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1.
PLoS Comput Biol ; 16(8): e1008080, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745134

RESUMO

Neural computation is determined by neurons' dynamics and circuit connectivity. Uncertain and dynamic environments may require neural hardware to adapt to different computational tasks, each requiring different connectivity configurations. At the same time, connectivity is subject to a variety of constraints, placing limits on the possible computations a given neural circuit can perform. Here we examine the hypothesis that the organization of neural circuitry favors computational flexibility: that it makes many computational solutions available, given physiological constraints. From this hypothesis, we develop models of connectivity degree distributions based on constraints on a neuron's total synaptic weight. To test these models, we examine reconstructions of the mushroom bodies from the first instar larva and adult Drosophila melanogaster. We perform a Bayesian model comparison for two constraint models and a random wiring null model. Overall, we find that flexibility under a homeostatically fixed total synaptic weight describes Kenyon cell connectivity better than other models, suggesting a principle shaping the apparently random structure of Kenyon cell wiring. Furthermore, we find evidence that larval Kenyon cells are more flexible earlier in development, suggesting a mechanism whereby neural circuits begin as flexible systems that develop into specialized computational circuits.


Assuntos
Modelos Neurológicos , Rede Nervosa , Sinapses/fisiologia , Animais , Drosophila melanogaster , Larva/citologia , Larva/fisiologia , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/fisiologia
2.
PLoS Comput Biol ; 16(8): e1008118, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764742

RESUMO

Hebbian plasticity, a mechanism believed to be the substrate of learning and memory, detects and further enhances correlated neural activity. Because this constitutes an unstable positive feedback loop, it requires additional homeostatic control. Computational work suggests that in recurrent networks, the homeostatic mechanisms observed in experiments are too slow to compensate instabilities arising from Hebbian plasticity and need to be complemented by rapid compensatory processes. We suggest presynaptic inhibition as a candidate that rapidly provides stability by compensating recurrent excitation induced by Hebbian changes. Presynaptic inhibition is mediated by presynaptic GABA receptors that effectively and reversibly attenuate transmitter release. Activation of these receptors can be triggered by excess network activity, hence providing a stabilising negative feedback loop that weakens recurrent interactions on sub-second timescales. We study the stabilising effect of presynaptic inhibition in recurrent networks, in which presynaptic inhibition is implemented as a multiplicative reduction of recurrent synaptic weights in response to increasing inhibitory activity. We show that networks with presynaptic inhibition display a gradual increase of firing rates with growing excitatory weights, in contrast to traditional excitatory-inhibitory networks. This alleviates the positive feedback loop between Hebbian plasticity and network activity and thereby allows homeostasis to act on timescales similar to those observed in experiments. Our results generalise to spiking networks with a biophysically more detailed implementation of the presynaptic inhibition mechanism. In conclusion, presynaptic inhibition provides a powerful compensatory mechanism that rapidly reduces effective recurrent interactions and thereby stabilises Hebbian learning.


Assuntos
Modelos Neurológicos , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Animais , Biologia Computacional , Homeostase , Aprendizagem , Memória , Neurônios/fisiologia
3.
Nat Commun ; 11(1): 3983, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770078

RESUMO

Frontal top-down cortical neurons projecting to sensory cortical regions are well-positioned to integrate long-range inputs with local circuitry in frontal cortex to implement top-down attentional control of sensory regions. How adolescence contributes to the maturation of top-down neurons and associated local/long-range input balance, and the establishment of attentional control is poorly understood. Here we combine projection-specific electrophysiological and rabies-mediated input mapping in mice to uncover adolescence as a developmental stage when frontal top-down neurons projecting from the anterior cingulate to visual cortex are highly functionally integrated into local excitatory circuitry and have heightened activity compared to adulthood. Chemogenetic suppression of top-down neuron activity selectively during adolescence, but not later periods, produces long-lasting visual attentional behavior deficits, and results in excessive loss of local excitatory inputs in adulthood. Our study reveals an adolescent sensitive period when top-down neurons integrate local circuits with long-range connectivity to produce attentional behavior.


