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1.
Arch Biochem Biophys ; 701: 108815, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33609537

RESUMO

Glaucoma is a neurodegenerative disease that affects eye structures and brain areas related to the visual system. Oxidative stress plays a key role in the development and progression of the disease. The aims of the present study were to evaluate the mitochondrial function and its participation in the brain redox metabolism in an experimental glaucoma model. 3-month-old female Wistar rats were subjected to cauterization of two episcleral veins of the left eye to elevate the intraocular pressure. Seven days after surgery, animals were sacrificed, the brain was carefully removed and the primary visual cortex was dissected. Mitochondrial bioenergetics and ROS production, and the antioxidant enzyme defenses from both mitochondrial and cytosolic fractions were evaluated. When compared to control, glaucoma decreased mitochondrial ATP production (23%, p < 0.05), with an increase in superoxide and hydrogen peroxide production (30%, p < 0.01 and 28%, p < 0.05, respectively), whereas no changes were observed in membrane potential and oxygen consumption rate. In addition, the glaucoma group displayed a decrease in complex II activity (34%, p < 0.01). Moreover, NOX4 expression was increased in glaucoma compared to the control group (27%, p < 0.05). Regarding the activity of enzymes associated with the regulation of the redox status, glaucoma showed an increase in mitochondrial SOD activity (34%, p < 0.05), mostly due to an increase in Mn-SOD (50%, p < 0.05). A decrease in mitochondrial GST activity was observed (11%, p < 0.05). GR and TrxR activity were decreased in both mitochondrial (16%, p < 0.05 and 20%, p < 0.05 respectively) and cytosolic (21%, p < 0.01 and 50%, p < 0.01 respectively) fractions in the glaucoma group. Additionally, glaucoma showed an increase in cytoplasmatic GPx (50%, p < 0.01). In this scenario, redox imbalance took place resulting in damage to mitochondrial lipids (39%, p < 0.01) and proteins (70%, p < 0.05). These results suggest that glaucoma leads to mitochondrial function impairment in brain visual targets, that is accompanied by an alteration in both mitochondrial and cytoplasmatic enzymatic defenses. As a consequence of redox imbalance, oxidative damage to macromolecules takes place and can further affect vital cellular functions. Understanding the role of the mitochondria in the development and progression of the disease could bring up new neuroprotective therapies.


Assuntos
Glaucoma/metabolismo , Mitocôndrias/metabolismo , Córtex Visual/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Glaucoma/patologia , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , NADPH Oxidase 4/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Córtex Visual/patologia
2.
J Neurosci ; 41(6): 1274-1287, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33380470

RESUMO

Microglia have crucial roles in sculpting synapses and maintaining neural circuits during development. To test the hypothesis that microglia continue to regulate neural circuit connectivity in adult brain, we have investigated the effects of chronic microglial depletion, via CSF1R inhibition, on synaptic connectivity in the visual cortex in adult mice of both sexes. We find that the absence of microglia dramatically increases both excitatory and inhibitory synaptic connections to excitatory cortical neurons assessed with functional circuit mapping experiments in acutely prepared adult brain slices. Microglia depletion leads to increased densities and intensities of perineuronal nets. Furthermore, in vivo calcium imaging across large populations of visual cortical neurons reveals enhanced neural activities of both excitatory neurons and parvalbumin-expressing interneurons in the visual cortex following microglia depletion. These changes recover following adult microglia repopulation. In summary, our new results demonstrate a prominent role of microglia in sculpting neuronal circuit connectivity and regulating subsequent functional activity in adult cortex.SIGNIFICANCE STATEMENT Microglia are the primary immune cell of the brain, but recent evidence supports that microglia play an important role in synaptic sculpting during development. However, it remains unknown whether and how microglia regulate synaptic connectivity in adult brain. Our present work shows chronic microglia depletion in adult visual cortex induces robust increases in perineuronal nets, and enhances local excitatory and inhibitory circuit connectivity to excitatory neurons. Microglia depletion increases in vivo neural activities of both excitatory neurons and parvalbumin inhibitory neurons. Our new results reveal new potential avenues to modulate adult neural plasticity by microglia manipulation to better treat brain disorders, such as Alzheimer's disease.


Assuntos
Microglia/metabolismo , Rede Nervosa/metabolismo , Estimulação Luminosa/métodos , Córtex Visual/metabolismo , Aminopiridinas/farmacologia , Animais , Feminino , Masculino , Camundongos , Microglia/química , Microglia/efeitos dos fármacos , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Pirróis/farmacologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Córtex Visual/química , Córtex Visual/efeitos dos fármacos
3.
Science ; 370(6523)2020 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-33335032

RESUMO

Myelin plasticity is critical for neurological function, including learning and memory. However, it is unknown whether this plasticity reflects uniform changes across all neuronal subtypes, or whether myelin dynamics vary between neuronal classes to enable fine-tuning of adaptive circuit responses. We performed in vivo two-photon imaging of myelin sheaths along single axons of excitatory callosal neurons and inhibitory parvalbumin-expressing interneurons in adult mouse visual cortex. We found that both neuron types show homeostatic myelin remodeling under normal vision. However, monocular deprivation results in adaptive myelin remodeling only in parvalbumin-expressing interneurons. An initial increase in elongation of myelin segments is followed by contraction of a separate cohort of segments. This data indicates that distinct classes of neurons individualize remodeling of their myelination profiles to diversify circuit tuning in response to sensory experience.


