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1.
Nat Commun ; 11(1): 5038, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028830

RESUMO

Epilepsy is one of the most common neurological disorders, yet its pathophysiology is poorly understood due to the high complexity of affected neuronal circuits. To identify dysfunctional neuronal subtypes underlying seizure activity in the human brain, we have performed single-nucleus transcriptomics analysis of >110,000 neuronal transcriptomes derived from temporal cortex samples of multiple temporal lobe epilepsy and non-epileptic subjects. We found that the largest transcriptomic changes occur in distinct neuronal subtypes from several families of principal neurons (L5-6_Fezf2 and L2-3_Cux2) and GABAergic interneurons (Sst and Pvalb), whereas other subtypes in the same families were less affected. Furthermore, the subtypes with the largest epilepsy-related transcriptomic changes may belong to the same circuit, since we observed coordinated transcriptomic shifts across these subtypes. Glutamate signaling exhibited one of the strongest dysregulations in epilepsy, highlighted by layer-wise transcriptional changes in multiple glutamate receptor genes and strong upregulation of genes coding for AMPA receptor auxiliary subunits. Overall, our data reveal a neuronal subtype-specific molecular phenotype of epilepsy.


Assuntos
Epilepsia Resistente a Medicamentos/genética , Epilepsia do Lobo Temporal/genética , Neurônios/patologia , Lobo Temporal/patologia , Transcriptoma/genética , Adolescente , Adulto , Biópsia , Estudos de Casos e Controles , Núcleo Celular/genética , Núcleo Celular/metabolismo , Conjuntos de Dados como Assunto , Epilepsia Resistente a Medicamentos/diagnóstico , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/cirurgia , Feminino , Ácido Glutâmico/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Microdissecção , Pessoa de Meia-Idade , Modelos Genéticos , Rede Nervosa/metabolismo , Rede Nervosa/patologia , Neurônios/citologia , Neurônios/metabolismo , RNA-Seq , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Glutamato/genética , Receptores de Glutamato/metabolismo , Transdução de Sinais/genética , Análise de Célula Única , Lobo Temporal/citologia , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/cirurgia , Transcrição Genética , Regulação para Cima , Adulto Jovem
2.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

Opioid addiction is a chronic, relapsing disorder associated with persistent changes in brain plasticity. Reconfiguration of neuronal connectivity may explain heightened abuse liability in individuals with a history of chronic drug exposure. To characterize network-level changes in neuronal activity induced by chronic opiate exposure, we compared FOS expression in mice that are morphine-naïve, morphine-dependent, or have undergone 4 wk of withdrawal from chronic morphine exposure, relative to saline-exposed controls. Pairwise interregional correlations in FOS expression data were used to construct network models that reveal a persistent reduction in connectivity strength following opiate dependence. Further, we demonstrate that basal gene expression patterns are predictive of changes in FOS correlation networks in the morphine-dependent state. Finally, we determine that regions of the hippocampus, striatum, and midbrain are most influential in driving transitions between opiate-naïve and opiate-dependent brain states using a control theoretic approach. This study provides a framework for predicting the influence of specific therapeutic interventions on the state of the opiate-dependent brain.


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
3.
PLoS One ; 15(5): e0233700, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32469963

