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1.
PLoS Genet ; 16(8): e1008942, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764744

RESUMO

To remodel functional neuronal connectivity, neurons often alter dendrite arbors through elimination and subsequent regeneration of dendritic branches. However, the intrinsic mechanisms underlying this developmentally programmed dendrite regeneration and whether it shares common machinery with injury-induced regeneration remain largely unknown. Drosophila class IV dendrite arborization (C4da) sensory neurons regenerate adult-specific dendrites after eliminating larval dendrites during metamorphosis. Here we show that the microRNA miR-87 is a critical regulator of dendrite regeneration in Drosophila. miR-87 knockout impairs dendrite regeneration after developmentally-programmed pruning, whereas miR-87 overexpression in C4da neurons leads to precocious initiation of dendrite regeneration. Genetic analyses indicate that the transcriptional repressor Tramtrack69 (Ttk69) is a functional target for miR-87-mediated repression as ttk69 expression is increased in miR-87 knockout neurons and reducing ttk69 expression restores dendrite regeneration to mutants lacking miR-87 function. We further show that miR-87 is required for dendrite regeneration after acute injury in the larval stage, providing a mechanistic link between developmentally programmed and injury-induced dendrite regeneration. These findings thus indicate that miR-87 promotes dendrite regrowth during regeneration at least in part through suppressing Ttk69 in Drosophila sensory neurons and suggest that developmental and injury-induced dendrite regeneration share a common intrinsic mechanism to reactivate dendrite growth.


Assuntos
Proteínas de Drosophila/genética , Metamorfose Biológica/genética , MicroRNAs/genética , Regeneração Nervosa/genética , Proteínas Repressoras/genética , Animais , Dendritos/genética , Dendritos/fisiologia , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Células Receptoras Sensoriais/metabolismo
2.
PLoS Comput Biol ; 16(7): e1007955, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32649658

RESUMO

During the exploration of novel environments, place fields are rapidly formed in hippocampal CA1 neurons. Place cell firing rate increases in early stages of exploration of novel environments but returns to baseline levels in familiar environments. Although similar in amplitude and width, place fields in familiar environments are more stable than in novel environments. We propose a computational model of the hippocampal CA1 network, which describes the formation, dynamics and stabilization of place fields. We show that although somatic disinhibition is sufficient to form place fields, dendritic inhibition along with synaptic plasticity is necessary for place field stabilization. Our model suggests that place cell stability can be attributed to strong excitatory synaptic weights and strong dendritic inhibition. We show that the interplay between somatic and dendritic inhibition balances the increased excitatory weights, such that place cells return to their baseline firing rate after exploration. Our model suggests that different types of interneurons are essential to unravel the mechanisms underlying place field plasticity. Finally, we predict that artificially induced dendritic events can shift place fields even after place field stabilization.


Assuntos
Região CA1 Hipocampal , Dendritos/fisiologia , Inibição Neural/fisiologia , Células de Lugar/fisiologia , Potenciais de Ação/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Biologia Computacional , Camundongos , Modelos Neurológicos , Plasticidade Neuronal/fisiologia
3.
PLoS Comput Biol ; 16(7): e1008087, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701953

RESUMO

The dynamics and the sharp onset of action potential (AP) generation have recently been the subject of intense experimental and theoretical investigations. According to the resistive coupling theory, an electrotonic interplay between the site of AP initiation in the axon and the somato-dendritic load determines the AP waveform. This phenomenon not only alters the shape of APs recorded at the soma, but also determines the dynamics of excitability across a variety of time scales. Supporting this statement, here we generalize a previous numerical study and extend it to the quantification of the input-output gain of the neuronal dynamical response. We consider three classes of multicompartmental mathematical models, ranging from ball-and-stick simplified descriptions of neuronal excitability to 3D-reconstructed biophysical models of excitatory neurons of rodent and human cortical tissue. For each model, we demonstrate that increasing the distance between the axonal site of AP initiation and the soma markedly increases the bandwidth of neuronal response properties. We finally consider the Liquid State Machine paradigm, exploring the impact of altering the site of AP initiation at the level of a neuronal population, and demonstrate that an optimal distance exists to boost the computational performance of the network in a simple classification task.


