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1.
Environ Health Perspect ; 128(1): 17011, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31939705

RESUMO

BACKGROUND: Pesticide residues have contaminated our environment and nutrition over the last century. Although these compounds are present at very low concentrations, their long-term effects on human health is of concern. The link between pesticide residues and Alzheimer's disease is not clear and difficult to establish. To date, no in vivo experiments have yet modeled the impact of this chronic contamination on neurodegenerative disorders. OBJECTIVES: We investigated the impact of fungicide residues on the pathological markers of Alzheimer's disease in a transgenic mouse model. METHODS: Transgenic (J20, hAPPSw/Ind) mice were chronically exposed to a cocktail of residues of cyprodinil, mepanipyrim, and pyrimethanil at 0.1µg/L in their drinking water for 9 months. We assessed the effects of fungicide residues on the pathological markers of the disease including Aß aggregates, neuroinflammation, and neuronal loss. Then, we studied the dynamics of Aß aggregation in vivo via a longitudinal study using two-photon microscopy. Finally, we investigated the molecular mechanisms involved in the production and clearance of Aß peptides. RESULTS: We found that a chronic exposure to three fungicide residues exacerbated aggregation, microgliosis, and neuronal loss. These fungicides also increased vascular amyloid aggregates reminiscent of cerebral amyloid angiopathy between 6 and 9 months of treatment. The mechanism of action revealed that fungicides promoted Aß peptide fibril formation in vitro and involved an in vivo overexpression of the levels of the ß-secretase-cleaving enzyme (BACE1) combined with impairment of Aß clearance through neprylisin (NEP). CONCLUSIONS: Chronic exposure of the J20 mouse model of Alzheimer's disease to a cocktail of fungicides, at the regulatory concentration allowed in tap water (0.1µg/L), strengthened the preexisting pathological markers: neuroinflammation, Aß aggregation, and APP ß-processing. We hypothesize prevention strategies toward pesticide long-term exposure may be an alternative to counterbalance the lack of treatment and to slow down the worldwide Alzheimer's epidemic. https://doi.org/10.1289/EHP5550.

2.
Proc Natl Acad Sci U S A ; 116(26): 13097-13106, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31182610

RESUMO

Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone-activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is not fully understood. Here, we show that deletion of the neurotrophin brain-derived neurotrophic factor (BDNF)-dependent GR-phosphorylation (PO4) sites impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor subunit A1 (GluA1) mediated by GR-PO4 Together, these findings indicate that regulation of GR-PO4 via activity-dependent BDNF signaling is important for the formation and maintenance of learning-dependent synapses. They also define a signaling mechanism underlying these effects.

3.
Hippocampus ; 29(5): 422-439, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-28888073

RESUMO

Hippocampal CA1 pyramidal neurons, a major component of the medial temporal lobe memory circuit, are selectively vulnerable during the progression of Alzheimer's disease (AD). The cellular mechanism(s) underlying degeneration of these neurons and the relationship to cognitive performance remains largely undefined. Here, we profiled neurotrophin and neurotrophin receptor gene expression within microdissected CA1 neurons along with regional hippocampal dissections from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or AD using laser capture microdissection (LCM), custom-designed microarray analysis, and qPCR of CA1 subregional dissections. Gene expression levels were correlated with cognitive test scores and AD neuropathology criteria. We found a significant downregulation of several neurotrophin genes (e.g., Gdnf, Ngfb, and Ntf4) in CA1 pyramidal neurons in MCI compared to NCI and AD subjects. In addition, the neurotrophin receptor transcripts TrkB and TrkC were decreased in MCI and AD compared to NCI. Regional hippocampal dissections also revealed select neurotrophic gene dysfunction providing evidence for vulnerability within the hippocampus proper during the progression of dementia. Downregulation of several neurotrophins of the NGF family and cognate neurotrophin receptor (TrkA, TrkB, and TrkC) genes correlated with antemortem cognitive measures including the Mini-Mental State Exam (MMSE), a composite global cognitive score (GCS), and Episodic, Semantic, and Working Memory, Perceptual Speed, and Visuospatial domains. Significant correlations were found between select neurotrophic expression downregulation and neuritic plaques (NPs) and neurofibrillary tangles (NFTs), but not diffuse plaques (DPs). These data suggest that dysfunction of neurotrophin signaling complexes have profound negative sequelae within vulnerable hippocampal cell types, which play a role in mnemonic and executive dysfunction during the progression of AD.