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and amyloid-beta (Aß) depositions generated by the proteolysis of amyloid precursor protein (APP) in the brain. In APPNL-F mice, APP gene was humanized and contains two familial AD mutations, and APP-unlike other mouse models of AD-is driven by the endogenous mouse APP promoter. Similar to people without apparent cognitive dysfunction but with heavy Aß plaque load, we found no significant decline in the working memory of adult APPNL-F mice, but these mice showed decline in the expression of normal anxiety. Using immunohistochemistry and 3D block-face scanning electron microscopy, we found no changes in GABAA receptor positivity and size of somatic and dendritic synapses of hippocampal interneurons. We did not find alterations in the level of expression of perineuronal nets around parvalbumin (PV) interneurons or in the density of PV- or somatostatin-positive hippocampal interneurons. However, in contrast to other investigated cell types, PV interneuron axons were occasionally mildly dystrophic around Aß plaques, and the synapses of PV-positive axon initial segment (AIS)-targeting interneurons were significantly enlarged. Our results suggest that PV interneurons are highly resistant to amyloidosis in APPNL-F mice and amyloid-induced increase in hippocampal pyramidal cell excitability may be compensated by PV-positive AIS-targeting cells. Mechanisms that make PV neurons more resilient could therefore be exploited in the treatment of AD for mitigating Aß-related inflammatory effects on neurons.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Interneurônios/metabolismo , Mutação , Rede Nervosa/metabolismo , Fragmentos de Peptídeos/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Animais , Axônios/metabolismo , Axônios/patologia , Hipocampo/patologia , Humanos , Interneurônios/patologia , Memória de Curto Prazo , Camundongos , Camundongos Transgênicos , Rede Nervosa/patologia , Fragmentos de Peptídeos/genética , Células Piramidais/metabolismo , Células Piramidais/patologia , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
4.
Nat Commun ; 11(1): 2612, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32457389

RESUMO

Tau is a hallmark pathology of Alzheimer's disease, and animal models have suggested that tau spreads from cell to cell through neuronal connections, facilitated by ß-amyloid (Aß). We test this hypothesis in humans using an epidemic spreading model (ESM) to simulate tau spread, and compare these simulations to observed patterns measured using tau-PET in 312 individuals along Alzheimer's disease continuum. Up to 70% of the variance in the overall spatial pattern of tau can be explained by our model. Surprisingly, the ESM predicts the spatial patterns of tau irrespective of whether brain Aß is present, but regions with greater Aß burden show greater tau than predicted by connectivity patterns, suggesting a role of Aß in accelerating tau spread. Altogether, our results provide evidence in humans that tau spreads through neuronal communication pathways even in normal aging, and that this process is accelerated by the presence of brain Aß.


Assuntos
Doença de Alzheimer/metabolismo , Proteínas de Membrana/metabolismo , Rede Nervosa/metabolismo , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Conectoma , Feminino , Humanos , Masculino , Modelos Neurológicos , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/patologia , Tomografia por Emissão de Pósitrons
5.
Proc Natl Acad Sci U S A ; 117(20): 11118-11125, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32358198

RESUMO

Cortical network functioning critically depends on finely tuned interactions to afford neuronal activity propagation over long distances while avoiding runaway excitation. This importance is highlighted by the pathological consequences and impaired performance resulting from aberrant network excitability in psychiatric and neurological diseases, such as epilepsy. Theory and experiment suggest that the control of activity propagation by network interactions can be adequately described by a branching process. This hypothesis is partially supported by strong evidence for balanced spatiotemporal dynamics observed in the cerebral cortex; however, evidence of a causal relationship between network interactions and cortex activity, as predicted by a branching process, is missing in humans. Here this cause-effect relationship is tested by monitoring cortex activity under systematic pharmacological reduction of cortical network interactions with antiepileptic drugs. This study reports that cortical activity cascades, presented by the propagating patterns of epileptic spikes, as well as temporal correlations decline precisely as predicted for a branching process. The results provide a missing link to the branching process theory of cortical network function with implications for understanding the foundations of cortical excitability and its monitoring in conditions like epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Eletrocorticografia , Epilepsia , Humanos , Redes Neurais de Computação , Neurônios/fisiologia
6.
J Neurosci ; 40(24): 4661-4672, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393538

