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1.
Aging (Albany NY) ; 13(17): 20935-20961, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34499614

RESUMO

Vascular dysfunction is entwined with aging and in the pathogenesis of Alzheimer's disease (AD) and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects using two-photon live animal imaging, behavioral tasks, and biochemical and histological analysis. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of Aß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia. Motivated by these findings, we exposed elderly patients with significant memory loss at baseline to HBOT and observed an increase in CBF and improvement in cognitive performances. This study demonstrates HBOT efficacy in hypoxia-related neurological conditions, particularly in AD and aging.


Assuntos
Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Oxigenoterapia Hiperbárica , Idoso , Doença de Alzheimer/diagnóstico por imagem , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Comportamento Animal , Circulação Cerebrovascular , Disfunção Cognitiva/metabolismo , Feminino , Humanos , Masculino , Transtornos da Memória/metabolismo , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Placa Amiloide/metabolismo
2.
Cereb Cortex ; 31(1): 248-266, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32954425

RESUMO

Loss of cognitive function with aging is a complex and poorly understood process. Recently, clinical research has linked the occurrence of cortical microinfarcts to cognitive decline. Cortical microinfarcts form following the occlusion of penetrating vessels and are considered to be restricted to the proximity of the occluded vessel. Whether and how such local events propagate and affect remote brain regions remain unknown. To this end, we combined histological analysis and longitudinal diffusion tensor imaging (DTI), following the targeted-photothrombotic occlusion of single cortical penetrating vessels. Occlusions resulted in distant tissue reorganization across the mouse brain. This remodeling co-occurred with the formation of a microglia/macrophage migratory path along subcortical white matter tracts, reaching the contralateral hemisphere through the corpus callosum and leaving a microstructural signature detected by DTI-tractography. CX3CR1-deficient mice exhibited shorter trail lengths, differential remodeling, and only ipsilateral white matter tract changes. We concluded that microinfarcts lead to brain-wide remodeling in a microglial CX3CR1-dependent manner.


Assuntos
Infarto Encefálico/patologia , Macrófagos/patologia , Microglia/patologia , Substância Branca/patologia , Animais , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/genética , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Imagem de Difusão por Ressonância Magnética , Imagem de Tensor de Difusão , Trombose Intracraniana/diagnóstico por imagem , Trombose Intracraniana/genética , Trombose Intracraniana/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vias Neurais/diagnóstico por imagem , Vias Neurais/patologia , Substância Branca/diagnóstico por imagem
3.
Nat Commun ; 9(1): 422, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29379017

RESUMO

Modeling studies suggest that clustered structural plasticity of dendritic spines is an efficient mechanism of information storage in cortical circuits. However, why new clustered spines occur in specific locations and how their formation relates to learning and memory (L&M) remain unclear. Using in vivo two-photon microscopy, we track spine dynamics in retrosplenial cortex before, during, and after two forms of episodic-like learning and find that spine turnover before learning predicts future L&M performance, as well as the localization and rates of spine clustering. Consistent with the idea that these measures are causally related, a genetic manipulation that enhances spine turnover also enhances both L&M and spine clustering. Biophysically inspired modeling suggests turnover increases clustering, network sparsity, and memory capacity. These results support a hotspot model where spine turnover is the driver for localization of clustered spine formation, which serves to modulate network function, thus influencing storage capacity and L&M.


Assuntos
Córtex Cerebral/fisiologia , Condicionamento Psicológico , Espinhas Dendríticas/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Memória Espacial/fisiologia , Animais , Córtex Cerebral/anatomia & histologia , Espinhas Dendríticas/patologia , Medo , Feminino , Microscopia Intravital , Masculino , Memória/fisiologia , Camundongos
4.
Adv Drug Deliv Rev ; 119: 73-100, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28778714

RESUMO

Developing efficient brain imaging technologies by combining a high spatiotemporal resolution and a large penetration depth is a key step for better understanding the neurovascular interface that emerges as a main pathway to neurodegeneration in many pathologies such as dementia. This review focuses on the advances in two complementary techniques: multi-photon laser scanning microscopy (MPLSM) and functional ultrasound imaging (fUSi). MPLSM has become the gold standard for in vivo imaging of cellular dynamics and morphology, together with cerebral blood flow. fUSi is an innovative imaging modality based on Doppler ultrasound, capable of recording vascular brain activity over large scales (i.e., tens of cubic millimeters) at unprecedented spatial and temporal resolution for such volumes (up to 10µm pixel size at 10kHz). By merging these two technologies, researchers may have access to a more detailed view of the various processes taking place at the neurovascular interface. MPLSM and fUSi are also good candidates for addressing the major challenge of real-time delivery, monitoring, and in vivo evaluation of drugs in neuronal tissue.