Assuntos
Potenciais de Ação , Segmento Inicial do Axônio/fisiologia , Axônios/fisiologia , Neurônios/fisiologia , Algoritmos , Animais , Córtex Cerebral/patologia , Biologia Computacional , Simulação por Computador , Dendritos/fisiologia , Humanos , Imageamento Tridimensional , Modelos Lineares , Aprendizado de Máquina , Modelos Neurológicos , Neocórtex/fisiologia , Canais de Potássio/fisiologia , Ratos
4.
PLoS Comput Biol ; 16(7): e1008078, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701987

RESUMO

Animals remember temporal links between their actions and subsequent rewards. We previously discovered a synaptic mechanism underlying such reward learning in D1 receptor (D1R)-expressing spiny projection neurons (D1 SPN) of the striatum. Dopamine (DA) bursts promote dendritic spine enlargement in a time window of only a few seconds after paired pre- and post-synaptic spiking (pre-post pairing), which is termed as reinforcement plasticity (RP). The previous study has also identified underlying signaling pathways; however, it still remains unclear how the signaling dynamics results in RP. In the present study, we first developed a computational model of signaling dynamics of D1 SPNs. The D1 RP model successfully reproduced experimentally observed protein kinase A (PKA) activity, including its critical time window. In this model, adenylate cyclase type 1 (AC1) in the spines/thin dendrites played a pivotal role as a coincidence detector against pre-post pairing and DA burst. In particular, pre-post pairing (Ca2+ signal) stimulated AC1 with a delay, and the Ca2+-stimulated AC1 was activated by the DA burst for the asymmetric time window. Moreover, the smallness of the spines/thin dendrites is crucial to the short time window for the PKA activity. We then developed a RP model for D2 SPNs, which also predicted the critical time window for RP that depended on the timing of pre-post pairing and phasic DA dip. AC1 worked for the coincidence detector in the D2 RP model as well. We further simulated the signaling pathway leading to Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and clarified the role of the downstream molecules of AC1 as the integrators that turn transient input signals into persistent spine enlargement. Finally, we discuss how such timing windows guide animals' reward learning.


Assuntos
Sinalização do Cálcio , Corpo Estriado/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Dopamina/fisiologia , Aprendizagem , Plasticidade Neuronal , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Simulação por Computador , Dendritos/fisiologia , Espinhas Dendríticas/fisiologia , Cinética , Camundongos , Neurônios/fisiologia , Receptores de Dopamina D2 , Recompensa
5.
PLoS Comput Biol ; 16(5): e1007932, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453795

RESUMO

Fast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.


Assuntos
Cloretos/química , Dendritos/fisiologia , Neurônios/fisiologia , Receptores de GABA/fisiologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Encéfalo/fisiologia , Simulação por Computador , Hipocampo/fisiologia , Humanos , Cinética , Masculino , Modelos Neurológicos , Técnicas de Cultura de Órgãos , Ligação Proteica , Células Piramidais/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A/fisiologia
6.
Proc Natl Acad Sci U S A ; 117(20): 10636-10638, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32366647

RESUMO

In a small fraction of Xenopus tadpoles, a single retinal ganglion cell (RGC) axon misprojects to the ipsilateral optic tectum. Presenting flashes of light to the ipsilateral eye causes that ipsilateral axon to fire, whereas stimulating the contralateral eye excites all other RGC inputs to the tectum. We performed time-lapse imaging of individual ipsilaterally projecting axons while stimulating either the ipsilateral or contralateral eye. Stimulating either eye alone reduced axon elaboration by increasing branch loss. New branch additions in the ipsi axon were exclusively increased by contralateral eye stimulation, which was enhanced by expressing tetanus neurotoxin (TeNT) in the ipsilateral axon, to prevent Hebbian stabilization. Together, our results reveal the existence of a non-cell-autonomous "Stentian" signal, engaged by activation of neighboring RGCs, that promotes exploratory axon branching in response to noncorrelated firing.


Assuntos
Neurogênese , Plasticidade Neuronal , Células Ganglionares da Retina/fisiologia , Potenciais de Ação , Animais , Axônios/fisiologia , Dendritos/fisiologia , Células Ganglionares da Retina/citologia , Potenciais Sinápticos , Visão Ocular , Xenopus
7.
Nat Commun ; 11(1): 2073, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350270

RESUMO

Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.