4.
Neuroendocrinology ; 109(3): 277-284, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30572337

RESUMO

Behavioral choices made by the brain during stress depend on glucocorticoid and brain-derived neurotrophic factor (BDNF) signaling pathways acting in synchrony in the mesolimbic (reward) and corticolimbic (emotion) neural networks. Deregulated expression of BDNF and glucocorticoid receptors in brain valuation areas may compromise the integration of signals. Glucocorticoid receptor phosphorylation upon BDNF signaling in neurons represents one mechanism underlying the integration of BDNF and glucocorticoid signals that when off balance may lay the foundation of maladaptations to stress. Here, we propose that BDNF signaling conditions glucocorticoid responses impacting neural plasticity in the mesocorticolimbic system. This provides a novel molecular framework for understanding how brain networks use BDNF and glucocorticoid signaling contingencies to forge receptive neuronal fields in temporal domains defined by behavioral experience, and in mood disorders.

5.
Cell Rep ; 23(4): 1045-1059, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29694884

RESUMO

Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked the in vivo dynamics of perivascular mural cells as a function of electroencephalogram (EEG) activity following status epilepticus. We segmented the cortical vascular bed to provide a size- and type-specific analysis of mural cell plasticity topologically. We find that mural cells are added and removed from veins, arterioles, and capillaries after seizure induction. Loss of mural cells is proportional to seizure severity and vascular pathology (e.g., rigidity, perfusion, and permeability). Treatment with platelet-derived growth factor subunits BB (PDGF-BB) reduced mural cell loss, vascular pathology, and epileptiform EEG activity. We propose that perivascular mural cells play a pivotal role in seizures and are potential targets for reducing pathophysiology.


Assuntos
Becaplermina/metabolismo , Permeabilidade Capilar , Artérias Cerebrais , Veias Cerebrais , Estado Epiléptico , Animais , Becaplermina/genética , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Artérias Cerebrais/fisiopatologia , Veias Cerebrais/metabolismo , Veias Cerebrais/patologia , Veias Cerebrais/fisiopatologia , Eletroencefalografia , Camundongos , Camundongos Transgênicos , Estado Epiléptico/genética , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia
6.
J Neurosci ; 38(6): 1335-1350, 2018 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-29295823

RESUMO

The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacity to handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronal genes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry is vulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress. Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes, we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number in PFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling, AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role in the regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, and knockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFC tissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitive impairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria and synaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions, constituting a pathological feature across disorders.SIGNIFICANCE STATEMENT The bioenergetic cost of chronic stress is too high to be sustainable by pyramidal prefrontal neurons. Cellular checkpoints have evolved to adjust the responses of mitochondria and synapses to the buildup of chronic stress. NR4A1 plays such a role by controlling the energetic competence of mitochondria with respect to synapse number. As an immediate-early gene, Nr4a1 promotes neuronal plasticity, but sustained expression or activity can be detrimental. NR4A1 expression and activity is sustained by chronic stress in animal models and in human studies of neuropathologies sensitive to the buildup of chronic stress. Therefore, antagonism of NR4A1 is a promising avenue for preventing the regressive synaptic reorganization in cortical systems in the context of chronic stress.


Assuntos
Mitocôndrias/metabolismo , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Córtex Pré-Frontal/fisiopatologia , Estresse Psicológico/fisiopatologia , Sinapses/metabolismo , Idoso , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Contagem de Células , Doença Crônica , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Espinhas Dendríticas , Feminino , Regulação da Expressão Gênica/genética , Elevação dos Membros Posteriores , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasticidade Neuronal/genética , Córtex Pré-Frontal/citologia , Células Piramidais/fisiologia , Ratos , Estresse Psicológico/psicologia
7.
F1000Res ; 6: 1208, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28781762

RESUMO

Glucocorticoids via the glucocorticoid receptor (GR) have effects on a variety of cell types, eliciting important physiological responses via changes in gene expression and signaling. Although decades of research have illuminated the mechanism of how this important steroid receptor controls gene expression using in vitro and cell culture-based approaches, how GR responds to changes in external signals in vivo under normal and pathological conditions remains elusive. The goal of this review is to highlight recent work on GR action in fat cells and liver to affect metabolism in vivo and the role GR ligands and receptor phosphorylation play in calibrating signaling outputs by GR in the brain in health and disease. We also suggest that both the brain and fat tissue communicate to affect physiology and behavior and that understanding this "brain-fat axis" will enable a more complete understanding of metabolic diseases and inform new ways to target them.