Assuntos
Envelhecimento/fisiologia , Atenção/fisiologia , Comportamento Animal/fisiologia , Neurônios/fisiologia , Potenciais de Ação/fisiologia , Animais , Channelrhodopsins/metabolismo , Giro do Cíngulo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Inibição Neural/fisiologia , Terminações Pré-Sinápticas/fisiologia , Raiva/fisiopatologia , Sinapses/fisiologia , Visão Ocular/fisiologia
4.
PLoS Comput Biol ; 16(7): e1008075, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32730255

RESUMO

We previously proposed, on theoretical grounds, that the cerebellum must regulate the dimensionality of its neuronal activity during motor learning and control to cope with the low firing frequency of inferior olive neurons, which form one of two major inputs to the cerebellar cortex. Such dimensionality regulation is possible via modulation of electrical coupling through the gap junctions between inferior olive neurons by inhibitory GABAergic synapses. In addition, we previously showed in simulations that intermediate coupling strengths induce chaotic firing of inferior olive neurons and increase their information carrying capacity. However, there is no in vivo experimental data supporting these two theoretical predictions. Here, we computed the levels of synchrony, dimensionality, and chaos of the inferior olive code by analyzing in vivo recordings of Purkinje cell complex spike activity in three different coupling conditions: carbenoxolone (gap junctions blocker), control, and picrotoxin (GABA-A receptor antagonist). To examine the effect of electrical coupling on dimensionality and chaotic dynamics, we first determined the physiological range of effective coupling strengths between inferior olive neurons in the three conditions using a combination of a biophysical network model of the inferior olive and a novel Bayesian model averaging approach. We found that effective coupling co-varied with synchrony and was inversely related to the dimensionality of inferior olive firing dynamics, as measured via a principal component analysis of the spike trains in each condition. Furthermore, for both the model and the data, we found an inverted U-shaped relationship between coupling strengths and complexity entropy, a measure of chaos for spiking neural data. These results are consistent with our hypothesis according to which electrical coupling regulates the dimensionality and the complexity in the inferior olive neurons in order to optimize both motor learning and control of high dimensional motor systems by the cerebellum.


Assuntos
Neurônios/fisiologia , Núcleo Olivar/fisiologia , Potenciais de Ação , Animais , Teorema de Bayes , Cerebelo/fisiologia , Simulação por Computador , Feminino , Junções Comunicantes/fisiologia , Modelos Neurológicos , Modelos Estatísticos , Dinâmica não Linear , Picrotoxina/farmacologia , Probabilidade , Células de Purkinje/fisiologia , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia
5.
PLoS Pathog ; 16(7): e1008654, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32673372

RESUMO

Prion protein (PrP) mutations are linked to genetic prion diseases, a class of phenotypically heterogeneous neurodegenerative disorders with invariably fatal outcome. How mutant PrP triggers neurodegeneration is not known. Synaptic dysfunction precedes neuronal loss but it is not clear whether, and through which mechanisms, disruption of synaptic activity ultimately leads to neuronal death. Here we show that mutant PrP impairs the secretory trafficking of AMPA receptors (AMPARs). Specifically, intracellular retention of the GluA2 subunit results in synaptic exposure of GluA2-lacking, calcium-permeable AMPARs, leading to increased calcium permeability and enhanced sensitivity to excitotoxic cell death. Mutant PrPs linked to different genetic prion diseases affect AMPAR trafficking and function in different ways. Our findings identify AMPARs as pathogenic targets in genetic prion diseases, and support the involvement of excitotoxicity in neurodegeneration. They also suggest a mechanistic explanation for how different mutant PrPs may cause distinct disease phenotypes.


Assuntos
Cálcio/metabolismo , Neurônios/metabolismo , Proteínas PrPSc/metabolismo , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Animais , Morte Celular/fisiologia , Camundongos , Permeabilidade , Transporte Proteico/fisiologia
6.
Science ; 369(6501): 253-254, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32675362
7.
Phys Rev Lett ; 125(2): 028101, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32701351

RESUMO

We propose an analytically tractable neural connectivity model with power-law distributed synaptic strengths. When threshold neurons with biologically plausible number of incoming connections are considered, our model features a continuous transition to chaos and can reproduce biologically relevant low activity levels and scale-free avalanches, i.e., bursts of activity with power-law distributions of sizes and lifetimes. In contrast, the Gaussian counterpart exhibits a discontinuous transition to chaos and thus cannot be poised near the edge of chaos. We validate our predictions in simulations of networks of binary as well as leaky integrate-and-fire neurons. Our results suggest that heavy-tailed synaptic distribution may form a weakly informative sparse-connectivity prior that can be useful in biological and artificial adaptive systems.


