , Animais , Epigênese Genética
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