RESUMO

It is widely assumed that electrical synapses in the mammalian brain, especially between interneurons, underlie neuronal synchrony. In the hippocampus, principal cells also establish electrical synapses with each other and have also been implicated in network oscillations, whereby the origin of fast electrical activity has been attributed to ectopic spikelets and dendro-dendritic or axo-axonal gap junctions. However, if electrical synapses were in axo-dendritic connections, where chemical synapses occur, the synaptic events would be mixed, having an electrical component preceding the chemical one. This type of communication is less well studied, mainly because it is not easily detected. Moreover, a possible scenario could be that an electrical synapse coexisted with a chemical one, but in a nonconductive state; hence, it would be considered inexistent. Could chemical synapses have a quiescent electrical component? If so, can silent electrical synapses be activated to be detected? We addressed this possibility, and we here report that, indeed, the connexin-36-containing glutamatergic mossy fiber synapses of the rat hippocampus express previously unrecognized electrical synapses, which are normally silent. We reveal that these synapses are pH sensitive, actuate in vitro and in vivo, and that the electrical signaling is bidirectional. With the simultaneous recording of hundreds of cells, we could reveal the existence of an electrical circuit in the hippocampus of adult rats of either sex consisting of principal cells where the nodes are interregional glutamatergic synapses containing silent but ready-to-use gap junctions.SIGNIFICANCE STATEMENT In this work, we present a series of experiments, both in vitro and in vivo, that reveal previously unrecognized silent pH-sensitive electrical synapses coexisting in one of the best studied glutamatergic synapses of the brain, the mossy fiber synapse of the hippocampus. This type of connectivity underlies an "electrical circuit" between two substructures of the adult rat hippocampus consisting of principal cells where the nodes are glutamatergic synapses containing silent but ready-to-use gap junctions. Its identification will allow us to explore the participation of such a circuit in physiological and pathophysiological functions and will provide valuable conceptual tools to understanding computational and regulatory mechanisms that may underlie network activity.


Assuntos
Sinapses Elétricas/fisiologia , Junções Comunicantes/fisiologia , Ácido Glutâmico/metabolismo , Hipocampo/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Células Cultivadas , Sinapses Elétricas/metabolismo , Junções Comunicantes/metabolismo , Hipocampo/metabolismo , Masculino , Rede Nervosa/metabolismo , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar
7.
Hum Genet ; 139(4): 545-555, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020363

RESUMO

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.


Assuntos
Potenciais de Ação , Encéfalo , Epilepsia , Proteínas de Membrana , Mutação de Sentido Incorreto , Rede Nervosa , Neurotransmissores/metabolismo , Potenciais Sinápticos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologia
8.
Nat Commun ; 11(1): 960, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075960

RESUMO

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the adult human hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. Futhermore, this model generalizes to an external set of tissue samples from prenatal human hippocampi. We examine variation in this specific gene expression pattern across the whole brain, finding a distinct anterioventral-posteriodorsal gradient. We find frontal and anterior temporal regions involved in social and motivational behaviors, and more functionally connected to the anterior hippocampus, to be clearly differentiated from posterior parieto-occipital regions involved in visuospatial cognition and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single molecular gradient.


Assuntos
Conectoma , Perfilação da Expressão Gênica , Hipocampo/fisiologia , Rede Nervosa/fisiologia , Encéfalo/metabolismo , Encéfalo/fisiologia , Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Modelos Neurológicos , Rede Nervosa/metabolismo , Vias Neurais/citologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/fisiologia , Lobo Temporal/citologia , Lobo Temporal/metabolismo , Lobo Temporal/fisiologia
9.
Nat Commun ; 11(1): 952, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075972

RESUMO

Neurons regulate their intrinsic physiological properties, which could influence network properties and contribute to behavioral plasticity. Recording from adult zebra finch brain slices we show that within each bird basal ganglia Area X-projecting (HVCX) neurons share similar spike waveform morphology and timing of spike trains, with modeling indicating similar magnitudes of five principal ion currents. These properties vary among birds in lawful relation to acoustic similarity of the birds' songs, with adult sibling pairs (same songs) sharing similar waveforms and spiking characteristics. The properties are maintained dynamically: HVCX within juveniles learning to sing show variable properties, whereas the uniformity rapidly degrades within hours in adults singing while exposed to abnormal (delayed) auditory feedback. Thus, within individual birds the population of current magnitudes covary over the arc of development, while rapidly responding to changes in feedback (in adults). This identifies network interactions with intrinsic properties that affect information storage and processing of learned vocalizations.