Assuntos
Bainha de Mielina/metabolismo , Neocórtex/metabolismo , Neurônios/metabolismo , Córtex Visual/metabolismo , Animais , Corpo Caloso/citologia , Corpo Caloso/metabolismo , Feminino , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Imagem Molecular , Neocórtex/citologia , Plasticidade Neuronal , Neurônios/classificação , Parvalbuminas/metabolismo , Córtex Visual/citologia
4.
Nat Commun ; 11(1): 2084, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350282

RESUMO

Single-cell RNA sequencing (scRNA-seq) provides details for individual cells; however, crucial spatial information is often lost. We present SpaOTsc, a method relying on structured optimal transport to recover spatial properties of scRNA-seq data by utilizing spatial measurements of a relatively small number of genes. A spatial metric for individual cells in scRNA-seq data is first established based on a map connecting it with the spatial measurements. The cell-cell communications are then obtained by "optimally transporting" signal senders to target signal receivers in space. Using partial information decomposition, we next compute the intercellular gene-gene information flow to estimate the spatial regulations between genes across cells. Four datasets are employed for cross-validation of spatial gene expression prediction and comparison to known cell-cell communications. SpaOTsc has broader applications, both in integrating non-spatial single-cell measurements with spatial data, and directly in spatial single-cell transcriptomics data to reconstruct spatial cellular dynamics in tissues.


Assuntos
Transdução de Sinais/genética , Análise de Célula Única , Transcriptoma/genética , Animais , Comunicação Celular , Análise por Conglomerados , Bases de Dados Genéticas , Drosophila/embriologia , Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Córtex Visual/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética
5.
Neuron ; 106(5): 769-777.e4, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32199104

RESUMO

Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which, in turn, may render them more vulnerable to such perturbations.


Assuntos
Homeostase/genética , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Córtex Visual/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Transtorno Autístico/genética , Comportamento Animal/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Silenciamento de Genes , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Asseio Animal/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Compostos de Lítio/farmacologia , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Vias Neurais , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Córtex Visual/citologia , Córtex Visual/metabolismo
6.
PLoS One ; 15(2): e0229590, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32084247

RESUMO

Orthographic processing is crucial in reading. For the Chinese language, sub-lexical processing has already taken place at radical level. Previous literature reported early position-specific radical representations and later position-general radical representations, implying a possible separating process of abstract position information irrespective of radicals per se from radical representations during orthographic processing. However, it remains largely unclear whether the abstract pattern of spatial arrangement of radicals can be rapidly extracted, and if so, whether this extraction takes place at the visual cortex, the very first processing center. As the visual cortex is documented to actively participate in orthographic processing, it may also play a role in the possible extraction of abstract orthographic patterns of Chinese characters. Hence, we hypothesize that abstract orthographic patterns of Chinese characters are covertly extracted at the visual cortex during reading. In this study, we investigated whether the visual cortex could rapidly extract abstract structural patterns of Chinese characters, using the event-related potential (ERP) technique. We adopted an active oddball paradigm with two types of deviant stimuli different only in one feature, structural or tonal, from standard stimuli; in each of the two sessions, subjects focused conscious attention on one feature and neglected the other. We observed that the ERPs recorded at occipital electrodes responded differentially to standard and structural deviant stimuli in both sessions, especially within the time range of the occipital P200 component. Then, we extracted three source waves arising from different levels of the visual cortex. Early response differences (from 88 to 456 ms after stimulus onset) were observed between the source waves, probably arising from left primary/secondary and bilateral associative visual cortices, in response to standard and deviant stimuli that violated abstract structural patterns, whether subjects focused their attention on the character structure or not. This suggests rapid extraction of abstract structural patterns of Chinese characters in the visual cortex, no matter the abstract structural pattern was explicit or implicit to subjects. Note that the source waves arising from right primary/secondary visual cortices in response to standard and structural deviant stimuli did not differ at all, indicating that this extraction of the abstract structural pattern of Chinese characters was left-lateralized. Besides, no difference was observed between source waves originating from any level of the visual cortex to standard and deviant stimuli that violated abstract tonal patterns, until 768 ms when a late effect related to conscious detection of targets occurred at higher levels of the visual cortex. Note that at late stages (later than 698 ms after stimulus onset), responses arising from bilateral associative visual cortices to standard and target stimuli differed for both sessions, no matter the structural or tonal feature was attended to. Our findings support the primitive intelligence of visual cortex to rapidly extract abstract orthographic patterns of Chinese characters that might be engaged in further lexical processing. Our findings also suggest that this rapid extraction can take place implicitly during reading.


