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1.
Nature ; 571(7765): 349-354, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31292549

RESUMO

Ascidian embryos highlight the importance of cell lineages in animal development. As simple proto-vertebrates, they also provide insights into the evolutionary origins of cell types such as cranial placodes and neural crest cells. Here we have determined single-cell transcriptomes for more than 90,000 cells that span the entirety of development-from the onset of gastrulation to swimming tadpoles-in Ciona intestinalis. Owing to the small numbers of cells in ascidian embryos, this represents an average of over 12-fold coverage for every cell at every stage of development. We used single-cell transcriptome trajectories to construct virtual cell-lineage maps and provisional gene networks for 41 neural subtypes that comprise the larval nervous system. We summarize several applications of these datasets, including annotating the synaptome of swimming tadpoles and tracing the evolutionary origin of cell types such as the vertebrate telencephalon.


Assuntos
Linhagem da Célula/genética , Ciona intestinalis/citologia , Ciona intestinalis/genética , Análise de Célula Única , Transcriptoma , Animais , Sequência de Bases , Evolução Biológica , Ciona intestinalis/classificação , Ciona intestinalis/crescimento & desenvolvimento , Gastrulação , Redes Reguladoras de Genes , Larva/citologia , Larva/genética , Sistema Nervoso/citologia , Sistema Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Notocorda/citologia , Notocorda/embriologia , Especificidade de Órgãos , Sinapses/genética , Sinapses/metabolismo
2.
Biophys Chem ; 253: 106212, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31280069

RESUMO

Many efforts have been spent in the last decade for the development of nanoscale synaptic devices integrated into neuromorphic circuits, trying to emulate the behavior of natural synapses. The study of brain properties with the standard approaches based on biocompatible electrodes coupled to conventional electronics, however, presents strong limitations, which in turn could be overcame by the in-situ growth of neuronal networks coupled to memristive devices. To meet this challenging task, here two different chips were designed and fabricated for culturing neuronal cells and sensing their electrophysiological activity. The first chip was designed to be connected to an external memristor, while the second chip was coated with TiO2 films owning memristive properties. The biocompatibility of chips was preliminary analyzed by culturing the hybrid motor-neuron cell line NSC-34 and by measuring the electrical activity of cells interfacing the chip with a standard patch-clamp setup. Next, neurons were seeded on chips and their activity measured with the same setup. For both cell types total current and voltage responses were evoked and recorded with optimal results with no breakdowns. In addition, an external stimulation was applied to cells through chip electrodes, being effective and causing no damage or pitfalls to the cells. Finally, the whole bio-hybrid system, i.e. the chip interconnected with a commercial memristor, was tested with promising results. Spontaneous electrical activity of neurons grown on the chip was indeed present and this signal was collected and sent to the memristor, changing its state. Taken together, we demonstrated the ability of memristor to work with a synaptic/plastic response together with natural systems, opening the way for the further implementation of basic computing elements able to perform both storage and processing of data, as in natural neurons.


Assuntos
Redes Neurais (Computação) , Neurônios/citologia , Animais , Eletrodos , Eletrônica , Camundongos , Neurônios/metabolismo , Sinapses/metabolismo , Células Tumorais Cultivadas
3.
Nat Methods ; 16(8): 699-702, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308551

RESUMO

Chemical inhibitors have revealed requirements for protein synthesis that drive cellular plasticity. We developed a genetically encodable protein synthesis inhibitor (gePSI) to achieve cell-type-specific temporal control of protein synthesis. Controlled expression of the gePSI in neurons or glia resulted in rapid, potent and reversible cell-autonomous inhibition of protein synthesis. Moreover, gePSI expression in a single neuron blocked the structural plasticity induced by single-synapse stimulation.