Assuntos
Modelos Neurológicos , Rede Nervosa/fisiologia , Sinapses/fisiologia , Animais , Encéfalo/anatomia & histologia , Encéfalo/fisiologia , Simulação por Computador , Rede Nervosa/anatomia & histologia , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Dinâmica não Linear
8.
PLoS Comput Biol ; 16(7): e1008020, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678847

RESUMO

Adaptation to statistics of sensory inputs is an essential ability of neural systems and extends their effective operational range. Having a broad operational range facilitates to react to sensory inputs of different granularities, thus is a crucial factor for survival. The computation of auditory cues for spatial localization of sound sources, particularly the interaural level difference (ILD), has long been considered as a static process. Novel findings suggest that this process of ipsi- and contra-lateral signal integration is highly adaptive and depends strongly on recent stimulus statistics. Here, adaptation aids the encoding of auditory perceptual space of various granularities. To investigate the mechanism of auditory adaptation in binaural signal integration in detail, we developed a neural model architecture for simulating functions of lateral superior olive (LSO) and medial nucleus of the trapezoid body (MNTB) composed of single compartment conductance-based neurons. Neurons in the MNTB serve as an intermediate relay population. Their signal is integrated by the LSO population on a circuit level to represent excitatory and inhibitory interactions of input signals. The circuit incorporates an adaptation mechanism operating at the synaptic level based on local inhibitory feedback signals. The model's predictive power is demonstrated in various simulations replicating physiological data. Incorporating the innovative adaptation mechanism facilitates a shift in neural responses towards the most effective stimulus range based on recent stimulus history. The model demonstrates that a single LSO neuron quickly adapts to these stimulus statistics and, thus, can encode an extended range of ILDs in the ipsilateral hemisphere. Most significantly, we provide a unique measurement of the adaptation efficacy of LSO neurons. Prerequisite of normal function is an accurate interaction of inhibitory and excitatory signals, a precise encoding of time and a well-tuned local feedback circuit. We suggest that the mechanisms of temporal competitive-cooperative interaction and the local feedback mechanism jointly sensitize the circuit to enable a response shift towards contra-lateral and ipsi-lateral stimuli, respectively.


Assuntos
Biologia Computacional , Neurônios/fisiologia , Núcleo Olivar/fisiologia , Sinapses/fisiologia , Corpo Trapezoide/fisiologia , Estimulação Acústica , Potenciais de Ação , Algoritmos , Animais , Vias Auditivas/fisiologia , Limiar Auditivo , Simulação por Computador , Sinais (Psicologia) , Gerbillinae , Humanos , Modelos Neurológicos , Distribuição Normal , Receptores de GABA/fisiologia , Reprodutibilidade dos Testes , Som , Localização de Som , Complexo Olivar Superior/fisiologia
9.
PLoS Comput Biol ; 16(7): e1008015, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32678848

RESUMO

Calmodulin-dependent kinase II (CaMKII) has long been known to play an important role in learning and memory as well as long term potentiation (LTP). More recently it has been suggested that it might be involved in the time averaging of synaptic signals, which can then lead to the high precision of information stored at a single synapse. However, the role of the scaffolding molecule, neurogranin (Ng), in governing the dynamics of CaMKII is not yet fully understood. In this work, we adopt a rule-based modeling approach through the Monte Carlo method to study the effect of Ca2+ signals on the dynamics of CaMKII phosphorylation in the postsynaptic density (PSD). Calcium surges are observed in synaptic spines during an EPSP and back-propagating action potential due to the opening of NMDA receptors and voltage dependent calcium channels. Using agent-based models, we computationally investigate the dynamics of phosphorylation of CaMKII monomers and dodecameric holoenzymes. The scaffolding molecule, Ng, when present in significant concentration, limits the availability of free calmodulin (CaM), the protein which activates CaMKII in the presence of calcium. We show that Ng plays an important modulatory role in CaMKII phosphorylation following a surge of high calcium concentration. We find a non-intuitive dependence of this effect on CaM concentration that results from the different affinities of CaM for CaMKII depending on the number of calcium ions bound to the former. It has been shown previously that in the absence of phosphatase, CaMKII monomers integrate over Ca2+ signals of certain frequencies through autophosphorylation (Pepke et al, Plos Comp. Bio., 2010). We also study the effect of multiple calcium spikes on CaMKII holoenzyme autophosphorylation, and show that in the presence of phosphatase, CaMKII behaves as a leaky integrator of calcium signals, a result that has been recently observed in vivo. Our models predict that the parameters of this leaky integrator are finely tuned through the interactions of Ng, CaM, CaMKII, and PP1, providing a mechanism to precisely control the sensitivity of synapses to calcium signals. Author Summary not valid for PLOS ONE submissions.


