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1.
Yakugaku Zasshi ; 140(10): 1207-1212, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999199

RESUMO

T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.


Assuntos
Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/fisiologia , Imidazóis/farmacologia , Neurônios/fisiologia , Compostos de Espiro/farmacologia , Acetilcolina/metabolismo , Animais , Encéfalo/fisiologia , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Fenômenos Eletrofisiológicos , Epilepsia/etiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase , Camundongos , Plasticidade Neuronal , Dor/etiologia , Ratos , Sono/fisiologia
2.
Nature ; 585(7824): 245-250, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32884146

RESUMO

Adaptive behaviour crucially depends on flexible decision-making, which in mammals relies on the frontal cortex, specifically the orbitofrontal cortex (OFC)1-9. How OFC encodes decision variables and instructs sensory areas to guide adaptive behaviour are key open questions. Here we developed a reversal learning task for head-fixed mice, monitored the activity of neurons of the lateral OFC using two-photon calcium imaging and investigated how OFC dynamically interacts with primary somatosensory cortex (S1). Mice learned to discriminate 'go' from 'no-go' tactile stimuli10,11 and adapt their behaviour upon reversal of stimulus-reward contingency ('rule switch'). Imaging individual neurons longitudinally across all behavioural phases revealed a distinct engagement of S1 and lateral OFC, with S1 neural activity reflecting initial task learning, whereas lateral OFC neurons responded saliently and transiently to the rule switch. We identified direct long-range projections from lateral OFC to S1 that can feed this activity back to S1 as value prediction error. This top-down signal updated sensory representations in S1 by functionally remapping responses in a subpopulation of neurons that was sensitive to reward history. Functional remapping crucially depended on top-down feedback as chemogenetic silencing of lateral OFC neurons disrupted reversal learning, as well as plasticity in S1. The dynamic interaction of lateral OFC with sensory cortex thus implements computations critical for value prediction that are history dependent and error based, providing plasticity essential for flexible decision-making.


Assuntos
Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Reversão de Aprendizagem/fisiologia , Córtex Somatossensorial/citologia , Córtex Somatossensorial/fisiologia , Percepção do Tato/fisiologia , Adaptação Psicológica , Animais , Mapeamento Encefálico , Sinalização do Cálcio , Tomada de Decisões/fisiologia , Discriminação Psicológica/fisiologia , Masculino , Camundongos , Estimulação Física , Células Receptoras Sensoriais/metabolismo
3.
Nat Commun ; 11(1): 4819, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968048

RESUMO

In many parts of the nervous system, experience-dependent refinement of neuronal circuits predominantly involves synapse elimination. The role of sleep in this process remains unknown. We investigated the role of sleep in experience-dependent dendritic spine elimination of layer 5 pyramidal neurons in the visual (V1) and frontal association cortex (FrA) of 1-month-old mice. We found that monocular deprivation (MD) or auditory-cued fear conditioning (FC) caused rapid spine elimination in V1 or FrA, respectively. MD- or FC-induced spine elimination was significantly reduced after total sleep or REM sleep deprivation. Total sleep or REM sleep deprivation also prevented MD- and FC-induced reduction of neuronal activity in response to visual or conditioned auditory stimuli. Furthermore, dendritic calcium spikes increased substantially during REM sleep, and the blockade of these calcium spikes prevented MD- and FC-induced spine elimination. These findings reveal an important role of REM sleep in experience-dependent synapse elimination and neuronal activity reduction.


Assuntos
Córtex Cerebral/fisiologia , Espinhas Dendríticas/fisiologia , Sono REM/fisiologia , Animais , Condicionamento Clássico , Medo/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Privação Sensorial/fisiologia , Privação do Sono , Sinapses , Córtex Visual/fisiologia
4.
Nat Commun ; 11(1): 3845, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737295

RESUMO

Many experimental studies suggest that animals can rapidly learn to identify odors and predict the rewards associated with them. However, the underlying plasticity mechanism remains elusive. In particular, it is not clear how olfactory circuits achieve rapid, data efficient learning with local synaptic plasticity. Here, we formulate olfactory learning as a Bayesian optimization process, then map the learning rules into a computational model of the mammalian olfactory circuit. The model is capable of odor identification from a small number of observations, while reproducing cellular plasticity commonly observed during development. We extend the framework to reward-based learning, and show that the circuit is able to rapidly learn odor-reward association with a plausible neural architecture. These results deepen our theoretical understanding of unsupervised learning in the mammalian brain.


