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1.
PLoS Comput Biol ; 16(9): e1008192, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32946433

RESUMO

Balanced excitation and inhibition is widely observed in cortex. How does this balance shape neural computations and stimulus representations? This question is often studied using computational models of neuronal networks in a dynamically balanced state. But balanced network models predict a linear relationship between stimuli and population responses. So how do cortical circuits implement nonlinear representations and computations? We show that every balanced network architecture admits stimuli that break the balanced state and these breaks in balance push the network into a "semi-balanced state" characterized by excess inhibition to some neurons, but an absence of excess excitation. The semi-balanced state produces nonlinear stimulus representations and nonlinear computations, is unavoidable in networks driven by multiple stimuli, is consistent with cortical recordings, and has a direct mathematical relationship to artificial neural networks.


Assuntos
Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Dinâmica não Linear , Animais , Córtex Cerebral/fisiologia , Biologia Computacional , Redes Neurais de Computação , Sinapses/fisiologia
2.
Nat Commun ; 11(1): 4559, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917906

RESUMO

The temporal embryonic origins of cortical GABA neurons are critical for their specialization. In the neonatal hippocampus, GABA cells born the earliest (ebGABAs) operate as 'hubs' by orchestrating population synchrony. However, their adult fate remains largely unknown. To fill this gap, we have examined CA1 ebGABAs using a combination of electrophysiology, neurochemical analysis, optogenetic connectivity mapping as well as ex vivo and in vivo calcium imaging. We show that CA1 ebGABAs not only operate as hubs during development, but also maintain distinct morpho-physiological and connectivity profiles, including a bias for long-range targets and local excitatory inputs. In vivo, ebGABAs are activated during locomotion, correlate with CA1 cell assemblies and display high functional connectivity. Hence, ebGABAs are specified from birth to ensure unique functions throughout their lifetime. In the adult brain, this may take the form of a long-range hub role through the coordination of cell assemblies across distant regions.


Assuntos
Neurônios GABAérgicos/fisiologia , Hipocampo/fisiologia , Animais , Axônios , Encéfalo , Região CA1 Hipocampal/fisiologia , Feminino , Masculino , Camundongos , Modelos Animais , Vias Neurais/fisiologia , Optogenética , Sinapses/fisiologia
3.
Nat Commun ; 11(1): 4632, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934230

RESUMO

Mapping neuroanatomy is a foundational goal towards understanding brain function. Electron microscopy (EM) has been the gold standard for connectivity analysis because nanoscale resolution is necessary to unambiguously resolve synapses. However, molecular information that specifies cell types is often lost in EM reconstructions. To address this, we devise a light microscopy approach for connectivity analysis of defined cell types called spectral connectomics. We combine multicolor labeling (Brainbow) of neurons with multi-round immunostaining Expansion Microscopy (miriEx) to simultaneously interrogate morphology, molecular markers, and connectivity in the same brain section. We apply this strategy to directly link inhibitory neuron cell types with their morphologies. Furthermore, we show that correlative Brainbow and endogenous synaptic machinery immunostaining can define putative synaptic connections between neurons, as well as map putative inhibitory and excitatory inputs. We envision that spectral connectomics can be applied routinely in neurobiology labs to gain insights into normal and pathophysiological neuroanatomy.


Assuntos
Conectoma/métodos , Microscopia/métodos , Neurônios/fisiologia , Animais , Encéfalo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neuroanatomia , Neurônios/química , Sinapses/química , Sinapses/fisiologia
4.
PLoS Comput Biol ; 16(8): e1007790, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32841234

RESUMO

The impairment of cognitive function in Alzheimer's disease is clearly correlated to synapse loss. However, the mechanisms underlying this correlation are only poorly understood. Here, we investigate how the loss of excitatory synapses in sparsely connected random networks of spiking excitatory and inhibitory neurons alters their dynamical characteristics. Beyond the effects on the activity statistics, we find that the loss of excitatory synapses on excitatory neurons reduces the network's sensitivity to small perturbations. This decrease in sensitivity can be considered as an indication of a reduction of computational capacity. A full recovery of the network's dynamical characteristics and sensitivity can be achieved by firing rate homeostasis, here implemented by an up-scaling of the remaining excitatory-excitatory synapses. Mean-field analysis reveals that the stability of the linearised network dynamics is, in good approximation, uniquely determined by the firing rate, and thereby explains why firing rate homeostasis preserves not only the firing rate but also the network's sensitivity to small perturbations.