Assuntos
Encéfalo/fisiologia , Circulação Cerebrovascular/fisiologia , Neurônios/fisiologia , Animais , Humanos , Microscopia Confocal/métodos , Ultrassonografia/métodos
5.
Neuron ; 88(6): 1173-1191, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26627310

RESUMO

Autism spectrum disorder (ASD) is a heritable, common neurodevelopmental disorder with diverse genetic causes. Several studies have implicated protein synthesis as one among several of its potential convergent mechanisms. We originally identified Janus kinase and microtubule-interacting protein 1 (JAKMIP1) as differentially expressed in patients with distinct syndromic forms of ASD, fragile X syndrome, and 15q duplication syndrome. Here, we provide multiple lines of evidence that JAKMIP1 is a component of polyribosomes and an RNP translational regulatory complex that includes fragile X mental retardation protein, DEAD box helicase 5, and the poly(A) binding protein cytoplasmic 1. JAKMIP1 loss dysregulates neuronal translation during synaptic development, affecting glutamatergic NMDAR signaling, and results in social deficits, stereotyped activity, abnormal postnatal vocalizations, and other autistic-like behaviors in the mouse. These findings define an important and novel role for JAKMIP1 in neural development and further highlight pathways regulating mRNA translation during synaptogenesis in the genesis of neurodevelopmental disorders.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Redes Reguladoras de Genes/fisiologia , Biossíntese de Proteínas/fisiologia , Proteínas de Ligação a RNA/fisiologia , Sinapses/fisiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Proteômica/métodos
6.
PLoS One ; 10(5): e0125633, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25951243

RESUMO

The establishment and maintenance of neuronal circuits depends on tight regulation of synaptic contacts. We hypothesized that CNTNAP2, a protein associated with autism, would play a key role in this process. Indeed, we found that new dendritic spines in mice lacking CNTNAP2 were formed at normal rates, but failed to stabilize. Notably, rates of spine elimination were unaltered, suggesting a specific role for CNTNAP2 in stabilizing new synaptic circuitry.


Assuntos
Espinhas Dendríticas/fisiologia , Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Feminino , Masculino , Camundongos
8.
Neuron ; 75(1): 121-32, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22794266

RESUMO

Several models of associative learning predict that stimulus processing changes during association formation. How associative learning reconfigures neural circuits in primary sensory cortex to "learn" associative attributes of a stimulus remains unknown. Using 2-photon in vivo calcium imaging to measure responses of networks of neurons in primary somatosensory cortex, we discovered that associative fear learning, in which whisker stimulation is paired with foot shock, enhances sparse population coding and robustness of the conditional stimulus, yet decreases total network activity. Fewer cortical neurons responded to stimulation of the trained whisker than in controls, yet their response strength was enhanced. These responses were not observed in mice exposed to a nonassociative learning procedure. Our results define how the cortical representation of a sensory stimulus is shaped by associative fear learning. These changes are proposed to enhance efficient sensory processing after associative learning.


Assuntos
Aprendizagem por Associação/fisiologia , Medo/fisiologia , Rede Nervosa/fisiologia , Córtex Somatossensorial/fisiologia , Vibrissas/fisiologia , Animais , Condicionamento Clássico/fisiologia , Estimulação Elétrica/métodos , Medo/psicologia , Camundongos , Camundongos Endogâmicos C57BL
9.
Cell ; 147(1): 235-46, 2011 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-21962519

RESUMO

Although many genes predisposing to autism spectrum disorders (ASD) have been identified, the biological mechanism(s) remain unclear. Mouse models based on human disease-causing mutations provide the potential for understanding gene function and novel treatment development. Here, we characterize a mouse knockout of the Cntnap2 gene, which is strongly associated with ASD and allied neurodevelopmental disorders. Cntnap2(-/-) mice show deficits in the three core ASD behavioral domains, as well as hyperactivity and epileptic seizures, as have been reported in humans with CNTNAP2 mutations. Neuropathological and physiological analyses of these mice before the onset of seizures reveal neuronal migration abnormalities, reduced number of interneurons, and abnormal neuronal network activity. In addition, treatment with the FDA-approved drug risperidone ameliorates the targeted repetitive behaviors in the mutant mice. These data demonstrate a functional role for CNTNAP2 in brain development and provide a new tool for mechanistic and therapeutic research in ASD.