Assuntos
Condicionamento Clássico/fisiologia , Rede Nervosa , Plasticidade Neuronal/fisiologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Olfato/fisiologia , Animais , Teorema de Bayes , Simulação por Computador , Mamíferos , Neurônios/citologia , Neurônios/fisiologia , Odorantes/análise , Bulbo Olfatório/fisiologia , Recompensa
5.
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
6.
PLoS Comput Biol ; 16(8): e1007659, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32764745

RESUMO

The brain consists of many interconnected networks with time-varying, partially autonomous activity. There are multiple sources of noise and variation yet activity has to eventually converge to a stable, reproducible state (or sequence of states) for its computations to make sense. We approached this problem from a control-theory perspective by applying contraction analysis to recurrent neural networks. This allowed us to find mechanisms for achieving stability in multiple connected networks with biologically realistic dynamics, including synaptic plasticity and time-varying inputs. These mechanisms included inhibitory Hebbian plasticity, excitatory anti-Hebbian plasticity, synaptic sparsity and excitatory-inhibitory balance. Our findings shed light on how stable computations might be achieved despite biological complexity. Crucially, our analysis is not limited to analyzing the stability of fixed geometric objects in state space (e.g points, lines, planes), but rather the stability of state trajectories which may be complex and time-varying.


Assuntos
Modelos Neurológicos , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Algoritmos , Animais , Encéfalo/fisiologia , Biologia Computacional , Simulação por Computador , Humanos
7.
Nat Commun ; 11(1): 4030, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32788588

RESUMO

Sensory information processing in robot skins currently rely on a centralized approach where signal transduction (on the body) is separated from centralized computation and decision-making, requiring the transfer of large amounts of data from periphery to central processors, at the cost of wiring, latency, fault tolerance and robustness. We envision a decentralized approach where intelligence is embedded in the sensing nodes, using a unique neuromorphic methodology to extract relevant information in robotic skins. Here we specifically address pain perception and the association of nociception with tactile perception to trigger the escape reflex in a sensorized robotic arm. The proposed system comprises self-healable materials and memtransistors as enabling technologies for the implementation of neuromorphic nociceptors, spiking local associative learning and communication. Configuring memtransistors as gated-threshold and -memristive switches, the demonstrated system features in-memory edge computing with minimal hardware circuitry and wiring, and enhanced fault tolerance and robustness.


Assuntos
Robótica , Processamento de Sinais Assistido por Computador , Transistores Eletrônicos , Potenciais de Ação/fisiologia , Lógica , Plasticidade Neuronal/fisiologia , Nociceptividade , Terminações Pré-Sinápticas/fisiologia
8.
Nat Commun ; 11(1): 3935, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769979

RESUMO

GABAA/glycine-mediated neuronal inhibition critically depends on intracellular chloride (Cl-) concentration which is mainly regulated by the K+-Cl- co-transporter 2 (KCC2) in the adult central nervous system (CNS). KCC2 heterogeneity thus affects information processing across CNS areas. Here, we uncover a gradient in Cl- extrusion capacity across the superficial dorsal horn (SDH) of the spinal cord (laminae I-II: LI-LII), which remains concealed under low Cl- load. Under high Cl- load or heightened synaptic drive, lower Cl- extrusion is unveiled in LI, as expected from the gradient in KCC2 expression found across the SDH. Blocking TrkB receptors increases KCC2 in LI, pointing to differential constitutive TrkB activation across laminae. Higher Cl- lability in LI results in rapidly collapsing inhibition, and a form of activity-dependent synaptic plasticity expressed as a continuous facilitation of excitatory responses. The higher metaplasticity in LI as compared to LII differentially affects sensitization to thermal and mechanical input. Thus, inconspicuous heterogeneity of Cl- extrusion across laminae critically shapes plasticity for selective nociceptive modalities.


Assuntos
Sensibilização do Sistema Nervoso Central/fisiologia , Cloretos/metabolismo , Plasticidade Neuronal/fisiologia , Nociceptividade/fisiologia , Células do Corno Posterior/fisiologia , Animais , Células Cultivadas , Masculino , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Camundongos , Modelos Neurológicos , Optogenética , Cultura Primária de Células , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Simportadores/metabolismo
9.
Proc Natl Acad Sci U S A ; 117(33): 20254-20264, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747543

RESUMO

Correlated activation of cortical neurons often occurs in the brain and repetitive correlated neuronal firing could cause long-term modifications of synaptic efficacy and intrinsic excitability. We found that repetitive optogenetic activation of neuronal populations in the mouse cortex caused enhancement of optogenetically evoked firing of local coactivated neurons as well as distant cortical neurons in both ipsilateral and contralateral hemispheres. This global enhancement of evoked responses required coactivation of a sufficiently large population of neurons either within one cortical area or distributed in several areas. Enhancement of neuronal firing was saturable after repeated episodes of coactivation, diminished by inhibition of N-methyl-d-aspartic acid receptors, and accompanied by elevated excitatory postsynaptic potentials, all consistent with activity-induced synaptic potentiation. Chemogenetic inhibition of neuronal activity of the thalamus decreased the enhancement effect, suggesting thalamic involvement. Thus, correlated excitation of large neuronal populations leads to global enhancement of neuronal excitability.