Assuntos
Tentilhões/fisiologia , Aprendizagem/fisiologia , Neurônios/fisiologia , Vocalização Animal/fisiologia , Potenciais de Ação , Animais , Retroalimentação Sensorial , Tentilhões/anatomia & histologia , Centro Vocal Superior/anatomia & histologia , Centro Vocal Superior/citologia , Centro Vocal Superior/metabolismo , Masculino , Modelos Neurológicos , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Plasticidade Neuronal
10.
Nat Commun ; 11(1): 1017, 2020 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-32094367

RESUMO

Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulty filtering information. Inhibitory interneurons filter information at pyramidal neurons of the anterior cingulate cortex (ACC), an integration hub for higher-order thalamic inputs important for social interaction. Humans with deletions including LMO4, an endogenous inhibitor of PTP1B, display intellectual disabilities and occasionally autism. PV-Lmo4KO mice ablate Lmo4 in PV interneurons and display ASD-like repetitive behaviors and social interaction deficits. Surprisingly, increased PV neuron-mediated peri-somatic feedforward inhibition to the pyramidal neurons causes a compensatory reduction in (somatostatin neuron-mediated) dendritic inhibition. These homeostatic changes increase filtering of mediodorsal-thalamocortical inputs but reduce filtering of cortico-cortical inputs and narrow the range of stimuli ACC pyramidal neurons can distinguish. Simultaneous ablation of PTP1B in PV-Lmo4KO neurons prevents these deficits, indicating that PTP1B activation in PV interneurons contributes to ASD-like characteristics and homeostatic maladaptation of inhibitory circuits may contribute to deficient information filtering in ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Giro do Cíngulo/fisiopatologia , Rede Nervosa/metabolismo , Parvalbuminas/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Potenciais de Ação/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Técnicas de Observação do Comportamento , Comportamento Animal/fisiologia , Dendritos/fisiologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Feminino , Giro do Cíngulo/citologia , Giro do Cíngulo/patologia , Humanos , Interneurônios/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Células Piramidais/metabolismo , Somatostatina/metabolismo , Técnicas Estereotáxicas , Tálamo/citologia , Tálamo/metabolismo
11.
J Clin Neurosci ; 73: 1-7, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32001110

RESUMO

This review focuses on the studies that have been reviewed to determine the influence of the thalamic reticular nucleus on neuropsychiatric diseases and deep brain stimulation. The literature reviewed to date describes how alterations in the thalamic reticular nucleus affect several functions that regulated brain rhythms and provokes symptoms of many disorders. The observations as the basis for the renewed interest in the thalamic reticular nucleus in experimental models and testing its effectiveness in patients with resistant neuropsychiatric disorders. The preclinical studies showed that deep brain stimulation in the thalamic reticular nucleus could have beneficial effects on EEG activity, including synchronization and desynchronization activity of the brain, as well as promoting an alleviate to neuropsychiatric diseases. These observations open up the possibility of studying the role played by neurotransmitters in the pathologic process and the deep brain stimulation in the thalamic reticular nucleus in experimental animal models and offer evidence of its possible action in the human brain.


Assuntos
Estimulação Encefálica Profunda/métodos , Transtornos Mentais/fisiopatologia , Transtornos Mentais/terapia , Núcleos Talâmicos/fisiologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Humanos , Transtornos Mentais/metabolismo , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Núcleos Talâmicos/metabolismo
12.
Cell Mol Life Sci ; 77(16): 3117-3127, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32077971

RESUMO

Complex brain circuitry with feedforward and feedback systems regulates neuronal activity, enabling neural networks to process and drive the entire spectrum of cognitive, behavioral, sensory, and motor functions. Simultaneous orchestration of distinct cells and interconnected neural circuits is underpinned by hundreds of synaptic adhesion molecules that span synaptic junctions. Dysfunction of a single molecule or molecular interaction at synapses can lead to disrupted circuit activity and brain disorders. Neuroligins, a family of cell adhesion molecules, were first identified as postsynaptic-binding partners of presynaptic neurexins and are essential for synapse specification and maturation. Here, we review recent advances in our understanding of how this family of adhesion molecules controls neuronal circuit assembly by acting in a synapse-specific manner.


