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1.
Nat Neurosci ; 24(11): 1508-1521, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34711959

RESUMO

Myelin, a lipid membrane that wraps axons, enabling fast neurotransmission and metabolic support to axons, is conventionally thought of as a static structure that is set early in development. However, recent evidence indicates that in the central nervous system (CNS), myelination is a protracted and plastic process, ongoing throughout adulthood. Importantly, myelin is emerging as a potential modulator of neuronal networks, and evidence from human studies has highlighted myelin as a major player in shaping human behavior and learning. Here we review how myelin changes throughout life and with learning. We discuss potential mechanisms of myelination at different life stages, explore whether myelin plasticity provides the regenerative potential of the CNS white matter, and question whether changes in myelin may underlie neurological disorders.


Assuntos
Encéfalo/fisiologia , Bainha de Mielina/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Substância Branca/fisiologia , Animais , Encéfalo/citologia , Humanos , Oligodendroglia/fisiologia , Substância Branca/citologia
2.
Nat Commun ; 12(1): 6102, 2021 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-34671032

RESUMO

Damage to the primary visual cortex (V1) causes homonymous visual-field loss long considered intractable. Multiple studies now show that perceptual training can restore visual functions in chronic cortically-induced blindness (CB). A popular hypothesis is that training can harness residual visual functions by recruiting intact extrageniculostriate pathways. Training may also induce plastic changes within spared regions of the damaged V1. Here, we link changes in luminance detection sensitivity with retinotopic fMRI activity before and after visual discrimination training in eleven patients with chronic, stroke-induced CB. We show that spared V1 activity representing perimetrically-blind locations prior to training predicts the amount of training-induced recovery of luminance detection sensitivity. Additionally, training results in an enlargement of population receptive fields in perilesional V1, which increases blind-field coverage and may support further recovery with subsequent training. These findings uncover fundamental changes in perilesional V1 cortex underlying training-induced restoration of conscious luminance detection sensitivity in CB.


Assuntos
Cegueira Cortical/reabilitação , Aprendizagem/fisiologia , Visão Ocular/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Adulto , Idoso , Cegueira Cortical/diagnóstico por imagem , Cegueira Cortical/fisiopatologia , Mapeamento Encefálico , Discriminação Psicológica/fisiologia , Feminino , Lateralidade Funcional/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Córtex Visual/diagnóstico por imagem , Campos Visuais/fisiologia
3.
Nat Rev Neurosci ; 22(11): 685-702, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34599308

RESUMO

The sympathetic nervous system prepares the body for 'fight or flight' responses and maintains homeostasis during daily activities such as exercise, eating a meal or regulation of body temperature. Sympathetic regulation of bodily functions requires the establishment and refinement of anatomically and functionally precise connections between postganglionic sympathetic neurons and peripheral organs distributed widely throughout the body. Mechanistic studies of key events in the formation of postganglionic sympathetic neurons during embryonic and early postnatal life, including axon growth, target innervation, neuron survival, and dendrite growth and synapse formation, have advanced the understanding of how neuronal development is shaped by interactions with peripheral tissues and organs. Recent progress has also been made in identifying how the cellular and molecular diversity of sympathetic neurons is established to meet the functional demands of peripheral organs. In this Review, we summarize current knowledge of signalling pathways underlying the development of the sympathetic nervous system. These findings have implications for unravelling the contribution of sympathetic dysfunction stemming, in part, from developmental perturbations to the pathophysiology of peripheral neuropathies and cardiovascular and metabolic disorders.


Assuntos
Axônios/fisiologia , Dendritos/fisiologia , Neurônios/fisiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Sistema Nervoso Simpático/crescimento & desenvolvimento , Sistema Nervoso Simpático/fisiopatologia , Animais , Axônios/patologia , Dendritos/patologia , Humanos , Plasticidade Neuronal/fisiologia , Neurônios/patologia , Doenças do Sistema Nervoso Periférico/patologia , Sistema Nervoso Simpático/citologia
4.
Nat Commun ; 12(1): 5388, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526497