Assuntos
Potenciais de Ação/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Excitabilidade Cortical , Corantes Fluorescentes , Masculino , Camundongos , Rede Nervosa , Transmissão Sináptica/fisiologia
10.
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
11.
Neuron ; 107(3): 580-589.e6, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32778224

RESUMO

To induce brain plasticity in humans, we casted the dominant upper extremity for 2 weeks and tracked changes in functional connectivity using daily 30-min scans of resting-state functional MRI (rs-fMRI). Casting caused cortical and cerebellar regions controlling the disused extremity to functionally disconnect from the rest of the somatomotor system, while internal connectivity within the disused sub-circuit was maintained. Functional disconnection was evident within 48 h, progressed throughout the cast period, and reversed after cast removal. During the cast period, large, spontaneous pulses of activity propagated through the disused somatomotor sub-circuit. The adult brain seems to rely on regular use to maintain its functional architecture. Disuse-driven spontaneous activity pulses may help preserve functionally disconnected sub-circuits.


Assuntos
Córtex Motor/diagnóstico por imagem , Plasticidade Neuronal/fisiologia , Restrição Física , Atividades Cotidianas , Moldes Cirúrgicos , Feminino , Lateralidade Funcional , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Força Muscular/fisiologia , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiologia , Extremidade Superior
12.
Science ; 369(6505): 858-862, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32792401

RESUMO

The conversion of neural stem cells into neurons is associated with the remodeling of organelles, but whether and how this is causally linked to fate change is poorly understood. We examined and manipulated mitochondrial dynamics during mouse and human cortical neurogenesis. We reveal that shortly after cortical stem cells have divided, daughter cells destined to self-renew undergo mitochondrial fusion, whereas those that retain high levels of mitochondria fission become neurons. Increased mitochondria fission promotes neuronal fate, whereas induction of mitochondria fusion after mitosis redirects daughter cells toward self-renewal. This occurs during a restricted time window that is doubled in human cells, in line with their increased self-renewal capacity. Our data reveal a postmitotic period of fate plasticity in which mitochondrial dynamics are linked with cell fate.


Assuntos
Córtex Cerebral/crescimento & desenvolvimento , Mitocôndrias/fisiologia , Dinâmica Mitocondrial , Mitose , Células-Tronco Neurais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Animais , Córtex Cerebral/citologia , Feminino , Células HEK293 , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Sirtuínas/metabolismo
13.
Nat Commun ; 11(1): 4276, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848151

RESUMO

The structural organization of excitatory inputs supporting spike-timing-dependent plasticity (STDP) remains unknown. We performed a spine STDP protocol using two-photon (2P) glutamate uncaging (pre) paired with postsynaptic spikes (post) in layer 5 pyramidal neurons from juvenile mice. Here we report that pre-post pairings that trigger timing-dependent LTP (t-LTP) produce shrinkage of the activated spine neck and increase in synaptic strength; and post-pre pairings that trigger timing-dependent LTD (t-LTD) decrease synaptic strength without affecting spine shape. Furthermore, the induction of t-LTP with 2P glutamate uncaging in clustered spines (<5 µm apart) enhances LTP through a NMDA receptor-mediated spine calcium accumulation and actin polymerization-dependent neck shrinkage, whereas t-LTD was dependent on NMDA receptors and disrupted by the activation of clustered spines but recovered when separated by >40 µm. These results indicate that synaptic cooperativity disrupts t-LTD and extends the temporal window for the induction of t-LTP, leading to STDP only encompassing LTP.