Assuntos
Sinalização do Cálcio , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Calmodulina/metabolismo , Neurogranina/metabolismo , Potenciais de Ação , Animais , Área Sob a Curva , Biologia Computacional , Simulação por Computador , Potenciação de Longa Duração , Camundongos , Método de Monte Carlo , Plasticidade Neuronal , Fosforilação , Densidade Pós-Sináptica/metabolismo , Ligação Proteica , Receptores de N-Metil-D-Aspartato/metabolismo , Software , Sinapses/fisiologia , Fatores de Tempo
10.
PLoS Comput Biol ; 16(7): e1008099, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32706788

RESUMO

Next-generation sequencing (NGS) technology has become a powerful tool for dissecting the molecular and pathological signatures of a variety of human diseases. However, the limited availability of biological samples from different disease stages is a major hurdle in studying disease progressions and identifying early pathological changes. Deep learning techniques have recently begun to be applied to analyze NGS data and thereby predict the progression of biological processes. In this study, we applied a deep learning technique called generative adversarial networks (GANs) to predict the molecular progress of Alzheimer's disease (AD). We successfully applied GANs to analyze RNA-seq data from a 5xFAD mouse model of AD, which recapitulates major AD features of massive amyloid-ß (Aß) accumulation in the brain. We examined how the generator is featured to have specific-sample generation and biological gene association. Based on the above observations, we suggested virtual disease progress by latent space interpolation to yield the transition curves of various genes with pathological changes from normal to AD state. By performing pathway analysis based on the transition curve patterns, we identified several pathological processes with progressive changes, such as inflammatory systems and synapse functions, which have previously been demonstrated to be involved in the pathogenesis of AD. Interestingly, our analysis indicates that alteration of cholesterol biosynthesis begins at a very early stage of AD, suggesting that it is the first effect to mediate the cholesterol metabolism of AD downstream of Aß accumulation. Here, we suggest that GANs are a useful tool to study disease progression, leading to the identification of early pathological signatures.


Assuntos
Doença de Alzheimer/fisiopatologia , RNA-Seq , Algoritmos , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Colesterol/metabolismo , Análise por Conglomerados , Aprendizado Profundo , Modelos Animais de Doenças , Progressão da Doença , Humanos , Inflamação , Camundongos , Modelos Genéticos , RNA Mensageiro/metabolismo , Sinapses/metabolismo , Lobo Temporal/metabolismo , Sequenciamento Completo do Exoma
11.
PLoS Comput Biol ; 16(7): e1008016, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716912

RESUMO

The mammalian sensory cortex is composed of multiple types of inhibitory and excitatory neurons, which form sophisticated microcircuits for processing and transmitting sensory information. Despite rapid progress in understanding the function of distinct neuronal populations, the parameters of connectivity that are required for the function of these microcircuits remain unknown. Recent studies found that two most common inhibitory interneurons, parvalbumin- (PV) and somatostatin-(SST) positive interneurons control sound-evoked responses, temporal adaptation and network dynamics in the auditory cortex (AC). These studies can inform our understanding of parameters for the connectivity of excitatory-inhibitory cortical circuits. Specifically, we asked whether a common microcircuit can account for the disparate effects found in studies by different groups. By starting with a cortical rate model, we find that a simple current-compensating mechanism accounts for the experimental findings from multiple groups. They key mechanisms are two-fold. First, PVs compensate for reduced SST activity when thalamic inputs are strong with less compensation when thalamic inputs are weak. Second, SSTs are generally disinhibited by reduced PV activity regardless of thalamic input strength. These roles are augmented by plastic synapses. These roles reproduce the differential effects of PVs and SSTs in stimulus-specific adaptation, forward suppression and tuning-curve adaptation, as well as the influence of PVs on feedforward functional connectivity in the circuit. This circuit exhibits a balance of inhibitory and excitatory currents that persists on stimulation. This approach brings together multiple findings from different laboratories and identifies a circuit that can be used in future studies of upstream and downstream sensory processing.


Assuntos
Córtex Auditivo/fisiologia , Biologia Computacional , Interneurônios/fisiologia , Modelos Neurológicos , Optogenética , Algoritmos , Animais , Simulação por Computador , Humanos , Interneurônios/classificação , Sinapses/fisiologia , Tálamo/fisiologia , Fatores de Tempo
12.
J Alzheimers Dis ; 76(1): 21-25, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32538855

RESUMO

There are a number of potential implications for the field of Alzheimer's disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19.