RESUMO

Autism spectrum disorder (ASD) is a multifactorial disorder with characteristic synaptic and gene expression changes. Early intervention during childhood is thought to benefit prognosis. Here, we examined the changes in cortical synaptogenesis, synaptic function, and gene expression from birth to the juvenile stage in a marmoset model of ASD induced by valproic acid (VPA) treatment. Early postnatally, synaptogenesis was reduced in this model, while juvenile-age VPA-treated marmosets showed increased synaptogenesis, similar to observations in human tissue. During infancy, synaptic plasticity transiently increased and was associated with altered vocalization. Synaptogenesis-related genes were downregulated early postnatally. At three months of age, the differentially expressed genes were associated with circuit remodeling, similar to the expression changes observed in humans. In summary, we provide a functional and molecular characterization of a non-human primate model of ASD, highlighting its similarity to features observed in human ASD.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Transmissão Sináptica/fisiologia , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/genética , Callithrix , Espinhas Dendríticas/fisiologia , Estimulação Elétrica , Perfilação da Expressão Gênica/métodos , Humanos , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Técnicas de Patch-Clamp/métodos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Ácido Valproico
5.
Elife ; 102021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34505576

RESUMO

The strength of cortical connectivity to the striatum influences the balance between behavioral variability and stability. Learning to consistently produce a skilled action requires plasticity in corticostriatal connectivity associated with repeated training of the action. However, it remains unknown whether such corticostriatal plasticity occurs during training itself or 'offline' during time away from training, such as sleep. Here, we monitor the corticostriatal network throughout long-term skill learning in rats and find that non-rapid-eye-movement (NREM) sleep is a relevant period for corticostriatal plasticity. We first show that the offline activation of striatal NMDA receptors is required for skill learning. We then show that corticostriatal functional connectivity increases offline, coupled to emerging consistent skilled movements, and coupled cross-area neural dynamics. We then identify NREM sleep spindles as uniquely poised to mediate corticostriatal plasticity, through interactions with slow oscillations. Our results provide evidence that sleep shapes cross-area coupling required for skill learning.


Assuntos
Corpo Estriado/fisiologia , Aprendizagem/fisiologia , Córtex Motor/fisiologia , Destreza Motora/fisiologia , Sono de Ondas Lentas/fisiologia , Animais , Eletrodos Implantados , Masculino , Plasticidade Neuronal/fisiologia , Desempenho Psicomotor/fisiologia , Ratos , Ratos Long-Evans , Silício , Fatores de Tempo
6.
Nat Commun ; 12(1): 5286, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489431

RESUMO

Vomeronasal information is critical in mice for territorial behavior. Consequently, learning the territorial spatial structure should incorporate the vomeronasal signals indicating individual identity into the hippocampal cognitive map. In this work we show in mice that navigating a virtual environment induces synchronic activity, with causality in both directionalities, between the vomeronasal amygdala and the dorsal CA1 of the hippocampus in the theta frequency range. The detection of urine stimuli induces synaptic plasticity in the vomeronasal pathway and the dorsal hippocampus, even in animals with experimentally induced anosmia. In the dorsal hippocampus, this plasticity is associated with the overexpression of pAKT and pGSK3ß. An amygdalo-entorhino-hippocampal circuit likely underlies this effect of pheromonal information on hippocampal learning. This circuit likely constitutes the neural substrate of territorial behavior in mice, and it allows the integration of social and spatial information.


Assuntos
Tonsila do Cerebelo/fisiologia , Região CA1 Hipocampal/fisiologia , Glicogênio Sintase Quinase 3 beta/genética , Percepção Olfatória/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Comportamento Espacial/fisiologia , Órgão Vomeronasal/fisiologia , Tonsila do Cerebelo/citologia , Animais , Anosmia/genética , Anosmia/metabolismo , Anosmia/fisiopatologia , Comportamento Animal , Região CA1 Hipocampal/citologia , Feminino , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Aprendizagem/fisiologia , Masculino , Camundongos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Feromônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Percepção Social , Percepção Espacial/fisiologia , Ritmo Teta/fisiologia , Órgão Vomeronasal/citologia
7.
PLoS One ; 16(9): e0257228, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34506579