8.
Sci Rep ; 6: 37231, 2016 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-27849045

RESUMO

Glucocorticoid resistance is a risk factor for Alzheimer's disease (AD). Molecular and cellular mechanisms of glucocorticoid resistance in the brain have remained unknown and are potential therapeutic targets. Phosphorylation of glucocorticoid receptors (GR) by brain-derived neurotrophic factor (BDNF) signaling integrates both pathways for remodeling synaptic structure and plasticity. The goal of this study is to test the role of the BDNF-dependent pathway on glucocorticoid signaling in a mouse model of glucocorticoid resistance. We report that deletion of GR phosphorylation at BDNF-responding sites and downstream signaling via the MAPK-phosphatase DUSP1 triggers tau phosphorylation and dendritic spine atrophy in mouse cortex. In human cortex, DUSP1 protein expression correlates with tau phosphorylation, synaptic defects and cognitive decline in subjects diagnosed with AD. These findings provide evidence for a causal role of BDNF-dependent GR signaling in tau neuropathology and indicate that DUSP1 is a potential target for therapeutic interventions.


Assuntos
Fatores de Crescimento Neural/genética , Interferência de RNA , Receptores de Glucocorticoides/genética , Transdução de Sinais/genética , Tauopatias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Células Cultivadas , Córtex Cerebral/metabolismo , Espinhas Dendríticas/metabolismo , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Feminino , Glucocorticoides/farmacologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Fatores de Crescimento Neural/metabolismo , Fosforilação/efeitos dos fármacos , Gravidez , Receptores de Glucocorticoides/metabolismo , Tauopatias/metabolismo
9.
Pharmacol Res ; 113(Pt A): 1-17, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27498156

RESUMO

Glucocorticoid actions are tailored to the organs and cells responding thanks to complex integration with ongoing signaling mediated by cytokines, hormones, neurotransmitters, and growth factors. Disruption of: (1) the amount of signaling molecules available locally; (2) the timing with other signaling pathways; (3) the post-translational modifications on glucocorticoid receptors; and (4) the receptors-interacting proteins within cellular organelles and functional compartments, can modify the sensitivity and efficacy of glucocorticoid responses with implications in physiology, diseases and treatments. Tissue sensitivity to glucocorticoids is sustained by multiple systems that do not operate in isolation. We take the example of the interplay between the glucocorticoid and brain-derived neurotrophic factor signaling pathways to deconstruct context-dependent glucocorticoid responses that play key roles in physiology, diseases and therapies.


Assuntos
Citocinas/metabolismo , Glucocorticoides/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neurotransmissores/metabolismo , Transdução de Sinais/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Humanos , Processamento de Proteína Pós-Traducional/fisiologia , Receptores de Glucocorticoides/metabolismo
10.
Neural Plast ; 2016: 3985063, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26885402

RESUMO

The brain evolved cellular mechanisms for adapting synaptic function to energy supply. This is particularly evident when homeostasis is challenged by stress. Signaling loops between the mitochondria and synapses scale neuronal connectivity with bioenergetics capacity. A biphasic "inverted U shape" response to the stress hormone glucocorticoids is demonstrated in mitochondria and at synapses, modulating neural plasticity and physiological responses. Low dose enhances neurotransmission, synaptic growth, mitochondrial functions, learning, and memory whereas chronic, higher doses produce inhibition of these functions. The range of physiological effects by stress and glucocorticoid depends on the dose, duration, and context at exposure. These criteria are met by neuronal activity and the circadian, stress-sensitive and ultradian, stress-insensitive modes of glucocorticoid secretion. A major hallmark of stress-related neuropsychiatric disorders is the disrupted glucocorticoid rhythms and tissue resistance to signaling with the glucocorticoid receptor (GR). GR resistance could result from the loss of context-dependent glucocorticoid signaling mediated by the downregulation of the activity-dependent neurotrophin BDNF. The coincidence of BDNF and GR signaling changes glucocorticoid signaling output with consequences on mitochondrial respiration efficiency, synaptic plasticity, and adaptive trajectories.