Assuntos
Encéfalo/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Humanos , Rede Nervosa/metabolismo , Neurônios/metabolismo , Sinapses/metabolismo , Sinapses/fisiologia , Transmissão Sináptica/fisiologia
13.
Epilepsia ; 61(2): 310-318, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31958887

RESUMO

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is typically unwitnessed but can be preceded by seizures in the period prior to death. Peri-ictal respiratory dysfunction is a likely mechanism for some SUDEP, and central apnea has been shown following amygdala stimulation. The amygdala is enriched in neuropeptides that modulate neuronal activity and can be transiently depleted following seizures. In a postmortem SUDEP series, we sought to investigate alterations of neuropeptidergic networks in the amygdala, including cases with recent poor seizure control. METHODS: In 15 SUDEP cases, 12 epilepsy controls, and 10 nonepilepsy controls, we quantified the labeling index (LI) for galanin, neuropeptide Y (NPY), and somatostatin (SST) in the lateral, basal, and accessory basal nuclei and periamygdala cortex with whole slide scanning image analysis. Within the SUDEP group, seven had recent generalized seizures with recovery 24 hours prior to death (SUDEP-R). RESULTS: Galanin, NPY, and SST LIs were significantly lower in all amygdala regions in SUDEP cases compared to epilepsy controls (P < .05 to P < .0005), and galanin LI was lower in the lateral nucleus compared to nonepilepsy controls (P < .05). There was no difference in the LI in the SUDEP-R group compared to other SUDEP. Higher LI was noted in epilepsy controls than nonepilepsy controls; this was significant for NPY in lateral and basal nuclei (P < .005 and P < .05). SIGNIFICANCE: A reduction in galanin in the lateral nucleus in SUDEP could represent acute depletion, relevant to postictal amygdala dysfunction. In addition, increased amygdala neuropeptides in epilepsy controls support their seizure-induced modulation, which is relatively deficient in SUDEP; this could represent a vulnerability factor for amygdala dysfunction in the postictal period.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuropeptídeos/metabolismo , Morte Súbita Inesperada na Epilepsia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cadáver , Causas de Morte , Epilepsia/metabolismo , Feminino , Galanina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Neuropeptídeo Y/metabolismo , Somatostatina/metabolismo , Bancos de Tecidos , Adulto Jovem
14.
Sci Rep ; 10(1): 1298, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992762

RESUMO

Functional magnetic resonance imaging (fMRI)-based functional connectivity (FC) commonly characterizes the functional connections in the brain. Conventional quantification of FC by Pearson's correlation captures linear, time-domain dependencies among blood-oxygen-level-dependent (BOLD) signals. We examined measures to quantify FC by investigating: (i) Is Pearson's correlation sufficient to characterize FC? (ii) Can alternative measures better quantify FC? (iii) What are the implications of using alternative FC measures? FMRI analysis in healthy adult population suggested that: (i) Pearson's correlation cannot comprehensively capture BOLD inter-dependencies. (ii) Eight alternative FC measures were similarly consistent between task and resting-state fMRI, improved age-based classification and provided better association with behavioral outcomes. (iii) Formulated hypotheses were: first, in lieu of Pearson's correlation, an augmented, composite and multi-metric definition of FC is more appropriate; second, canonical large-scale brain networks may depend on the chosen FC measure. A thorough notion of FC promises better understanding of variations within a given population.