RESUMO

Synaptic strengths between neurons in brain networks are highly adaptive due to synaptic plasticity. Spike-timing-dependent plasticity (STDP) is a form of synaptic plasticity induced by temporal correlations between the firing activity of neurons. The development of experimental techniques in recent years enabled the realization of brain-inspired neuromorphic devices. Particularly, magnetic tunnel junctions (MTJs) provide a suitable means for the implementation of learning processes in molecular junctions. Here, we first considered a two-neuron motif subjected to STDP. By employing theoretical analysis and computer simulations we showed that the dynamics and emergent structure of the motif can be predicted by introducing an effective two-neuron synaptic conductance. Then, we considered a phenyl-based single-molecule MTJ connected to two ferromagnetic (FM) cobalt electrodes and investigated its electrical properties using the non-equilibrium Green's function (NEGF) formalism. Similar to the two-neuron motif, we introduced an effective spin-polarized conductance in the MTJ. Depending on the polarity, frequency and strength of the bias voltage applied to the MTJ, the system can learn input signals by adaptive changes of the effective conductance. Interestingly, this voltage-dependent plasticity is an intrinsic property of the MTJ where its behavior is reminiscent of the classical temporally asymmetric STDP. Furthermore, the shape of voltage-dependent plasticity in the MTJ is determined by the molecule-electrode coupling strength or the length of the molecule. Our results may be relevant for the development of single-molecule devices that capture the adaptive properties of synapses in the brain.


Assuntos
Plasticidade Neuronal/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Algoritmos , Humanos , Modelos Neurológicos
8.
Invest Ophthalmol Vis Sci ; 62(12): 24, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34550300

RESUMO

Purpose: To discuss the potential contribution of rod and cone synapses to the loss of visual function in retinal injury and disease. Methods: The published literature and the authors' own work were reviewed. Results: Retinal detachment is used as a case study of rod spherule and cone pedicle plasticity after injury. Both rod and cone photoreceptors terminals are damaged after detachment although the structural changes observed are only partially overlapping. For second-order neurons, only those associated with rod spherules respond consistently to injury by remodeling. Examination of signaling pathways involved in plasticity of conventional synapses and in neural development has been and may continue to be productive in discovering novel therapeutic targets. Rho kinase (ROCK) inhibition is an example of therapy that may reduce synaptic damage by preserving normal synaptic structure of rod and cone cells. Conclusions: We hypothesize that synaptic damage contributes to poor visual restoration after otherwise successful anatomical repair of retinal detachment. A similar situation may exist for patients with degenerative retinal disease. Thus, synaptic structure and function should be routinely studied, as this information may disclose therapeutic strategies to mitigate visual loss.


Assuntos
Células Fotorreceptoras de Vertebrados/fisiologia , Descolamento Retiniano/fisiopatologia , Sinapses/fisiologia , Transtornos da Visão/fisiopatologia , Animais , Humanos , Plasticidade Neuronal/fisiologia , Transdução de Sinais/fisiologia , Visão Ocular/fisiologia
9.
Clin Neurophysiol ; 132(11): 2827-2839, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34592560

RESUMO

OBJECTIVE: While previous studies showed that the single nucleotide polymorphism (Val66Met) of brain-derived neurotrophic factor (BDNF) can impact neuroplasticity, the influence of BDNF genotype on cortical circuitry and relationship to neuroplasticity remain relatively unexplored in human. METHODS: Using individualised transcranial magnetic stimulation (TMS) parameters, we explored the influence of the BDNF Val66Met polymorphism on excitatory and inhibitory neural circuitry, its relation to I-wave TMS (ITMS) plasticity and effect on the excitatory/inhibitory (E/I) balance in 18 healthy individuals. RESULTS: Excitatory and inhibitory indexes of neurotransmission were reduced in Met allele carriers. An E/I balance was evident, which was influenced by BDNF with higher E/I ratios in Val/Val homozygotes. Both long-term potentiation (LTP-) and depression (LTD-) like ITMS plasticity were greater in Val/Val homozygotes. LTP- but not LTD-like effects were restored in Met allele carriers by increasing stimulus intensity to compensate for reduced excitatory transmission. CONCLUSIONS: The influence of BDNF genotype may extend beyond neuroplasticity to neurotransmission. The E/I balance was evident in human motor cortex, modulated by BDNF and measurable using TMS. Given the limited sample, these preliminary findings warrant further investigation. SIGNIFICANCE: These novel findings suggest a broader role of BDNF genotype on neurocircuitry in human motor cortex.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciais Pós-Sinápticos Inibidores/fisiologia , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Adulto , Eletromiografia/métodos , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Metionina/genética , Estimulação Magnética Transcraniana/métodos , Valina/genética
10.
Clin Neurophysiol ; 132(10): 2568-2607, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34482205