Assuntos
Doença de Alzheimer , Infecções por Coronavirus , Diabetes Mellitus Tipo 2 , Interferon Tipo I , Pandemias , Pneumonia Viral , Idoso , Betacoronavirus , Humanos , Sinapses
13.
Science ; 368(6496)2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32527803

RESUMO

Regulation of neurotransmitter receptor content at synapses is achieved through a dynamic equilibrium between biogenesis and degradation pathways, receptor stabilization at synaptic sites, and receptor trafficking in and out synapses. In the past 20 years, the movements of receptors to and from synapses have emerged as a series of highly regulated processes that mediate postsynaptic plasticity. Our understanding of the properties and roles of receptor movements has benefited from technological advances in receptor labeling and tracking capacities, as well as from new methods to interfere with their movements. Focusing on two key glutamatergic receptors, we review here our latest understanding of the characteristics of receptor movements and their role in tuning the efficacy of synaptic transmission in health and brain disease.


Assuntos
Receptores de Glutamato/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Encefalopatias/metabolismo , Humanos , Plasticidade Neuronal , Ácido gama-Aminobutírico/fisiologia
14.
PLoS Comput Biol ; 16(6): e1007265, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32516336

RESUMO

Modern electrophysiological recordings and optical imaging techniques have revealed a diverse spectrum of spatiotemporal neural activities underlying fundamental cognitive processing. Oscillations, traveling waves and other complex population dynamical patterns are often concomitant with sensory processing, information transfer, decision making and memory consolidation. While neural population models such as neural mass, population density and kinetic theoretical models have been used to capture a wide range of the experimentally observed dynamics, a full account of how the multi-scale dynamics emerges from the detailed biophysical properties of individual neurons and the network architecture remains elusive. Here we apply a recently developed coarse-graining framework for reduced-dimensional descriptions of neuronal networks to model visual cortical dynamics. We show that, without introducing any new parameters, how a sequence of models culminating in an augmented system of spatially-coupled ODEs can effectively model a wide range of the observed cortical dynamics, ranging from visual stimulus orientation dynamics to traveling waves induced by visual illusory stimuli. In addition to an efficient simulation method, this framework also offers an analytic approach to studying large-scale network dynamics. As such, the dimensional reduction naturally leads to mesoscopic variables that capture the interplay between neuronal population stochasticity and network architecture that we believe to underlie many emergent cortical phenomena.


Assuntos
Córtex Cerebral/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Oscilometria , Algoritmos , Tomada de Decisões , Fenômenos Eletrofisiológicos , Entropia , Humanos , Modelos Estatísticos , Imagem Óptica , Dinâmica Populacional , Processos Estocásticos , Sinapses/fisiologia
15.
Nat Commun ; 11(1): 2979, 2020 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-32532981

RESUMO

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity. Its expression is mediated by the removal of AMPA receptors from postsynaptic membranes. Under basal conditions, endocytosed AMPA receptors are rapidly recycled back to the plasma membrane. In NMDAR-LTD, however, they are diverted to late endosomes for degradation. The mechanism for this switch is largely unclear. Additionally, the inducibility of NMDAR-LTD is greatly reduced in adulthood. The underlying mechanism and physiological significance of this phenomenon are elusive. Here, we report that autophagy inhibition is essential for the induction and developmental dampening of NMDAR-LTD. Autophagy is inhibited during NMDAR-LTD to decrease endocytic recycling. Autophagy inhibition is both necessary and sufficient for LTD induction. In adulthood, autophagy is up-regulated to make LTD induction harder, thereby preventing the adverse effect of excessive LTD on memory consolidation. These findings reveal the unrecognized functions of autophagy in synaptic plasticity, endocytic recycling, and memory.


Assuntos
Autofagia/fisiologia , Endocitose/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia , Animais , Autofagia/genética , Células Cultivadas , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Cultura de Tecidos
16.
Science ; 369(6501): 270-275, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32527927

RESUMO

Synapses connect neurons together to form the circuits of the brain, and their molecular composition controls innate and learned behavior. We analyzed the molecular and morphological diversity of 5 billion excitatory synapses at single-synapse resolution across the mouse brain from birth to old age. A continuum of changes alters synapse composition in all brain regions across the life span. Expansion in synapse diversity produces differentiation of brain regions until early adulthood, and compositional changes cause dedifferentiation in old age. The spatiotemporal synaptome architecture of the brain potentially accounts for life-span transitions in intellectual ability, memory, and susceptibility to behavioral disorders.