Assuntos
Transtorno Autístico/genética , Encéfalo/crescimento & desenvolvimento , Modelos Animais de Doenças , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Animais , Transtorno Autístico/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Movimento Celular , Epilepsia/genética , Humanos , Interneurônios/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/genética , Camundongos Knockout , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Neurônios/patologia
10.
Mol Cell Neurosci ; 32(1-2): 15-26, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16530423

RESUMO

Mutations in doublecortin (DCX) cause X-linked lissencephaly ("smooth brain") and double cortex syndrome in humans. DCX is highly phosphorylated in migrating neurons. Here, we demonstrate that dephosphorylation of specific sites phosphorylated by JNK is mediated by Neurabin II, which recruits the phosphatase PP1. During cortical development, the expression pattern of PP1 is widespread, while the expression of DCX and Neurabin II is dynamic, and they are coexpressed in migrating neurons. In vitro, DCX is site-specific dephosphorylated by PP1 without the presence of Neurabin II, this dephosphorylation requires an intact RVXF motif in DCX. Overexpression of the coiled-coil domain of Neurabin II, which is sufficient for interacting with DCX and recruiting the endogenous Neurabin II with PP1, induced dephosphorylation of DCX on one of the JNK-phosphorylated sites. We hypothesize that the transient recruitment of DCX to different scaffold proteins, JIP-1/2, which will regulate its phosphorylation by JNK, and Neurabin II, which will regulate its dephosphorylation by PP1, plays an important role in normal neuronal migration.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Motivos de Aminoácidos/fisiologia , Animais , Sítios de Ligação/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular , Movimento Celular/fisiologia , Córtex Cerebral/citologia , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Substâncias Macromoleculares/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/química , Proteínas Associadas aos Microtúbulos/química , Proteínas do Tecido Nervoso/química , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Neurônios/citologia , Neuropeptídeos/química , Fosforilação , Proteína Fosfatase 1 , Estrutura Terciária de Proteína/fisiologia
11.
Cell Cycle ; 3(6): 747-51, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15118415

RESUMO

The mammalian cortex is generally subdivided into six organized layers, which are formed during development in an organized fashion. This organized cortical layering is disrupted in case of mutations in the doublecortin (DCX) gene. DCX is a Microtubule Associated Protein (MAP). However, besides stabilization of microtubules, it may be involved in additional functions. The participation of this molecule in signal transduction is beginning to emerge via discovery of interacting molecules and its regulation by phosphorylation using several different kinases. We raise the hypothesis, that the combinatorial phosphorylation of DCX by different kinases and at different sites may be a molecular regulatory switch in the transition of a migrating neuron through multiple phases of migration. Our recent research has suggested the involvement of DCX in the JNK (Jun-N-terminal Kinase) pathway. The JNK pathway is linked to the reelin pathway, known to regulate cortical layering. Positioning of DCX in this signaling pathway opens up additional possibilities of understanding how migrating neurons are controlled.


Assuntos
Proteínas Associadas aos Microtúbulos/metabolismo , Neuropeptídeos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Humanos , Fosforilação , Proteína Reelina
12.
EMBO J ; 23(4): 823-32, 2004 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-14765123

RESUMO

Mutations in the X-linked gene DCX result in lissencephaly in males, and abnormal neuronal positioning in females, suggesting a role for this gene product during neuronal migration. In spite of several known protein interactions, the involvement of DCX in a signaling pathway is still elusive. Here we demonstrate that DCX is a substrate of JNK and interacts with both c-Jun N-terminal kinase (JNK) and JNK interacting protein (JIP). The localization of this signaling module in the developing brain suggests its functionality in migrating neurons. The localization of DCX at neurite tips is determined by its interaction with JIP and by the interaction of the latter with kinesin. DCX is phosphorylated by JNK in growth cones. DCX mutated in sites phosphorylated by JNK affected neurite outgrowth, and the velocity and relative pause time of migrating neurons. We hypothesize that during neuronal migration, there is a need to regulate molecular motors that are working in the cell in opposite directions: kinesin (a plus-end directed molecular motor) versus dynein (a minus-end directed molecular motor).


Assuntos
Cones de Crescimento/fisiologia , Proteínas Quinases JNK Ativadas por Mitógeno/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Neurônios/fisiologia , Neuropeptídeos/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Encéfalo/citologia , Encéfalo/embriologia , Encéfalo/metabolismo , Movimento Celular , Células Cultivadas , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Cones de Crescimento/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Cinesinas/genética , Cinesinas/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Mutagênese Sítio-Dirigida , Neuritos/fisiologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Fosforilação , Ligação Proteica , Ratos , Transdução de Sinais
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