RESUMO

Transcranial magnetic stimulation (TMS) is a powerful tool to probe in vivo brain circuits, as it allows to assess several cortical properties such asexcitability, plasticity and connectivity in humans. In the last 20 years, TMS has been applied to patients with dementia, enabling the identification of potential markers of thepathophysiology and predictors of cognitive decline; moreover, applied repetitively, TMS holds promise as a potential therapeutic intervention. The objective of this paper is to present a comprehensive review of studies that have employed TMS in dementia and to discuss potential clinical applications, from the diagnosis to the treatment. To provide a technical and theoretical framework, we first present an overview of the basic physiological mechanisms of the application of TMS to assess cortical excitability, excitation and inhibition balance, mechanisms of plasticity and cortico-cortical connectivity in the human brain. We then review the insights gained by TMS techniques into the pathophysiology and predictors of progression and response to treatment in dementias, including Alzheimer's disease (AD)-related dementias and secondary dementias. We show that while a single TMS measure offers low specificity, the use of a panel of measures and/or neurophysiological index can support the clinical diagnosis and predict progression. In the last part of the article, we discuss the therapeutic uses of TMS. So far, only repetitive TMS (rTMS) over the left dorsolateral prefrontal cortex and multisite rTMS associated with cognitive training have been shown to be, respectively, possibly (Level C of evidence) and probably (Level B of evidence) effective to improve cognition, apathy, memory, and language in AD patients, especially at a mild/early stage of the disease. The clinical use of this type of treatment warrants the combination of brain imaging techniques and/or electrophysiological tools to elucidate neurobiological effects of neurostimulation and to optimally tailor rTMS treatment protocols in individual patients or specific patient subgroups with dementia or mild cognitive impairment.


Assuntos
Encéfalo/fisiologia , Demência/fisiopatologia , Demência/terapia , Plasticidade Neuronal/fisiologia , Estimulação Magnética Transcraniana/métodos , Demência/psicologia , Eletroencefalografia/métodos , Eletroencefalografia/tendências , Humanos , Estimulação Magnética Transcraniana/tendências
11.
Cells ; 10(9)2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34571950

RESUMO

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABAARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca2+-permeable GluA2-lacking AMPARs and increased intracellular Ca2+ levels due to a higher Ca2+ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.


Assuntos
Cálcio/metabolismo , Hipocampo/metabolismo , Neurônios/metabolismo , Proteínas Nogo/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Receptores de AMPA/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
12.
Cells ; 10(9)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34571993

RESUMO

Alzheimer's disease (AD) is one of the most common neurodegenerative pathologies. Its incidence is in dramatic growth in Western societies and there is a need of both biomarkers to support the clinical diagnosis and drugs for the treatment of AD. The diagnostic criteria of AD are based on clinical data. However, it is necessary to develop biomarkers considering the neuropathology of AD. The A2A receptor, a G-protein coupled member of the P1 family of adenosine receptors, has different functions crucial for neurodegeneration. Its activation in the hippocampal region regulates synaptic plasticity and in particular glutamate release, NMDA receptor activation and calcium influx. Additionally, it exerts effects in neuroinflammation, regulating the secretion of pro-inflammatory cytokines. In AD patients, its expression is increased in the hippocampus/entorhinal cortex more than in the frontal cortex, a phenomenon not observed in age-matched control brains, indicating an association with AD pathology. It is upregulated in peripheral blood cells of patients affected by AD, thus reflecting its increase at central neuronal level. This review offers an overview on the main AD biomarkers and the potential role of A2A adenosine receptor as a new marker and therapeutic target.


Assuntos
Doença de Alzheimer/genética , Receptor A2A de Adenosina/fisiologia , Adenosina/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Córtex Entorrinal/metabolismo , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Humanos , Plasticidade Neuronal/fisiologia , Receptor A2A de Adenosina/genética , Receptor A2A de Adenosina/metabolismo , Receptores de N-Metil-D-Aspartato
13.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575969

RESUMO

A growing body of evidence suggests that nucleus accumbens (NAc) plays a significant role not only in the physiological processes associated with reward and satisfaction but also in many diseases of the central nervous system. Summary of the current state of knowledge on the morphological and functional basis of such a diverse function of this structure may be a good starting point for further basic and clinical research. The NAc is a part of the brain reward system (BRS) characterized by multilevel organization, extensive connections, and several neurotransmitter systems. The unique role of NAc in the BRS is a result of: (1) hierarchical connections with the other brain areas, (2) a well-developed morphological and functional plasticity regulating short- and long-term synaptic potentiation and signalling pathways, (3) cooperation among several neurotransmitter systems, and (4) a supportive role of neuroglia involved in both physiological and pathological processes. Understanding the complex function of NAc is possible by combining the results of morphological studies with molecular, genetic, and behavioral data. In this review, we present the current views on the NAc function in physiological conditions, emphasizing the role of its connections, neuroplasticity processes, and neurotransmitter systems.