Assuntos
Encéfalo , Sinapses , Animais , Atlas como Assunto , Encéfalo/fisiologia , Encéfalo/ultraestrutura , Conjuntos de Dados como Assunto , Longevidade , Masculino , Camundongos , Neurônios/fisiologia , Sinapses/fisiologia , Sinaptossomos/fisiologia , Sinaptossomos/ultraestrutura
17.
Proc Natl Acad Sci U S A ; 117(25): 14464-14472, 2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32518114

RESUMO

Assemblies are large populations of neurons believed to imprint memories, concepts, words, and other cognitive information. We identify a repertoire of operations on assemblies. These operations correspond to properties of assemblies observed in experiments, and can be shown, analytically and through simulations, to be realizable by generic, randomly connected populations of neurons with Hebbian plasticity and inhibition. Assemblies and their operations constitute a computational model of the brain which we call the Assembly Calculus, occupying a level of detail intermediate between the level of spiking neurons and synapses and that of the whole brain. The resulting computational system can be shown, under assumptions, to be, in principle, capable of carrying out arbitrary computations. We hypothesize that something like it may underlie higher human cognitive functions such as reasoning, planning, and language. In particular, we propose a plausible brain architecture based on assemblies for implementing the syntactic processing of language in cortex, which is consistent with recent experimental results.


Assuntos
Córtex Cerebral/fisiologia , Cognição/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Sinapses/fisiologia , Córtex Cerebral/citologia , Simulação por Computador , Humanos , Idioma
18.
Nat Commun ; 11(1): 3208, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32587250

RESUMO

Inner hair cells (IHCs) are the primary receptors for hearing. They are housed in the cochlea and convey sound information to the brain via synapses with the auditory nerve. IHCs have been thought to be electrically and metabolically independent from each other. We report that, upon developmental maturation, in mice 30% of the IHCs are electrochemically coupled in 'mini-syncytia'. This coupling permits transfer of fluorescently-labeled metabolites and macromolecular tracers. The membrane capacitance, Ca2+-current, and resting current increase with the number of dye-coupled IHCs. Dual voltage-clamp experiments substantiate low resistance electrical coupling. Pharmacology and tracer permeability rule out coupling by gap junctions and purinoceptors. 3D electron microscopy indicates instead that IHCs are coupled by membrane fusion sites. Consequently, depolarization of one IHC triggers presynaptic Ca2+-influx at active zones in the entire mini-syncytium. Based on our findings and modeling, we propose that IHC-mini-syncytia enhance sensitivity and reliability of cochlear sound encoding.


Assuntos
Cóclea , Células Ciliadas Auditivas Internas , Audição/fisiologia , Animais , Sinalização do Cálcio , Cóclea/citologia , Cóclea/inervação , Nervo Coclear/metabolismo , Tomografia com Microscopia Eletrônica , Células Gigantes , Células Ciliadas Auditivas Internas/citologia , Células Ciliadas Auditivas Internas/fisiologia , Camundongos , Técnicas de Patch-Clamp , Roedores/fisiologia , Sinapses/metabolismo
19.
Nat Commun ; 11(1): 2753, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488078

RESUMO

Imbuing bio-inspired sensory devices with intelligent functions of human sensory organs has been limited by challenges in emulating the preprocessing abilities of sensory organs such as reception, filtering, adaptation, and sensory memory at the device level itself. Merkel cells, which is a part of tactile sensory organs, form synapse-like connections with afferent neuron terminals referred to as Merkel cell-neurite complexes. Here, inspired by structure and intelligent functions of Merkel cell-neurite complexes, we report a flexible, artificial, intrinsic-synaptic tactile sensory organ that mimics synapse-like connections using an organic synaptic transistor with ferroelectric nanocomposite gate dielectric of barium titanate nanoparticles and poly(vinylidene fluoride-trifluoroethylene). Modulation of the post-synaptic current of the device induced by ferroelectric dipole switching due to triboelectric-capacitive coupling under finger touch allowed reception and slow adaptation. Modulation of synaptic weight by varying the nanocomposite composition of gate dielectric layer enabled tuning of filtering and sensory memory functions.


Assuntos
Órgãos Artificiais , Células Receptoras Sensoriais/fisiologia , Tato/fisiologia , Técnicas Biossensoriais/instrumentação , Humanos , Aprendizagem/fisiologia , Memória/fisiologia , Células de Merkel , Neuritos , Sinapses/fisiologia , Percepção do Tato , Transistores Eletrônicos
20.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
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