Assuntos
Engenharia Genética , Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , Sinapses/metabolismo , Animais , Células Cultivadas , Células HeLa , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Inibidores da Síntese de Proteínas/química , Ratos , Sinapses/efeitos dos fármacos
4.
Psychopharmacology (Berl) ; 236(9): 2761-2771, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31165206

RESUMO

RATIONALE: As the hub of memory and space, hippocampus is very sensitive to a wide variety of injuries and is one of the earliest brain structures to develop neurodegenerative changes in AD. Previous research has showed a protective effect of potassium 2-(l-hydroxypentyl)-benzoate (PHPB) on cognitive deficits in animal models of AD. However, it is unclear whether this protective effect is associated with hippocampal alterations. OBJECTIVES: The present study was conducted to evaluate the protective effect of PHPB on hippocampal neurodegenerative changes in middle-aged APP/PS1 mice. METHODS: Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups. PHPB-treated APP/PS1 group received 30 mg/kg PHPB by oral gavage once daily for 12 weeks. Wild-type group and APP/PS1 group received the same volume of water alone. Twelve weeks later, mice (13-month-old) were tested for in vivo 1H-MRS examination and then sacrificed for subsequent biochemical and pathological examinations using transmission electron microscopy, Golgi staining, immunohistochemistry, and western blotting. RESULTS: We found that PHPB treatment significantly improved the micromorphology of hippocampal neurons and subcellular organelles, ameliorated synapse loss and presynaptic axonal dystrophy, increased hippocampal dendritic spine density and dendritic complexity, enhanced the expression of hippocampal synapse-associated proteins, and improved hippocampal metabolism in middle-aged APP/PS1 mice. CONCLUSIONS: Our study showed for the first time the protective effect of PHPB on hippocampal neurons, synapses, and dystrophic axons in APP/PS1 mice, which to some extent revealed the possible mechanism for its ability to improve cognition in animal models of AD.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Axônios/metabolismo , Hipocampo/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Presenilina-1/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Axônios/efeitos dos fármacos , Axônios/patologia , Benzoatos/administração & dosagem , Cognição/efeitos dos fármacos , Cognição/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pentanóis/administração & dosagem , Potássio/administração & dosagem , Presenilina-1/genética , Distribuição Aleatória , Sinapses/genética , Sinapses/patologia , Resultado do Tratamento
5.
Nat Commun ; 10(1): 2431, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160566

RESUMO

Contextual modulation of neuronal responses by surrounding environments is a fundamental attribute of sensory processing. In the mammalian retina, responses of On-Off direction selective ganglion cells (DSGCs) are modulated by motion contexts. However, the underlying mechanisms are unknown. Here, we show that posterior-preferring DSGCs (pDSGCs) are sensitive to discontinuities of moving contours owing to contextually modulated cholinergic excitation from starburst amacrine cells (SACs). Using a combination of synapse-specific genetic manipulations, patch clamp electrophysiology and connectomic analysis, we identified distinct circuit motifs upstream of On and Off SACs that are required for the contextual modulation of pDSGC activity for bright and dark contrasts. Furthermore, our results reveal a class of wide-field amacrine cells (WACs) with straight, unbranching dendrites that function as "continuity detectors" of moving contours. Therefore, divergent circuit motifs in the On and Off pathways extend the information encoding of On-Off DSGCs beyond their direction selectivity during complex stimuli.


Assuntos
Acetilcolina/metabolismo , Células Amácrinas/metabolismo , Percepção de Movimento/fisiologia , Células Ganglionares da Retina/metabolismo , Sinapses/metabolismo , Visão Ocular/fisiologia , Ácido gama-Aminobutírico/metabolismo , Células Amácrinas/fisiologia , Animais , Conectoma , Dendritos/metabolismo , Ácido Glutâmico/metabolismo , Camundongos , Técnicas de Patch-Clamp , Receptores de GABA-A/genética , Células Ganglionares da Retina/fisiologia , Percepção Visual/fisiologia
6.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216630