Assuntos
Encéfalo/fisiologia , Sistema Nervoso Central/fisiologia , Plasticidade Neuronal/fisiologia , Núcleo Accumbens/fisiologia , Animais , Humanos , Satisfação Pessoal , Recompensa
14.
Nat Neurosci ; 24(10): 1441-1451, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34545249

RESUMO

Associative memories are stored in distributed networks extending across multiple brain regions. However, it is unclear to what extent sensory cortical areas are part of these networks. Using a paradigm for visual category learning in mice, we investigated whether perceptual and semantic features of learned category associations are already represented at the first stages of visual information processing in the neocortex. Mice learned categorizing visual stimuli, discriminating between categories and generalizing within categories. Inactivation experiments showed that categorization performance was contingent on neuronal activity in the visual cortex. Long-term calcium imaging in nine areas of the visual cortex identified changes in feature tuning and category tuning that occurred during this learning process, most prominently in the postrhinal area (POR). These results provide evidence for the view that associative memories form a brain-wide distributed network, with learning in early stages shaping perceptual representations and supporting semantic content downstream.


Assuntos
Aprendizagem/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Animais , Mapeamento Encefálico , Sinalização do Cálcio/fisiologia , Condicionamento Operante , Discriminação Psicológica , Agonistas GABAérgicos/farmacologia , Generalização Psicológica , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Muscimol/farmacologia , Neocórtex/fisiologia , Plasticidade Neuronal/fisiologia , Estimulação Luminosa , Recrutamento Neurofisiológico
15.
Nat Rev Neurosci ; 22(11): 657-673, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34545240

RESUMO

Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Sistema Nervoso Central/fisiologia , Imunidade Celular/fisiologia , Plasticidade Neuronal/fisiologia , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Transtorno do Espectro Autista/imunologia , Sistema Nervoso Central/citologia , Humanos , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Esquizofrenia/imunologia
16.
Nat Commun ; 12(1): 4737, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362910

RESUMO

Glucocorticoid hormones (GCs) - acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) - are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.


Assuntos
Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de Mineralocorticoides/genética , Receptores de Mineralocorticoides/metabolismo , Receptores de Esteroides/metabolismo , Animais , Regulação da Expressão Gênica , Genoma , Hipocampo/patologia , Humanos , Masculino , Ligação Proteica , RNA/metabolismo , Ratos , Ratos Wistar , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/metabolismo , Elementos de Resposta , Fatores de Transcrição
17.
Elife ; 102021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34346310

RESUMO

Gap junctions between neurons serve as electrical synapses, in addition to conducting metabolites and signaling molecules. During development, early-appearing gap junctions are thought to prefigure chemical synapses, which appear much later. We present evidence for this idea at a central, glutamatergic synapse and provide some mechanistic insights. Loss or reduction in the levels of the gap junction protein Gjd2b decreased the frequency of glutamatergic miniature excitatory postsynaptic currents (mEPSCs) in cerebellar Purkinje neurons (PNs) in larval zebrafish. Ultrastructural analysis in the molecular layer showed decreased synapse density. Further, mEPSCs had faster kinetics and larger amplitudes in mutant PNs, consistent with their stunted dendritic arbors. Time-lapse microscopy in wild-type and mutant PNs reveals that Gjd2b puncta promote the elongation of branches and that CaMKII may be a critical mediator of this process. These results demonstrate that Gjd2b-mediated gap junctions regulate glutamatergic synapse formation and dendritic elaboration in PNs.


Assuntos
Conexinas/genética , Proteínas do Olho/genética , Junções Comunicantes/genética , Plasticidade Neuronal/fisiologia , Células de Purkinje/fisiologia , Sinapses/fisiologia , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/fisiologia , Animais , Conexinas/metabolismo , Proteínas do Olho/metabolismo , Junções Comunicantes/metabolismo , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
18.
ACS Appl Mater Interfaces ; 13(33): 39641-39651, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34374517