Assuntos
Espinhas Dendríticas/fisiologia , Plasticidade Neuronal/fisiologia , Potenciais de Ação/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Técnicas In Vitro , Potenciação de Longa Duração/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica , Modelos Neurológicos , Células Piramidais/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia
14.
Nat Commun ; 11(1): 4275, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848155

RESUMO

New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Adulto , Células-Tronco Adultas/citologia , Células-Tronco Adultas/fisiologia , Animais , Giro Denteado/citologia , Giro Denteado/fisiologia , Humanos , Modelos Neurológicos , Plasticidade Neuronal
15.
Neuron ; 107(3): 395-396, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758442

RESUMO

In this issue of Neuron, Vandael et al. (2020) reveal that post-tetanic potentiation at dentate gyrus mossy fiber synapses is induced by natural activity patterns. This plasticity is mediated by an increase in readily releasable vesicle pool size and is extended in the absence of activity, forming a "pool engram."


Assuntos
Fibras Musgosas Hipocampais , Plasticidade Neuronal , Sinapses
16.
Neuron ; 107(3): 401-403, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758445

RESUMO

Characterizing the brain's ability to adapt to changing environments has been at the forefront of neuroscience for decades. In this issue of Neuron, Newbold et al. build on this neuroplasticity work using precision neuroimaging and arm casting to unmask previously unknown pulses of spontaneous activity.


Assuntos
Neuroimagem , Neurociências , Encéfalo , Humanos , Plasticidade Neuronal
17.
Wei Sheng Yan Jiu ; 49(3): 473-479, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32693900

RESUMO

OBJECTIVE: To investigate the effects of PM_(2. 5) exposure on the development of synaptic plasticity and Wnt/ß-catenin pathway in hippocampus of offspring rats. METHODS: Healthy 7-week-old SPF SD rats(n=36) mated with a male to female ratio of 2∶1. Pregnant rats were randomly divided into three groups, including control group, low PM_(2. 5) group, and high PM_(2. 5) group, with eight rats in each group. The low and high PM_(2. 5) concentrations in dynamic exposure cabinet were approximately two times and four times higher than the annual average PM_(2. 5) concentration in Tangshan city respectively. The exposure started from pregnant day 0, until postnatal day 21(PND21) of offspring rats. After weaning, the offspring rats continued to be exposed to PM_(2. 5) until PND42. PND21 and PND42 pups were subjected to Morris water maze and new object recognition experiments. Western blot was used to detect post synaptic density-95(PSD-95), synaptophysin(SYN), growth associated protein(GAP-43), glycogen synthase kinase 3ß(GSK-3ß), ß-catenin protein levels and phosphorylation levels of GSK-3ß and ß-catenin in the hippocampus of offspring rats. RESULTS: Compared with the control group, the learning and memory abilities of the pups of each PM_(2. 5) group were significantly decreased with a dose dependent manner. Compared with the control group, the protein level of SYN, GAP-43 and PSD-95 in hippocampus of PND0 rats of each PM_(2. 5)groups were decreased(P<0. 05), and the protein level of SYN of each PM_(2. 5)group and PSD-95 of high PM_(2. 5) group in PND21 and PND42 were decreased(P<0. 05), and the level of GAP-43 of low PM_(2. 5) group in PND42 were decreased(P<0. 05). Compared with the low PM_(2. 5) group, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND21, the level of PSD-95 of high PM_(2. 5) group in PND0 and PND42 were decreased(P<0. 05). Compared with the control group, the level of p-GSK-3ß in hippocampus of each PM_(2. 5)group in PND0, PND21 and PND42 was decreased(P<0. 05), and with the increase of PM_(2. 5) exposure dose, the trend is more obvious. The protein level of p-ß-catenin in hippocampus of high PM_(2. 5) group in PND0 and PND42 was significantly increased(P<0. 05). The level of p-ß-catenin in high-dose PND21 pups compared with the control group was significantly reduced(P<0. 05). CONCLUSION: Exposure to PM_(2. 5) in early life can damage the synaptic plasticity and decrease the protein levels of ß-catenin and p-GSK-3ß in the Wnt/ß-catenin pathway of hippocampus in offspring rats.


Assuntos
Via de Sinalização Wnt , beta Catenina , Animais , Feminino , Glicogênio Sintase Quinase 3 beta , Hipocampo , Masculino , Plasticidade Neuronal , Gravidez , Ratos , Ratos Sprague-Dawley
18.
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
19.
Proc Natl Acad Sci U S A ; 117(32): 19556-19565, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694207

RESUMO

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


Assuntos
Encéfalo/fisiopatologia , Dependência de Morfina/fisiopatologia , Rede Nervosa/fisiopatologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Conectoma , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Morfina/administração & dosagem , Morfina/efeitos adversos , Dependência de Morfina/metabolismo , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Plasticidade Neuronal/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Síndrome de Abstinência a Substâncias/genética , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/fisiopatologia
20.
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
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