Assuntos
Doença/genética , Modelos Genéticos , Mutação de Sentido Incorreto/genética , PTEN Fosfo-Hidrolase/genética , Animais , Comportamento Animal , Caenorhabditis elegans/fisiologia , Células Cultivadas , Dendritos/fisiologia , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Ensaios Enzimáticos , Células HEK293 , Humanos , Neoplasias/genética , Sistema Nervoso/crescimento & desenvolvimento , Fosforilação , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Saccharomyces cerevisiae/metabolismo
8.
Nat Rev Neurosci ; 21(6): 303-321, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393820

RESUMO

Dendrites have always fascinated researchers: from the artistic drawings by Ramon y Cajal to the beautiful recordings of today, neuroscientists have been striving to unravel the mysteries of these structures. Theoretical work in the 1960s predicted important dendritic effects on neuronal processing, establishing computational modelling as a powerful technique for their investigation. Since then, modelling of dendrites has been instrumental in driving neuroscience research in a targeted manner, providing experimentally testable predictions that range from the subcellular level to the systems level, and their relevance extends to fields beyond neuroscience, such as machine learning and artificial intelligence. Validation of modelling predictions often requires - and drives - new technological advances, thus closing the loop with theory-driven experimentation that moves the field forward. This Review features the most important, to our understanding, contributions of modelling of dendritic computations, including those pending experimental verification, and highlights studies of successful interactions between the modelling and experimental neuroscience communities.


Assuntos
Dendritos/fisiologia , Modelos Neurológicos , Neurociências/métodos , Animais , Humanos
9.
Proc Natl Acad Sci U S A ; 117(22): 12155-12163, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430325

RESUMO

Microtubule polarity in axons and dendrites defines the direction of intracellular transport in neurons. Axons contain arrays of uniformly polarized microtubules with plus-ends facing the tips of the processes (plus-end-out), while dendrites contain microtubules with a minus-end-out orientation. It has been shown that cytoplasmic dynein, targeted to cortical actin, removes minus-end-out microtubules from axons. Here we have identified Spindly, a protein known for recruitment of dynein to kinetochores in mitosis, as a key factor required for dynein-dependent microtubule sorting in axons of Drosophila neurons. Depletion of Spindly affects polarity of axonal microtubules in vivo and in primary neuronal cultures. In addition to these defects, depletion of Spindly in neurons causes major collapse of axonal patterning in the third-instar larval brain as well as severe coordination impairment in adult flies. These defects can be fully rescued by full-length Spindly, but not by variants with mutations in its dynein-binding site. Biochemical analysis demonstrated that Spindly binds F-actin, suggesting that Spindly serves as a link between dynein and cortical actin in axons. Therefore, Spindly plays a critical role during neurodevelopment by mediating dynein-driven sorting of axonal microtubules.


Assuntos
Axônios/fisiologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Dineínas/metabolismo , Microtúbulos/fisiologia , Neurônios/fisiologia , Actinas/metabolismo , Animais , Transporte Biológico , Proteínas de Ciclo Celular/genética , Células Cultivadas , Córtex Cerebral/metabolismo , Dendritos/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Cinetocoros/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/citologia
10.
Nat Commun ; 11(1): 2101, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355170

RESUMO

Neural computation relies on the integration of synaptic inputs across a neuron's dendritic arbour. However, it is far from understood how different cell types tune this process to establish cell-type specific computations. Here, using two-photon imaging of dendritic Ca2+ signals, electrical recordings of somatic voltage and biophysical modelling, we demonstrate that four morphologically distinct types of mouse retinal ganglion cells with overlapping excitatory synaptic input (transient Off alpha, transient Off mini, sustained Off, and F-mini Off) exhibit type-specific dendritic integration profiles: in contrast to the other types, dendrites of transient Off alpha cells were spatially independent, with little receptive field overlap. The temporal correlation of dendritic signals varied also extensively, with the highest and lowest correlation in transient Off mini and transient Off alpha cells, respectively. We show that differences between cell types can likely be explained by differences in backpropagation efficiency, arising from the specific combinations of dendritic morphology and ion channel densities.