RESUMO

An imbalance of excitatory and inhibitory neurotransmission leading to over excitation plays a crucial role in generating seizures, while enhancing GABAergic mechanisms are critical in terminating seizures. In recent years, it has been reported in many studies that astrocytes are deeply involved in synaptic transmission. Astrocytes form a critical component of the "tripartite" synapses by wrapping around the pre- and post-synaptic elements. From this location, astrocytes are known to greatly influence the dynamics of ions and transmitters in the synaptic cleft. Despite recent extensive research on excitatory tripartite synapses, inhibitory tripartite synapses have received less attention, even though they influence inhibitory synaptic transmission by affecting chloride and GABA concentration dynamics. In this review, we will discuss the diverse actions of astrocytic chloride and GABA homeostasis at GABAergic tripartite synapses. We will then consider the pathophysiological impacts of disturbed GABA homeostasis at the tripartite synapse.


Assuntos
Astrócitos/metabolismo , Neurônios GABAérgicos/metabolismo , Receptores de GABA/metabolismo , Transdução de Sinais , Sinapses/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Transporte Biológico , Junções Comunicantes/metabolismo , Humanos , Transmissão Sináptica , Canais de Ânion Dependentes de Voltagem/metabolismo
7.
Nat Commun ; 10(1): 2819, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249307

RESUMO

Hippocampal hyperactivity is correlated with psychosis in schizophrenia patients and likely attributable to deficits in GABAergic signaling. Here we attempt to reverse this deficit by overexpression of the α5-GABAA receptor within the ventral hippocampus (vHipp). Indeed, this is sufficient to normalize vHipp activity and downstream alterations in dopamine neuron function in the MAM rodent model. This approach also attenuated behavioral deficits in cognitive flexibility. To understand the specific pathways that mediate these effects, we used chemogenetics to manipulate discrete projections from the vHipp to the nucleus accumbens (NAc) or prefrontal cortex (mPFC). We found that inhibition of the vHipp-NAc, but not the vHipp-mPFC pathway, normalized aberrant dopamine neuron activity. Conversely, inhibition of the vHipp-mPFC improved cognitive function. Taken together, these results demonstrate that restoring GABAergic signaling in the vHipp improves schizophrenia-like deficits and that distinct behavioral alterations are mediated by discrete projections from the vHipp to the NAc and mPFC.


Assuntos
Hipocampo/metabolismo , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Animais , Comportamento Animal , Cognição , Neurônios Dopaminérgicos/metabolismo , Feminino , Masculino , Vias Neurais , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/genética , Sinapses/genética
8.
Life Sci ; 231: 116567, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202839

RESUMO

AIMS: Metabotropic glutamate receptor 5 (mGluR5), a member of group I mGluR, exerts its effect via elevation of intracellular Ca2+ level. We here characterized Ca2+ signals in the tsA201 cells transfected with mGluR5 and investigated the role of passages for mGluR5-induced Ca2+ signals in synaptic plasticity. MAIN METHODS: Using a genetically encoded Ca2+ indicator, GCamp2, Ca2+ signals were reliably induced by bath application of (S)-3,5-dihydroxyphenylglycine, the group I mGluR agonist, in the tsA201 cells transfected with mGluR5. Using whole-cell recordings in the substantia gelatinosa (SG) neurons of the spinal trigeminal subnucleus caudalis (Vc), excitatory postsynaptic currents were recorded by stimulating the trigeminal tract. KEY FINDINGS: Ca2+ signals were mediated by "classical" or "canonical" transient receptor potential (TRPC) channels, particularly TRPC1/3/4/6, but not TRPC5, naturally existing in the tsA201 cells. Interestingly, the induction of Ca2+ signals was independent of the phospholipase C signaling pathway; instead, it critically involves the cyclic adenosine diphosphate ribose/ryanodine receptor-dependent signaling pathway and only partially protein kinase C. On the other hand, both TRPC3 and TRPC4 mediated mGluR1/5-induced long-lasting potentiation of excitatory synaptic transmission from the trigeminal primary afferents to the SG neurons of the Vc. SIGNIFICANCE: This study demonstrates that endogenous TRPC channels contribute to mGluR5-induced Ca2+ signals in tsA201 cells and synaptic plasticity at excitatory synapses.