Assuntos
Doença de Alzheimer/fisiopatologia , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Sinapses/fisiologia , Homeostase/fisiologia , Humanos
5.
PLoS Biol ; 18(8): e3000826, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776935

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and ßCaMKII-deficient (αßCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αßCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αßCaMKII DKO neurons was restored by active ßCaMKII but not inactive ßCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to ßCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cálcio/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/genética , Animais , Astrócitos/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fosforilação , Cultura Primária de Células , Subunidades Proteicas/deficiência , Sinapses/fisiologia , Transmissão Sináptica , Imagem com Lapso de Tempo
6.
Yakugaku Zasshi ; 140(8): 985-992, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32741872

RESUMO

Central neural circuits in the brain receive and integrate environmental and internal information to enable the animals to execute appropriate behaviors and physiological responses. Communication between the brain and peripheral organs via peripheral neural circuits maintains energy homeostasis in the body. Therefore it is important to investigate the anatomical organization of central and peripheral neural circuits for elucidating the mechanisms of energy homeostasis. Transsynaptic viral tracers can travel through connected neurons via synaptic connections and have been used to delineate the anatomical organization of neural circuits with specific functions. Herein, I review our recent studies investigating neural circuits and their involvement in physiological changes using transsynaptic tracers.


Assuntos
Encéfalo/fisiologia , Herpesvirus Suídeo 1 , Vias Neurais/fisiologia , Sinapses/fisiologia , Hormônio Liberador da Corticotropina , Metabolismo Energético , Homeostase , Hipotálamo
7.
J Pharmacol Sci ; 144(2): 76-82, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32736867

RESUMO

Astrocytes, comprising the primary glial-cell type, are involved in the formation and maturation of synapses, and thus contribute to sustainable synaptic transmission between neurons. Given that the animals in higher phylogenetic tree have brains with a higher density of glial cells with respect to neurons, there is a possibility that the relative astrocytic density directly influences synaptic transmission. However, the notion has not been tested thoroughly. Here we addressed it, by using a primary culture preparation where single hippocampal neurons are surrounded by a variable but a countable number of cortical astrocytes in dot-patterned microislands, and recording synaptic transmission by patch-clamp electrophysiology. Neurons with a higher astrocytic density showed a higher amplitude of the evoked excitatory postsynaptic current than that of neurons with a lower astrocytic density. The size of the readily releasable pool of synaptic vesicles per neuron was significantly larger. The frequency of spontaneous synaptic transmission was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was comparable, but the percentage of functional ones was increased, indicating a lower ratio of presynaptically silent synapses. Taken together, the higher astrocytic density enhanced excitatory synaptic transmission by increasing the fraction of functional synapses through presynaptic un-silencing.


Assuntos
Astrócitos/fisiologia , Encéfalo/citologia , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Astrócitos/patologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores , Feminino , Camundongos Endogâmicos ICR , Neurônios/patologia , Filogenia , Gravidez
8.
Nat Commun ; 11(1): 4250, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843635

RESUMO

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/fisiopatologia , Memória de Curto Prazo/fisiologia , Esquizofrenia/fisiopatologia , Sinapses/fisiologia , Adolescente , Adulto , Encefalite Antirreceptor de N-Metil-D-Aspartato/psicologia , Feminino , Humanos , Masculino , Modelos Neurológicos , Rede Nervosa/fisiopatologia , Plasticidade Neuronal , Córtex Pré-Frontal/fisiopatologia , Receptores de N-Metil-D-Aspartato/fisiologia , Psicologia do Esquizofrênico , Adulto Jovem
9.
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
10.
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
11.
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
12.
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
13.
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
14.
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
15.
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
16.
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
17.
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
19.
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
20.
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
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