Assuntos
Conectoma , Imagem por Ressonância Magnética , Rede Nervosa , Oxigênio/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo
15.
J Neurosci ; 40(5): 944-954, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996470

RESUMO

The brilliant and often prescient hypotheses of Ramon y Cajal have proven foundational for modern neuroscience, but his statement that "In adult centers the nerve paths are something fixed, ended, immutable … " is an exception that did not stand the test of empirical study. Mechanisms of cellular and circuit-level plasticity continue to shape and reshape many regions of the adult nervous system long after the neurodevelopmental period. Initially focused on neurons alone, the field has followed a meteoric trajectory in understanding of activity-regulated neurodevelopment and ongoing neuroplasticity with an arc toward appreciating neuron-glial interactions and the role that each neural cell type plays in shaping adaptable neural circuity. In this review, as part of a celebration of the 50th anniversary of Society for Neuroscience, we provide a historical perspective, following this arc of inquiry from neuronal to neuron-glial mechanisms by which activity and experience modulate circuit structure and function. The scope of this consideration is broad, and it will not be possible to cover the wealth of knowledge about all aspects of activity-dependent circuit development and plasticity in depth.


Assuntos
Encéfalo/metabolismo , Rede Nervosa/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Animais , Encéfalo/citologia , Humanos , Rede Nervosa/citologia
16.
PLoS One ; 15(1): e0227917, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978183

RESUMO

Experimental studies highlight the important role of the extracellular matrix (ECM) in the regulation of neuronal excitability and synaptic connectivity in the nervous system. In its turn, the neural ECM is formed in an activity-dependent manner. Its maturation closes the so-called critical period of neural development, stabilizing the efficient configurations of neural networks in the brain. ECM is locally remodeled by proteases secreted and activated in an activity-dependent manner into the extracellular space and this process is important for physiological synaptic plasticity. We ask if ECM remodeling may be exaggerated under pathological conditions and enable activity-dependent switches between different regimes of ECM expression. We consider an analytical model based on known mechanisms of interaction between neuronal activity and expression of ECM, ECM receptors and ECM degrading proteases. We demonstrate that either inhibitory or excitatory influence of ECM on neuronal activity may lead to the bistability of ECM expression, so two stable stationary states are observed. Noteworthy, only in the case when ECM has predominant inhibitory influence on neurons, the bistability is dependent on the activity of proteases. Excitatory ECM-neuron feedback influences may also result in spontaneous oscillations of ECM expression, which may coexist with a stable stationary state. Thus, ECM-neuronal interactions support switches between distinct dynamic regimes of ECM expression, possibly representing transitions into disease states associated with remodeling of brain ECM.


Assuntos
Matriz Extracelular/genética , Neurogênese/genética , Peptídeo Hidrolases/genética , Receptores de Superfície Celular/genética , Potenciais de Ação/genética , Animais , Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Modelos Teóricos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Neurônios/metabolismo , Sinapses/genética
17.
Neuron ; 105(4): 688-699.e8, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31813651

RESUMO

The mammalian striatum is involved in many complex behaviors and yet is composed largely of a single neuron class: the spiny projection neuron (SPN). It is unclear to what extent the functional specialization of the striatum is due to the molecular specialization of SPN subtypes. We sought to define the molecular and anatomical diversity of adult SPNs using single-cell RNA sequencing (scRNA-seq) and quantitative RNA in situ hybridization (ISH). We computationally distinguished discrete versus continuous heterogeneity in scRNA-seq data and found that SPNs in the striatum can be classified into four major discrete types with no implied spatial relationship between them. Within these discrete types, we find continuous heterogeneity encoding spatial gradients of gene expression and defining anatomical location in a combinatorial mechanism. Our results suggest that neuronal circuitry has a substructure at far higher resolution than is typically interrogated, which is defined by the precise identity and location of a neuron.