Assuntos
Sinalização do Cálcio/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Receptor de Glutamato Metabotrópico 5/metabolismo , Canais de Cátion TRPC/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismo , Sinapses/metabolismo , Transmissão Sináptica , Nervo Trigêmeo/metabolismo , Núcleo Espinal do Trigêmeo/metabolismo
9.
Cell Mol Life Sci ; 76(16): 3229-3248, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197404

RESUMO

The extracellular matrix (ECM) plays diverse roles in several physiological and pathological conditions. In the brain, the ECM is unique both in its composition and in functions. Furthermore, almost all the cells in the central nervous system contribute to different aspects of this intricate structure. Brain ECM, enriched with proteoglycans and other small proteins, aggregate into distinct structures around neurons and oligodendrocytes. These special structures have cardinal functions in the normal functioning of the brain, such as learning, memory, and synapse regulation. In this review, we have compiled the current knowledge about the structure and function of important ECM molecules in the brain and their proteolytic remodeling by matrix metalloproteinases and other enzymes, highlighting the special structures they form. In particular, the proteoglycans in brain ECM, which are essential for several vital functions, are emphasized in detail.


Assuntos
Encéfalo/metabolismo , Matriz Extracelular/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Matriz Extracelular/química , Humanos , Ácido Hialurônico/metabolismo , Proteólise , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Receptores de Superfície Celular/metabolismo , Sinapses/metabolismo , Tenascina/metabolismo
10.
Nat Commun ; 10(1): 2167, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092821

RESUMO

Ribbon synapses transmit information in sensory systems, but their development is not well understood. To test the hypothesis that ribbon assembly stabilizes nascent synapses, we performed simultaneous time-lapse imaging of fluorescently-tagged ribbons in retinal cone bipolar cells (BCs) and postsynaptic densities (PSD95-FP) of retinal ganglion cells (RGCs). Ribbons and PSD95-FP clusters were more stable when these components colocalized at synapses. However, synapse density on ON-alpha RGCs was unchanged in mice lacking ribbons (ribeye knockout). Wildtype BCs make both ribbon-containing and ribbon-free synapses with these GCs even at maturity. Ribbon assembly and cone BC-RGC synapse maintenance are thus regulated independently. Despite the absence of synaptic ribbons, RGCs continued to respond robustly to light stimuli, although quantitative examination of the responses revealed reduced frequency and contrast sensitivity.


Assuntos
Células Fotorreceptoras Retinianas Cones/fisiologia , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Microscopia Intravital/métodos , Luz , Proteínas Luminescentes/química , Proteínas Luminescentes/genética , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Estimulação Luminosa , Cultura Primária de Células , Células Bipolares da Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Imagem com Lapso de Tempo/métodos
11.
Life Sci ; 229: 187-199, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31108095