Assuntos
Transtornos Mentais/metabolismo , Estresse Psicológico/metabolismo , Encéfalo/metabolismo , Humanos , Mitocôndrias , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Sinapses/metabolismo
11.
Mol Cell Biol ; 36(6): 1019-31, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26787837

RESUMO

Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Palmitatos/metabolismo , Receptores de Dopamina D3/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/genética , Membrana Celular/metabolismo , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Mutação , Ligação Proteica , Mapas de Interação de Proteínas , Transporte Proteico , Receptores de Dopamina D3/análise , Receptores de Dopamina D3/genética , Transdução de Sinais
12.
Neurobiol Dis ; 88: 107-17, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26774030

RESUMO

Clinical and experimental evidence point to a possible role of cerebrovascular dysfunction in Alzheimer's disease (AD). The 5xFAD mouse model of AD expresses human amyloid precursor protein and presenilin genes with mutations found in AD patients. It remains unknown whether amyloid deposition driven by these mutations is associated with cerebrovascular changes. 5xFAD and wild type mice (2 to 12months old; M2 to M12) were used. Thinned skull in vivo 2-photon microscopy was used to determine Aß accumulation on leptomeningeal or superficial cortical vessels over time. Parenchymal microvascular damage was assessed using FITC-microangiography. Collagen-IV and CD31 were used to stain basal lamina and endothelial cells. Methoxy-XO4, Thioflavin-S or 6E10 were used to visualize Aß accumulation in living mice or in fixed brain tissues. Positioning of reactive IBA1 microglia and GFAP astrocytes at the vasculature was rendered using confocal microscopy. Platelet-derived growth factor receptor beta (PDGFRß) staining was used to visualize perivascular pericytes. In vivo 2-photon microscopy revealed Methoxy-XO4(+) amyloid perivascular deposits on leptomeningeal and penetrating cortical vessels in 5xFAD mice, typical of cerebral amyloid angiopathy (CAA). Amyloid deposits were visible in vivo at M3 and aggravated over time. Progressive microvascular damage was concomitant to parenchymal Aß plaque accumulation in 5xFAD mice. Microvascular inflammation in 5xFAD mice presented with sporadic FITC-albumin leakages at M4 becoming more prevalent at M9 and M12. 3D colocalization showed inflammatory IBA1(+) microglia proximal to microvascular FITC-albumin leaks. The number of perivascular PDGFRß(+) pericytes was significantly decreased at M4 in the fronto-parietal cortices, with a trend decrease observed in the other structures. At M9-M12, PDGFRß(+) pericytes displayed hypertrophic perivascular ramifications contiguous to reactive microglia. Cerebral amyloid angiopathy and microvascular inflammation occur in 5xFAD mice concomitantly to parenchymal plaque deposition. The prospect of cerebrovascular pharmacology in AD is discussed.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Vasos Sanguíneos/patologia , Circulação Cerebrovascular/genética , Fatores Etários , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Colágeno Tipo IV/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Mutação/genética , Pericitos/metabolismo , Pericitos/patologia , Placa Amiloide/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas , Presenilina-1/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo
13.
J Vis Exp ; (118)2016 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-28060355

RESUMO

Remodeling of the brain vasculature is a common trait of brain pathologies. In vivo imaging techniques are fundamental to detect cerebrovascular plasticity or damage occurring overtime and in relation to neuronal activity or blood flow. In vivo two-photon microscopy allows the study of the structural and functional plasticity of large cellular units in the living brain. In particular, the thinned-skull window preparation allows the visualization of cortical regions of interest (ROI) without inducing significant brain inflammation. Repetitive imaging sessions of cortical ROI are feasible, providing the characterization of disease hallmarks over time during the progression of numerous CNS diseases. This technique accessing the pial structures within 250 µm of the brain relies on the detection of fluorescent probes encoded by genetic cellular markers and/or vital dyes. The latter (e.g., fluorescent dextrans) are used to map the luminal compartment of cerebrovascular structures. Germane to the protocol described herein is the use of an in vivo marker of amyloid deposits, Methoxy-O4, to assess Alzheimer's disease (AD) progression. We also describe the post-acquisition image processing used to track vascular changes and amyloid depositions. While focusing presently on a model of AD, the described protocol is relevant to other CNS disorders where pathological cerebrovascular changes occur.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Doença de Alzheimer/diagnóstico por imagem , Animais , Progressão da Doença , Humanos
14.
Proc Natl Acad Sci U S A ; 112(51): 15737-42, 2015 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-26630005