Assuntos
Dendritos/fisiologia , Células Ganglionares da Retina/citologia , Sinapses/fisiologia , Potenciais de Ação , Animais , Sinalização do Cálcio , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Neurológicos , Fótons , Retina/fisiologia
11.
PLoS Comput Biol ; 16(4): e1007756, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32251448

RESUMO

Recent advances in electron microscopy have enabled the imaging of single cells in 3D at nanometer length scale resolutions. An uncharted frontier for in silico biology is the ability to simulate cellular processes using these observed geometries. Enabling such simulations requires watertight meshing of electron micrograph images into 3D volume meshes, which can then form the basis of computer simulations of such processes using numerical techniques such as the finite element method. In this paper, we describe the use of our recently rewritten mesh processing software, GAMer 2, to bridge the gap between poorly conditioned meshes generated from segmented micrographs and boundary marked tetrahedral meshes which are compatible with simulation. We demonstrate the application of a workflow using GAMer 2 to a series of electron micrographs of neuronal dendrite morphology explored at three different length scales and show that the resulting meshes are suitable for finite element simulations. This work is an important step towards making physical simulations of biological processes in realistic geometries routine. Innovations in algorithms to reconstruct and simulate cellular length scale phenomena based on emerging structural data will enable realistic physical models and advance discovery at the interface of geometry and cellular processes. We posit that a new frontier at the intersection of computational technologies and single cell biology is now open.


Assuntos
Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Algoritmos , Simulação por Computador , Dendritos/fisiologia , Difusão , Análise de Elementos Finitos , Humanos , Modelos Biológicos , Modelos Teóricos , Software , Telas Cirúrgicas
12.
Proc Natl Acad Sci U S A ; 117(18): 10055-10066, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32312822

RESUMO

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit ACTL6B (originally named BAF53b). Accordingly, ACTL6B was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking ACTL6B showed corpus callosum hypoplasia, indicating a conserved role for ACTL6B in facilitating neural connectivity. Actl6b knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of Actl6b relieved repression of early response genes including AP1 transcription factors (Fos, Fosl2, Fosb, and Junb), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. ACTL6B loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Hipocampo/patologia , Actinas/genética , Trifosfato de Adenosina/genética , Animais , Transtorno do Espectro Autista/patologia , Comportamento Animal/fisiologia , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Pareamento Cromossômico/genética , Pareamento Cromossômico/fisiologia , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Dendritos/genética , Dendritos/fisiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Humanos , Camundongos , Camundongos Knockout , Mutação/genética , Neurônios/metabolismo , Neurônios/patologia , Fatores de Transcrição/genética
13.
PLoS Comput Biol ; 16(4): e1007175, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32310936

RESUMO

Analytical forms for neuronal firing rates are important theoretical tools for the analysis of network states. Since the 1960s, the majority of approaches have treated neurons as being electrically compact and therefore isopotential. These approaches have yielded considerable insight into how single-cell properties affect network activity; however, many neuronal classes, such as cortical pyramidal cells, are electrically extended objects. Calculation of the complex flow of electrical activity driven by stochastic spatio-temporal synaptic input streams in these structures has presented a significant analytical challenge. Here we demonstrate that an extension of the level-crossing method of Rice, previously used for compact cells, provides a general framework for approximating the firing rate of neurons with spatial structure. Even for simple models, the analytical approximations derived demonstrate a surprising richness including: independence of the firing rate to the electrotonic length for certain models, but with a form distinct to the point-like leaky integrate-and-fire model; a non-monotonic dependence of the firing rate on the number of dendrites receiving synaptic drive; a significant effect of the axonal and somatic load on the firing rate; and the role that the trigger position on the axon for spike initiation has on firing properties. The approach necessitates only calculating the mean and variances of the non-thresholded voltage and its rate of change in neuronal structures subject to spatio-temporal synaptic fluctuations. The combination of simplicity and generality promises a framework that can be built upon to incorporate increasing levels of biophysical detail and extend beyond the low-rate firing limit treated in this paper.