RESUMO

Spinal cord injury (SCI) is a serious neurological disease without efficacious drugs. Anti-apoptosis and suppressing dendritic/synaptic degeneration in the anterior horn are essential targets after SCI. Previous studies found that hyperbaric oxygen therapy (HBOT) significantly protected rats after SCI. However, its potential effects and mechanisms remain unknown. The BDNF/TrkB signaling pathways evidently contribute to the SCI recovery. Currently, we mainly investigate the potential effects and mechanism of HBOT on anti-apoptosis and ameliorating impaired dendrites, dendritic spines and synapses after SCI. Establish SCI model and randomly divide rats into 5 groups. After SCI, rats were subjected to HBOT. ANA-12 is the specific inhibitor of BDNF/TrkB signal pathway. Changes in neurological deficit, neuronal morphology, apoptosis, protein expression and dendrite/synapse were examined by Basso-Beattie-Bresnahan (BBB) locomotor rating scale, Hematoxylin-eosin (HE) and Nissl staining, TUNEL staining, RT-PCR, Western blot, immunofluorescence and Golgi-Cox staining. We found HBOT suppressed dendritic/synaptic degeneration and alleviated apoptosis, consistent with the increase of BDNF and TrkB expression and improved neurological recovery. In contrast to the positive effects of HBOT, inhibitor increased degeneration and apoptosis. Moreover, we observed that these HBOT-mediated protective effects were significantly inhibited by inhibitor, consistent with the lower expression of BDNF/TrkB and worse neurobehavioral state. These findings suggest that hyperbaric oxygen therapy ameliorates spinal cord injury-induced neurological impairment by anti-apoptosis and suppressing dendritic/synaptic degeneration via upregulating the BDNF/TrkB signaling pathways.


Assuntos
Apoptose , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Dendritos/metabolismo , Oxigenação Hiperbárica/métodos , Degeneração Neural/prevenção & controle , Receptor trkB/metabolismo , Traumatismos da Medula Espinal/terapia , Sinapses/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Dendritos/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor trkB/genética , Recuperação de Função Fisiológica , Transdução de Sinais , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Sinapses/patologia
12.
Adv Neurobiol ; 22: 331-350, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073943

RESUMO

The firing rate of neuronal spiking in vitro and in vivo significantly varies over extended timescales, characterized by long-memory processes and complex statistics, and appears in spontaneous as well as evoked activity upon repeated stimulus presentation. These variations in response features and their statistics, in face of repeated instances of a given physical input, are ubiquitous in all levels of brain-behavior organization. They are expressed in single neuron and network response variability but even appear in variations of subjective percepts or psychophysical choices and have been described as stemming from history-dependent, stochastic, or rate-determined processes.But what are the sources underlying these temporally rich variations in firing rate? Are they determined by interactions of the nervous system as a whole, or do isolated, single neurons or neuronal networks already express these fluctuations independent of higher levels? These questions motivated the application of a method that allows for controlled and specific long-term activation of a single neuron or neuronal network, isolated from higher levels of cortical organization.This chapter highlights the research done in cultured cortical networks to study (1) the inherent non-stationarity of neuronal network activity, (2) single neuron response fluctuations and underlying processes, and (3) the interface layer between network and single cell, the non-stationary efficacy of the ensemble of synapses impinging onto the observed neuron.


Assuntos
Potenciais de Ação , Eletrofisiologia/instrumentação , Eletrofisiologia/métodos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Técnicas In Vitro , Sinapses/metabolismo
13.
Arch Pharm Res ; 42(5): 407-415, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30937842

RESUMO

Autophagy is an essential process for maintaining cellular homeostasis, a critical process in all cell types. Because neurons are post-mitotic cells, maintaining cellular and functional homeostasis is more important in neurons than in other types of cells. Synapses are fundamental units needed for neural communication, and synapses with consistent protein quality are essential for neural functionality. Dysregulation of autophagy in neurons has been shown to be related to neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. This review describes the role of autophagy in the maintenance of synaptic functionality and the association between synaptic autophagy and neurodegenerative diseases.


Assuntos
Doença de Alzheimer/patologia , Autofagia , Encéfalo/patologia , Doença de Parkinson/patologia , Sinapses/patologia , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Encéfalo/citologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Humanos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Sinapses/metabolismo
14.
Neurorehabil Neural Repair ; 33(4): 271-283, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30979358