RESUMO

Neurotrophins and glucocorticoids are robust synaptic modifiers, and deregulation of their activities is a risk factor for developing stress-related disorders. Low levels of brain-derived neurotrophic factor (BDNF) increase the desensitization of glucocorticoid receptors (GR) and vulnerability to stress, whereas higher levels of BDNF facilitate GR-mediated signaling and the response to antidepressants. However, the molecular mechanism underlying neurotrophic-priming of GR function is poorly understood. Here we provide evidence that activation of a TrkB-MAPK pathway, when paired with the deactivation of a GR-protein phosphatase 5 pathway, resulted in sustained GR phosphorylation at BDNF-sensitive sites that is essential for the transcription of neuronal plasticity genes. Genetic strategies that disrupted GR phosphorylation or TrkB signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine. Our findings reveal that the coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.


Assuntos
Antidepressivos/farmacologia , Plasticidade Neuronal/fisiologia , Receptores de Glucocorticoides/fisiologia , Transdução de Sinais/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Feminino , Fluoxetina/farmacologia , Sistema de Sinalização das MAP Quinases , Glicoproteínas de Membrana/fisiologia , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação , Proteínas Tirosina Quinases/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor trkB
15.
Adv Exp Med Biol ; 872: 33-57, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26215989

RESUMO

Well-defined as signaling hormones for the programming of cell type-specific and context-dependent gene expression signatures, glucocorticoids control experience-driven allostasis. One unifying model is that glucocorticoids help maintaining the integrity and plasticity of cellular networks in changing environments through the mobilization of cellular energy stores, profiling of gene expression, and changes in the electrical and morphological properties of cells. The nucleus is their primary site of action, yet recent discoveries point to additional gene transcription-independent functions at the plasma membrane of neuronal synapses. Glucocorticoids are secreted factors that reflect intrinsically the changes coming from the external world, temporally and regionally, during development and adulthood. In this review, we will enumerate the properties and signaling attributes of glucocorticoids and their receptors that characterize them as allostatic modulators. The molecular mechanisms used to support their role at the synapse will be highlighted.


Assuntos
Glucocorticoides/metabolismo , Transdução de Sinais , Regulação Alostérica , Animais , Disponibilidade Biológica , Humanos , Fosforilação , Receptores de Glucocorticoides/metabolismo
16.
Med Sci (Paris) ; 31(4): 383-8, 2015 Apr.
Artigo em Francês | MEDLINE | ID: mdl-25958756

RESUMO

If the engram of long-term memory is encoded by structural changes of neuronal circuits, they are expected to be present at distant time points after learning, to be specific of circuits activated by learning, and sensitive to behavioral contingencies. In this review we present new concepts that emerged from in vivo imaging studies that tracked the structural bases of the memory trace. A fine balance of spine formation and spine elimination needed for behavioral adaptation to new experience is regulated by glucocorticoids, which are secreted in synchrony with circadian rhythms and in response to stress. Disruption of glucocorticoid oscillations frequently observed in psychiatric disorders like depression and post-traumatic stress produces spine turnover defects and learning disabilities. These new findings provide a new framework for explaining the potent but complex mnemonic effects of glucocorticoids.