RESUMO

Biomaterial-based memristors (bio-memristors) are often adopted to emulate biological synapse functions and applied to construct neural computing networks in brain-inspired chip systems. However, the randomness of conductive filament formation in bio-memristors inhibits their switching performance by causing the dispersion of the device-switching parameters. In this case, a facile porous silk fibroin (p-SF) memristor was obtained through a protein surface reconstruction strategy, in which the size of the hole can be adjusted by the density of hybrid nanoseeds. The porous SF memristors exhibit greatly enhanced electrical characteristics, including uniform I-V cycles, centralized distribution of the switching voltages, and both high and low resistances, compared to devices without pores. The results of three-dimensional (3D) simulations based on classical density functional theory (cDFT) suggest that the reconstructed pores in the SF layers guide the formation and fracture of Ag filaments under an electric field and enhance the overall conductivity by separating Ag+ ion and electron diffusion pathways. Ag+ ions are predicted to preferentially diffuse through pores, whereas electrons diffuse through the SF network. Interestingly, the device conductance can be bidirectionally modulated gradually by positive and negative voltages, can faithfully simulate short-term and long-term plasticity, and can even realize the triplet-spike-timing-dependent plasticity (triplet-STDP) rule, which can be used for pattern recognition in biological systems. The simulation results reveal that a memristor network of this type has an accuracy of ∼95.78% in memory learning and the capability of pattern learning. This work provides a facile technology route to improve the performance of bionic-material memristors.


Assuntos
Sinapses Elétricas/química , Sinapses Elétricas/metabolismo , Fibroínas/química , Encéfalo , Cátions/química , Simulação por Computador , Teoria da Densidade Funcional , Condutividade Elétrica , Modelos Biológicos , Redes Neurais de Computação , Plasticidade Neuronal/fisiologia , Porosidade , Prata/química , Propriedades de Superfície
19.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360882

RESUMO

The human natural killer (HNK-1) carbohydrate plays important roles during nervous system development, regeneration after trauma and synaptic plasticity. Four proteins have been identified as receptors for HNK-1: the laminin adhesion molecule, high-mobility group box 1 and 2 (also called amphoterin) and cadherin 2 (also called N-cadherin). Because of HNK-1's importance, we asked whether additional receptors for HNK-1 exist and whether the four identified proteins share any similarity in their primary structures. A set of 40,000 sequences homologous to the known HNK-1 receptors was selected and used for large-scale sequence alignments and motif searches. Although there are conserved regions and highly conserved sites within each of these protein families, there was no sequence similarity or conserved sequence motifs found to be shared by all families. Since HNK-1 receptors have not been compared regarding binding constants and since it is not known whether the sulfated or non-sulfated part of HKN-1 represents the structurally crucial ligand, the receptors are more heterogeneous in primary structure than anticipated, possibly involving different receptor or ligand regions. We thus conclude that the primary protein structure may not be the sole determinant for a bona fide HNK-1 receptor, rendering receptor structure more complex than originally assumed.


Assuntos
Antígenos CD57/metabolismo , Caderinas/metabolismo , Proteína HMGB1/metabolismo , Proteína HMGB2/metabolismo , Laminina/metabolismo , Oligossacarídeos/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Antígenos CD57/química , Caderinas/química , Proteína HMGB1/química , Proteína HMGB2/química , Humanos , Laminina/química , Ligantes , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Oligossacarídeos/química , Ligação Proteica , Domínios Proteicos
20.
Sci Rep ; 11(1): 16357, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381140

RESUMO

Pyk2 is a Ca2+-activated non-receptor tyrosine kinase enriched in the forebrain, especially in pyramidal neurons of the hippocampus. Previous reports suggested its role in hippocampal synaptic plasticity and spatial memory but with contradictory findings possibly due to experimental conditions. Here we address this issue and show that novel object location, a simple test of spatial memory induced by a single training session, is altered in Pyk2 KO mice and that re-expression of Pyk2 in the dorsal hippocampus corrects this deficit. Bilateral targeted deletion of Pyk2 in dorsal hippocampus CA1 region also alters novel object location. Long term potentiation (LTP) in CA1 is impaired in Pyk2 KO mice using a high frequency stimulation induction protocol but not with a theta burst protocol, explaining differences between previous reports. The same selective LTP alteration is observed in mice with Pyk2 deletion in dorsal hippocampus CA1 region. Thus, our results establish the role of Pyk2 in specific aspects of spatial memory and synaptic plasticity and show the dependence of the phenotype on the type of experiments used to reveal it. In combination with other studies, we provide evidence for a selective role of non-receptor tyrosine kinases in specific aspects of hippocampal neurons synaptic plasticity.


Assuntos
Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Quinase 2 de Adesão Focal/metabolismo , Plasticidade Neuronal/fisiologia , Memória Espacial/fisiologia , Sinapses/metabolismo , Sinapses/fisiologia , Animais , Humanos , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia
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