Assuntos
Corpo Estriado/citologia , Corpo Estriado/metabolismo , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Neurônios/metabolismo , Animais , Corpo Estriado/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Rede Nervosa/química , Neurônios/química
18.
Nat Commun ; 10(1): 5561, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31804491

RESUMO

Fast-spiking parvalbumin-expressing interneurons (PVIs) and granule cells (GCs) of the dentate gyrus receive layer-specific dendritic inhibition. Its impact on PVI and GC excitability is, however, unknown. By applying whole-cell recordings, GABA uncaging and single-cell-modeling, we show that proximal dendritic inhibition in PVIs is less efficient in lowering perforant path-mediated subthreshold depolarization than distal inhibition but both are highly efficient in silencing PVIs. These inhibitory effects can be explained by proximal shunting and distal strong hyperpolarizing inhibition. In contrast, GC proximal but not distal inhibition is the primary regulator of their excitability and recruitment. In GCs inhibition is hyperpolarizing along the entire somato-dendritic axis with similar strength. Thus, dendritic inhibition differentially controls input-output transformations in PVIs and GCs. Dendritic inhibition in PVIs is suited to balance PVI discharges in dependence on global network activity thereby providing strong and tuned perisomatic inhibition that contributes to the sparse representation of information in GC assemblies.


Assuntos
Dendritos/fisiologia , Giro Denteado/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Inibição Neural/fisiologia , Neurônios/fisiologia , Parvalbuminas/metabolismo , Potenciais de Ação/fisiologia , Animais , Giro Denteado/citologia , Giro Denteado/metabolismo , Feminino , Interneurônios/citologia , Interneurônios/metabolismo , Masculino , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos Wistar
19.
Cell Rep ; 29(13): 4646-4656.e4, 2019 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-31875567

RESUMO

Stem cell-derived neurons are generally obtained in mass cultures that lack both spatial organization and any meaningful connectivity. We implement a microfluidic system for long-term culture of human neurons with patterned projections and synaptic terminals. Co-culture of human midbrain dopaminergic and striatal medium spiny neurons on the microchip establishes an orchestrated nigro-striatal circuitry with functional dopaminergic synapses. We use this platform to dissect the mitochondrial dysfunctions associated with a genetic form of Parkinson's disease (PD) with OPA1 mutations. Remarkably, we find that axons of OPA1 mutant dopaminergic neurons exhibit a significant reduction of mitochondrial mass. This defect causes a significant loss of dopaminergic synapses, which worsens in long-term cultures. Therefore, PD-associated depletion of mitochondria at synapses might precede loss of neuronal connectivity and neurodegeneration. In vitro reconstitution of human circuitries by microfluidic technology offers a powerful system to study brain networks by establishing ordered neuronal compartments and correct synapse identity.


Assuntos
Neurônios Dopaminérgicos/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Dispositivos Lab-On-A-Chip , Mitocôndrias/metabolismo , Neostriado/metabolismo , Substância Negra/metabolismo , Sinapses/metabolismo , Axônios/metabolismo , Células Cultivadas , GTP Fosfo-Hidrolases/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética , Rede Nervosa/metabolismo , Neuritos/metabolismo , Doença de Parkinson/metabolismo
20.
Nat Rev Neurosci ; 20(12): 763-778, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31712782

RESUMO

Perceptual disturbances in psychosis, such as auditory verbal hallucinations, are associated with increased baseline activity in the associative auditory cortex and increased dopamine transmission in the associative striatum. Perceptual disturbances are also associated with perceptual biases that suggest increased reliance on prior expectations. We review theoretical models of perceptual inference and key supporting physiological evidence, as well as the anatomy of associative cortico-striatal loops that may be relevant to auditory perceptual inference. Integrating recent findings, we outline a working framework that bridges neurobiology and the phenomenology of perceptual disturbances via theoretical models of perceptual inference.


Assuntos
Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Dopamina/metabolismo , Alucinações/metabolismo , Rede Nervosa/metabolismo , Transtornos Psicóticos/metabolismo , Alucinações/psicologia , Humanos , Transtornos Psicóticos/psicologia
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