RESUMO

BACKGROUND: Growing evidences suggest that brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) plays a key role in the regulation of hippocampal synaptic plasticity in a prenatal stress (PNS) rat model. Repetitive transcranial magnetic stimulation (rTMS) is currently being acknowledged to affect attention and memory in both preclinical and clinical studies, although the mechanism is still unclear. OBJECTIVE: The current study aimed to explore whether a whole brain rTMS (5 Hz, 14 days) could ameliorate cognitive dysfunction-induced PNS in male offspring, and examine if the positive effect of rTMS was associated with the BDNF/TrkB signaling in the hippocampus. METHODS: The rats were randomly divided into 5 groups: CON, PNS, PNS + rTMS, PNS + rTMS + DMSO (dimethyl sulfoxide), and PNS + rTMS + K252a. Spatial cognition was evaluated by using Morris water maze test. Following behavioral assessment, both paired-pulse facilitation and long-term potentiation were recorded from Schaffer collaterals to CA1 region in the hippocampus. Synaptic, apoptotic, and BDNF/TrkB signaling proteins were measured by Western blot. RESULTS: PNS-exposed offspring exhibited cognitive deficits, long-term potentiation inhibition in the hippocampus, the decrease of synaptic and BDNF/TrkB signaling proteins expression, apoptosis, and reduced number of cells in the CA1 region. Five-hertz rTMS significantly alleviated the PNS-induced abnormalities. However, the effect of rTMS was antagonized by intracerebroventricular infusion of K252a (a TrkB inhibitor). CONCLUSIONS: The findings suggest that 5-Hz rTMS significantly improves the impairment of spatial cognition and hippocampal synaptic plasticity, which is possibly associated with the activation of BDNF/TrkB signaling.


Assuntos
Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/terapia , Efeitos Tardios da Exposição Pré-Natal , Estresse Psicológico/complicações , Estimulação Magnética Transcraniana , Animais , Apoptose/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Gravidez , Distribuição Aleatória , Ratos Wistar , Receptor trkB/metabolismo , Transdução de Sinais , Estresse Psicológico/metabolismo , Sinapses/metabolismo
15.
Nature ; 568(7752): 336-343, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30996318

RESUMO

The brains of humans and other mammals are highly vulnerable to interruptions in blood flow and decreases in oxygen levels. Here we describe the restoration and maintenance of microcirculation and molecular and cellular functions of the intact pig brain under ex vivo normothermic conditions up to four hours post-mortem. We have developed an extracorporeal pulsatile-perfusion system and a haemoglobin-based, acellular, non-coagulative, echogenic, and cytoprotective perfusate that promotes recovery from anoxia, reduces reperfusion injury, prevents oedema, and metabolically supports the energy requirements of the brain. With this system, we observed preservation of cytoarchitecture; attenuation of cell death; and restoration of vascular dilatory and glial inflammatory responses, spontaneous synaptic activity, and active cerebral metabolism in the absence of global electrocorticographic activity. These findings demonstrate that under appropriate conditions the isolated, intact large mammalian brain possesses an underappreciated capacity for restoration of microcirculation and molecular and cellular activity after a prolonged post-mortem interval.


Assuntos
Autopsia , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Circulação Cerebrovascular , Microcirculação , Suínos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Sobrevivência Celular , Artérias Cerebrais/fisiologia , Modelos Animais de Doenças , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/patologia , Inflamação/metabolismo , Inflamação/patologia , Neuroglia/citologia , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Perfusão , Traumatismo por Reperfusão/prevenção & controle , Suínos/sangue , Sinapses/metabolismo , Sinapses/patologia , Fatores de Tempo , Vasodilatação
16.
Neuron ; 102(1): 48-59, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30946825

RESUMO

Addiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual's vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction. We conclude by exploring how epigenetic mechanisms might serve as therapeutic targets for addiction treatments.