Assuntos
Glucocorticoides/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/fisiologia , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Memória de Longo Prazo/fisiologia , Plasticidade Neuronal/efeitos dos fármacos
17.
Mol Cell Biol ; 33(18): 3700-14, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23878391

RESUMO

Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glucocorticoides/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Evolução Biológica , Fator Neurotrófico Derivado do Encéfalo/deficiência , Fator Neurotrófico Derivado do Encéfalo/genética , Células Cultivadas , Sequência Conservada , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dexametasona/farmacologia , Glucocorticoides/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutagênese Sítio-Dirigida , Neurônios/metabolismo , Fosforilação , Regiões Promotoras Genéticas , Ratos , Receptor trkB/deficiência , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de Glucocorticoides/deficiência , Receptores de Glucocorticoides/genética , Transdução de Sinais , Transcriptoma
18.
Nat Neurosci ; 16(6): 698-705, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23624512

RESUMO

Excessive glucocorticoid exposure during chronic stress causes synapse loss and learning impairment. Under normal physiological conditions, glucocorticoid activity oscillates in synchrony with the circadian rhythm. Whether and how endogenous glucocorticoid oscillations modulate synaptic plasticity and learning is unknown. Here we show that circadian glucocorticoid peaks promote postsynaptic dendritic spine formation in the mouse cortex after motor skill learning, whereas troughs are required for stabilizing newly formed spines that are important for long-term memory retention. Conversely, chronic and excessive exposure to glucocorticoids eliminates learning-associated new spines and disrupts previously acquired memories. Furthermore, we show that glucocorticoids promote rapid spine formation through a non-transcriptional mechanism by means of the LIM kinase-cofilin pathway and increase spine elimination through transcriptional mechanisms involving mineralocorticoid receptor activation. Together, these findings indicate that tightly regulated circadian glucocorticoid oscillations are important for learning-dependent synaptic formation and maintenance. They also delineate a new signaling mechanism underlying these effects.


Assuntos
Córtex Cerebral/fisiologia , Ritmo Circadiano/fisiologia , Espinhas Dendríticas/metabolismo , Glucocorticoides/farmacologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Sinapses/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Glucocorticoides/administração & dosagem , Aprendizagem/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Fatores de Tempo
19.
Proc Natl Acad Sci U S A ; 109(4): 1305-10, 2012 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-22232675

RESUMO

Regulation of the hypothalamic-pituitary-adrenal (HPA) axis is critical for adaptation to environmental changes. The principle regulator of the HPA axis is corticotrophin-releasing hormone (CRH), which is made in the parventricular nucleus and is an important target of negative feedback by glucocorticoids. However, the molecular mechanisms that regulate CRH are not fully understood. Disruption of normal HPA axis activity is a major risk factor of neuropsychiatric disorders in which decreased expression of the glucocorticoid receptor (GR) has been documented. To investigate the role of the GR in CRH neurons, we have targeted the deletion of the GR, specifically in the parventricular nucleus. Impairment of GR function in the parventricular nucleus resulted in an enhancement of CRH expression and an up-regulation of hypothalamic levels of BDNF and disinhibition of the HPA axis. BDNF is a stress and activity-dependent factor involved in many activities modulated by the HPA axis. Significantly, ectopic expression of BDNF in vivo increased CRH, whereas reduced expression of BDNF, or its receptor TrkB, decreased CRH expression and normal HPA functions. We find the differential regulation of CRH relies upon the cAMP response-element binding protein coactivator CRTC2, which serves as a switch for BDNF and glucocorticoids to direct the expression of CRH.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Glucocorticoides/metabolismo , Homeostase/fisiologia , Hipotálamo/fisiologia , Receptores de Glucocorticoides/metabolismo , Transativadores/metabolismo , Análise de Variância , Animais , Imunoprecipitação da Cromatina , Sistema Hipotálamo-Hipofisário/fisiologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Confocal , Mutagênese Sítio-Dirigida , Neurônios/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição
20.
Commun Integr Biol ; 4(3): 281-3, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21980558

RESUMO

Mitogen-activated protein kinase (MAPK) signaling influences a variety of neuronal properties, including structural characteristics such as spine density, and physiological features like long-term potentiation. Spatiotemporal control of MAPK signaling is crucial to generate specific changes in neuronal physiology. However, while many studies have concentrated on the activation of MAPK signaling by trophic factors such as BDNF and neuronal activity, the mechanisms that lead to its termination have not been well described. Two recent reports begin to address this question by focusing on the role of the MAPK phosphatase, MKP-1, in neuronal function. The first study provides a cellular mechanism underlying MKP-1 action in the brain.1 The second study describes potential roles of MKP-1 during stress and major depression.2.

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