Assuntos
Potenciais de Ação , Axônios/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Biologia Computacional , Dendritos/fisiologia , Modelos Neurológicos , Distribuição Normal , Optogenética , Linguagens de Programação , Processos Estocásticos
14.
PLoS Comput Biol ; 16(4): e1007661, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32348299

RESUMO

In most neuronal models, ion concentrations are assumed to be constant, and effects of concentration variations on ionic reversal potentials, or of ionic diffusion on electrical potentials are not accounted for. Here, we present the electrodiffusive Pinsky-Rinzel (edPR) model, which we believe is the first multicompartmental neuron model that accounts for electrodiffusive ion concentration dynamics in a way that ensures a biophysically consistent relationship between ion concentrations, electrical charge, and electrical potentials in both the intra- and extracellular space. The edPR model is an expanded version of the two-compartment Pinsky-Rinzel (PR) model of a hippocampal CA3 neuron. Unlike the PR model, the edPR model includes homeostatic mechanisms and ion-specific leakage currents, and keeps track of all ion concentrations (Na+, K+, Ca2+, and Cl-), electrical potentials, and electrical conductivities in the intra- and extracellular space. The edPR model reproduces the membrane potential dynamics of the PR model for moderate firing activity. For higher activity levels, or when homeostatic mechanisms are impaired, the homeostatic mechanisms fail in maintaining ion concentrations close to baseline, and the edPR model diverges from the PR model as it accounts for effects of concentration changes on neuronal firing. We envision that the edPR model will be useful for the field in three main ways. Firstly, as it relaxes commonly made modeling assumptions, the edPR model can be used to test the validity of these assumptions under various firing conditions, as we show here for a few selected cases. Secondly, the edPR model should supplement the PR model when simulating scenarios where ion concentrations are expected to vary over time. Thirdly, being applicable to conditions with failed homeostasis, the edPR model opens up for simulating a range of pathological conditions, such as spreading depression or epilepsy.


Assuntos
Potenciais de Ação , Eletrofisiologia/métodos , Modelos Neurológicos , Neurônios/fisiologia , Animais , Cálcio/metabolismo , Calibragem , Simulação por Computador , Dendritos/fisiologia , Difusão , Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Homeostase , Humanos , Canais Iônicos/metabolismo , Íons , Potenciais da Membrana , Ratos
15.
Neural Netw ; 127: 110-120, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32339806

RESUMO

It was recently found that dendrites are not just a passive channel. They can perform mixed computation of analog and digital signals, and therefore can be abstracted as information processors. Moreover, dendrites possess a feedback mechanism. Motivated by these computational and feedback characteristics, this article proposes a new variant of neural-like P systems, dendrite P (DeP) systems, where neurons simulate the computational function of dendrites and perform a firing-storing process instead of the storing-firing process in spiking neural P (SNP) systems. Moreover, the behavior of the neurons is characterized by dendrite rules that are abstracted by two characteristics of dendrites. Different from the usual firing rules in SNP systems, the firing of a dendrite rule is controlled by the states of the corresponding source neurons. Therefore, DeP systems can provide a collaborative control capability for neurons. We discuss the computational power of DeP systems. In particular, it is proven that DeP systems are Turing-universal number generating/accepting devices. Moreover, we construct a small universal DeP system consisting of 115 neurons for computing functions.


Assuntos
Dendritos , Modelos Neurológicos , Redes Neurais de Computação , Potenciais de Ação/fisiologia , Dendritos/fisiologia , Humanos , Neurônios/fisiologia , Sinapses/fisiologia
16.
Proc Natl Acad Sci U S A ; 117(15): 8616-8623, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32229571

RESUMO

In the adult brain, vascular endothelial growth factor D (VEGFD) is required for structural integrity of dendrites and cognitive abilities. Alterations of dendritic architectures are hallmarks of many neurologic disorders, including stroke-induced damage caused by toxic extrasynaptic NMDA receptor (eNMDAR) signaling. Here we show that stimulation of eNMDARs causes a rapid shutoff of VEGFD expression, leading to a dramatic loss of dendritic structures. Using the mouse middle cerebral artery occlusion (MCAO) stroke model, we have established the therapeutic potential of recombinant mouse VEGFD delivered intraventricularly to preserve dendritic architecture, reduce stroke-induced brain damage, and facilitate functional recovery. An easy-to-use therapeutic intervention for stroke was developed that uses a new class of VEGFD-derived peptide mimetics and postinjury nose-to-brain delivery.