Assuntos
Encéfalo/metabolismo , Epigênese Genética/genética , Plasticidade Neuronal/genética , Transtornos Relacionados ao Uso de Substâncias/genética , Sinapses/genética , Transmissão Sináptica/genética , Animais , Variação Biológica Individual , Encéfalo/fisiopatologia , Cromatina/metabolismo , Humanos , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Sinapses/metabolismo
17.
Nano Lett ; 19(5): 2858-2870, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-30983361

RESUMO

Synapses compute and transmit information to connect neural circuits and are at the basis of brain operations. Alterations in their function contribute to a vast range of neuropsychiatric and neurodegenerative disorders and synapse-based therapeutic intervention, such as selective inhibition of synaptic transmission, may significantly help against serious pathologies. Graphene is a two-dimensional nanomaterial largely exploited in multiple domains of science and technology, including biomedical applications. In hippocampal neurons in culture, small graphene oxide nanosheets (s-GO) selectively depress glutamatergic activity without altering cell viability. Glutamate is the main excitatory neurotransmitter in the central nervous system and growing evidence suggests its involvement in neuropsychiatric disorders. Here we demonstrate that s-GO directly targets the release of presynaptic vesicle. We propose that s-GO flakes reduce the availability of transmitter, via promoting its fast release and subsequent depletion, leading to a decline ofglutamatergic neurotransmission. We injected s-GO in the hippocampus in vivo, and 48 h after surgery ex vivo patch-clamp recordings from brain slices show a significant reduction in glutamatergic synaptic activity in respect to saline injections.


Assuntos
Grafite/farmacologia , Nanoestruturas/química , Doenças Neurodegenerativas/tratamento farmacológico , Neurônios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Fármacos atuantes sobre Aminoácidos Excitatórios/síntese química , Fármacos atuantes sobre Aminoácidos Excitatórios/química , Fármacos atuantes sobre Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Grafite/síntese química , Grafite/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Nanoestruturas/uso terapêutico , Doenças Neurodegenerativas/fisiopatologia , Neurônios/metabolismo , Cultura Primária de Células , Pontos Quânticos/química , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Transmissão Sináptica/efeitos dos fármacos
18.
Cell Mol Life Sci ; 76(11): 2133-2169, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30937469

RESUMO

To correctly transfer information, neuronal networks need to continuously adjust their synaptic strength to extrinsic stimuli. This ability, termed synaptic plasticity, is at the heart of their function and is, thus, tightly regulated. In glutamatergic neurons, synaptic strength is controlled by the number and function of AMPA receptors at the postsynapse, which mediate most of the fast excitatory transmission in the central nervous system. Their trafficking to, at, and from the synapse, is, therefore, a key mechanism underlying synaptic plasticity. Intensive research over the last 20 years has revealed the increasing importance of interacting proteins, which accompany AMPA receptors throughout their lifetime and help to refine the temporal and spatial modulation of their trafficking and function. In this review, we discuss the current knowledge about the roles of key partners in regulating AMPA receptor trafficking and focus especially on the movement between the intracellular, extrasynaptic, and synaptic pools. We examine their involvement not only in basal synaptic function, but also in Hebbian and homeostatic plasticity. Included in our review are well-established AMPA receptor interactants such as GRIP1 and PICK1, the classical auxiliary subunits TARP and CNIH, and the newest additions to AMPA receptor native complexes.


Assuntos
Proteínas de Transporte/metabolismo , Rede Nervosa/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/fisiologia , Proteínas Nucleares/metabolismo , Receptores de AMPA/metabolismo , Animais , Proteínas de Transporte/genética , Proteínas do Ovo/genética , Proteínas do Ovo/metabolismo , Regulação da Expressão Gênica , Ácido Glutâmico/metabolismo , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Redes Neurais (Computação) , Neurônios/citologia , Neurônios/metabolismo , Proteínas Nucleares/genética , Transporte Proteico , Receptores de AMPA/genética , Sinapses/metabolismo , Transmissão Sináptica
19.
PLoS Pathog ; 15(4): e1007712, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30970042

RESUMO

Although considerable evidence supports that misfolded prion protein (PrPSc) is the principal component of "prions", underpinning both transmissibility and neurotoxicity, clear consensus around a number of fundamental aspects of pathogenesis has not been achieved, including the time of appearance of neurotoxic species during disease evolution. Utilizing a recently reported electrophysiology paradigm, we assessed the acute synaptotoxicity of ex vivo PrPSc prepared as crude homogenates from brains of M1000 infected wild-type mice (cM1000) harvested at time-points representing 30%, 50%, 70% and 100% of the terminal stage of disease (TSD). Acute synaptotoxicity was assessed by measuring the capacity of cM1000 to impair hippocampal CA1 region long-term potentiation (LTP) and post-tetanic potentiation (PTP) in explant slices. Of particular note, cM1000 from 30% of the TSD was able to cause significant impairment of LTP and PTP, with the induced failure of LTP increasing over subsequent time-points while the capacity of cM1000 to induce PTP failure appeared maximal even at this early stage of disease progression. Evidence that the synaptotoxicity directly related to PrP species was demonstrated by the significant rescue of LTP dysfunction at each time-point through immuno-depletion of >50% of total PrP species from cM1000 preparations. Moreover, similar to our previous observations at the terminal stage of M1000 prion disease, size fractionation chromatography revealed that capacity for acute synpatotoxicity correlated with predominance of oligomeric PrP species in infected brains across all time points, with the profile appearing maximised by 50% of the TSD. Using enhanced sensitivity western blotting, modestly proteinase K (PK)-resistant PrPSc was detectable at very low levels in cM1000 at 30% of the TSD, becoming robustly detectable by 70% of the TSD at which time substantial levels of highly PK-resistant PrPSc was also evident. Further illustrating the biochemical evolution of acutely synaptotoxic species the synaptotoxicity of cM1000 from 30%, 50% and 70% of the TSD, but not at 100% TSD, was abolished by digestion of immuno-captured PrP species with mild PK treatment (5µg/ml for an hour at 37°C), demonstrating that the predominant synaptotoxic PrPSc species up to and including 70% of the TSD were proteinase-sensitive. Overall, these findings in combination with our previous assessments of transmitting prions support that synaptotoxic and infectious M1000 PrPSc species co-exist from at least 30% of the TSD, simultaneously increasing thereafter, albeit with eventual plateauing of transmitting conformers.


Assuntos
Evolução Biológica , Encefalopatias/patologia , Proteínas PrPSc/metabolismo , Doenças Priônicas/patologia , Príons/patogenicidade , Sinapses/patologia , Animais , Encefalopatias/etiologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Doenças Priônicas/etiologia , Proteólise , Sinapses/metabolismo
20.
Mol Brain ; 12(1): 29, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30935412

RESUMO

Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressant drugs in pregnant women. Infants born following prenatal exposure to SSRIs have a higher risk for behavioral abnormalities, however, the underlying mechanisms remains unknown. Therefore, we examined the effects of prenatal fluoxetine, the most commonly prescribed SSRI, in mice. Intriguingly, chronic in utero fluoxetine treatment impaired working memory and social novelty recognition in adult males. In the medial prefrontal cortex (mPFC), a key region regulating these behaviors, we found augmented spontaneous inhibitory synaptic transmission onto the layer 5 pyramidal neurons. Fast-spiking interneurons in mPFC exhibited enhanced intrinsic excitability and serotonin-induced excitability due to upregulated serotonin (5-HT) 2A receptor (5-HT2AR) signaling. More importantly, the behavioral deficits in prenatal fluoxetine treated mice were reversed by the application of a 5-HT2AR antagonist. Taken together, our findings suggest that alterations in inhibitory neuronal modulation are responsible for the behavioral alterations following prenatal exposure to SSRIs.


Assuntos
Memória de Curto Prazo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Recognição (Psicologia)/efeitos dos fármacos , Inibidores de Captação de Serotonina/efeitos adversos , Comportamento Social , Sinapses/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Comportamento Animal , Feminino , Fluoxetina/efeitos adversos , Interneurônios/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/tratamento farmacológico , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Sinapses/efeitos dos fármacos
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