Assuntos
Lesões Encefálicas/prevenção & controle , Dendritos/fisiologia , Modelos Animais de Doenças , Mucosa Nasal/metabolismo , Fragmentos de Peptídeos/administração & dosagem , Acidente Vascular Cerebral/complicações , Fator D de Crescimento do Endotélio Vascular/administração & dosagem , Administração Intranasal , Animais , Lesões Encefálicas/etiologia , Lesões Encefálicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Recuperação de Função Fisiológica
17.
Neuron ; 106(3): 452-467.e8, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32155441

RESUMO

Dendrite arbor pattern determines the functional characteristics of a neuron. It is founded on primary branch structure, defined through cell intrinsic and transcription-factor-encoded mechanisms. Developing arbors have extensive acentrosomal microtubule dynamics, and here, we report an unexpected role for the atypical actin motor Myo6 in creating primary branch structure by specifying the position, polarity, and targeting of these events. We carried out in vivo time-lapse imaging of Drosophila adult sensory neuron differentiation, integrating machine-learning-based quantification of arbor patterning with molecular-level tracking of cytoskeletal remodeling. This revealed that Myo6 and the transcription factor Knot regulate transient surges of microtubule polymerization at dendrite tips; they drive retrograde extension of an actin filament array that specifies anterograde microtubule polymerization and guides these microtubules to subdivide the tip into multiple branches. Primary branches delineate functional compartments; this tunable branching mechanism is key to define and diversify dendrite arbor compartmentalization.


Assuntos
Dendritos/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Neurogênese , Animais , Linhagem Celular , Células Cultivadas , Dendritos/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Microtúbulos/metabolismo , Cadeias Pesadas de Miosina/genética , Fatores de Transcrição/metabolismo
18.
Nat Commun ; 11(1): 1554, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32214100

RESUMO

The brain identifies potentially salient features within continuous information streams to process hierarchical temporal events. This requires the compression of information streams, for which effective computational principles are yet to be explored. Backpropagating action potentials can induce synaptic plasticity in the dendrites of cortical pyramidal neurons. By analogy with this effect, we model a self-supervising process that increases the similarity between dendritic and somatic activities where the somatic activity is normalized by a running average. We further show that a family of networks composed of the two-compartment neurons performs a surprisingly wide variety of complex unsupervised learning tasks, including chunking of temporal sequences and the source separation of mixed correlated signals. Common methods applicable to these temporal feature analyses were previously unknown. Our results suggest the powerful ability of neural networks with dendrites to analyze temporal features. This simple neuron model may also be potentially useful in neural engineering applications.


Assuntos
Dendritos/fisiologia , Aprendizagem , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Potenciais de Ação , Encéfalo/fisiologia , Biologia Computacional , Potenciais da Membrana , Rede Nervosa
19.
Neuron ; 106(4): 566-578.e8, 2020 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-32169170

RESUMO

The balance between excitatory and inhibitory (E and I) synapses is thought to be critical for information processing in neural circuits. However, little is known about the spatial principles of E and I synaptic organization across the entire dendritic tree of mammalian neurons. We developed a new open-source reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual genetically-labeled layer 2/3 (L2/3) cortical pyramidal neurons (PNs) in vivo. We mapped over 90,000 E and I synapses across twelve L2/3 PNs and uncovered structured organization of E and I synapses across dendritic domains as well as within individual dendritic segments. Despite significant domain-specific variation in the absolute density of E and I synapses, their ratio is strikingly balanced locally across dendritic segments. Computational modeling indicates that this spatially precise E/I balance dampens dendritic voltage fluctuations and strongly impacts neuronal firing output.


Assuntos
Mapeamento Encefálico/métodos , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Sinapses , Animais , Dendritos/fisiologia , Dendritos/ultraestrutura , Humanos , Células Piramidais/fisiologia , Células Piramidais/ultraestrutura , Software , Sinapses/fisiologia , Sinapses/ultraestrutura
20.
Nat Methods ; 17(3): 291-294, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123393

RESUMO

Imaging neurons and neural circuits over large volumes at high speed and subcellular resolution is a difficult task. Incorporating a Bessel focus module into a two-photon fluorescence mesoscope, we achieved rapid volumetric imaging of neural activity over the mesoscale with synaptic resolution. We applied the technology to calcium imaging of entire dendritic spans of neurons as well as neural ensembles within multiple cortical regions over two hemispheres of the awake mouse brain.


Assuntos
Encéfalo/fisiologia , Dendritos/fisiologia , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Neurônios/fisiologia , Sinapses/fisiologia , Algoritmos , Animais , Cálcio/química , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Radiocirurgia , Ácido gama-Aminobutírico
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