Assuntos
Reconhecimento Visual de Modelos/fisiologia , Leitura , Percepção Visual/fisiologia , Adulto , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , China , Eletroencefalografia/métodos , Potenciais Evocados/fisiologia , Feminino , Humanos , Idioma , Masculino , Lobo Occipital/fisiologia , Fonética , Tempo de Reação/fisiologia , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Adulto Jovem
7.
Neuron ; 105(5): 895-908.e5, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901303

RESUMO

Modulation of synaptic strength through trafficking of AMPA receptors (AMPARs) is a fundamental mechanism underlying synaptic plasticity, learning, and memory. However, the dynamics of AMPAR trafficking in vivo and its correlation with learning have not been resolved. Here, we used in vivo two-photon microscopy to visualize surface AMPARs in mouse cortex during the acquisition of a forelimb reaching task. Daily training leads to an increase in AMPAR levels at a subset of spatially clustered dendritic spines in the motor cortex. Surprisingly, we also observed increases in spine AMPAR levels in the visual cortex. There, synaptic potentiation depends on the availability of visual input during motor training, and optogenetic inhibition of visual cortex activity impairs task performance. These results indicate that motor learning induces widespread cortical synaptic potentiation by increasing the net trafficking of AMPARs into spines, including in non-motor brain regions.


Assuntos
Espinhas Dendríticas/metabolismo , Aprendizagem , Atividade Motora , Córtex Motor/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Receptores de AMPA/metabolismo , Córtex Visual/metabolismo , Animais , Membro Anterior , Microscopia Intravital , Camundongos , Microscopia de Fluorescência , Optogenética , Transporte Proteico , Desempenho Psicomotor , Análise Espaço-Temporal
8.
Brain Struct Funct ; 225(1): 129-148, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31781971

RESUMO

Visual cortex (VC) over-activation analysed by evoked responses has been demonstrated in congenital deafness and after long-term acquired hearing loss in humans. However, permanent hearing deprivation has not yet been explored in animal models. Thus, the present study aimed to examine functional and molecular changes underlying the visual and auditory cross-modal reaction. For such purpose, we analysed cortical visual evoked potentials (VEPs) and the gene expression (RT-qPCR) of a set of markers for neuronal activation (c-Fos) and activity-dependent homeostatic compensation (Arc/Arg3.1). To determine the state of excitation and inhibition, we performed RT-qPCR and quantitative immunocytochemistry for excitatory (receptor subunits GluA2/3) and inhibitory (GABAA-α1, GABAB-R2, GAD65/67 and parvalbumin-PV) markers. VC over-activation was demonstrated by a significant increase in VEPs wave N1 and by up-regulation of the activity-dependent early genes c-Fos and Arc/Arg3.1 (thus confirming, by RT-qPCR, our previously published immunocytochemical results). GluA2 gene and protein expression were significantly increased in the auditory cortex (AC), particularly in layers 2/3 pyramidal neurons, but inhibitory markers (GAD65/67 and PV-GABA interneurons) were also significantly upregulated in the AC, indicating a concurrent increase in inhibition. Therefore, after permanent hearing loss in the rat, the VC is not only over-activated but also potentially balanced by homeostatic regulation, while excitatory and inhibitory markers remain imbalanced in the AC, most likely resulting from changes in horizontal intermodal regulation.


Assuntos
Córtex Auditivo/fisiologia , Percepção Auditiva/fisiologia , Surdez/fisiopatologia , Neurônios/fisiologia , Privação Sensorial/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Animais , Córtex Auditivo/metabolismo , Potenciais Evocados Auditivos do Tronco Encefálico , Potenciais Evocados Visuais , Expressão Gênica , Glutamato Descarboxilase/metabolismo , Parvalbuminas/metabolismo , Ratos Wistar , Receptores de AMPA/metabolismo , Córtex Visual/metabolismo
9.
J Neurosci ; 40(4): 769-783, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31801811

RESUMO

C1q, the initiator of the classical complement cascade, mediates synapse elimination in the postnatal mouse dorsolateral geniculate nucleus of the thalamus and sensorimotor cortex. Here, we asked whether C1q plays a role in experience-dependent synaptic refinement in the visual system at later stages of development. The binocular zone of primary visual cortex (V1b) undergoes spine loss and changes in neuronal responsiveness following the closure of one eye during a defined critical period [a process referred to as ocular dominance plasticity (ODP)]. We therefore hypothesized that ODP would be impaired in the absence of C1q, and that V1b development would also be abnormal without C1q-mediated synapse elimination. However, when we examined several features of V1b development in mice lacking C1q, we found that the densities of most spine populations on basal and proximal apical dendrites, as well as firing rates and ocular dominance, were normal. C1q was only transiently required for the development of spines on apical, but not basal, secondary dendrites. Dendritic morphologies were also unaffected. Although we did not observe the previously described spine loss during ODP in either genotype, our results reveal that the animals lacking C1q had normal shifts in neuronal responsiveness following eye closure. Experiments were performed in both male and female mice. These results suggest that the development and plasticity of the mouse V1b is grossly normal in the absence of C1q.SIGNIFICANCE STATEMENT These findings illustrate that the development and experience-dependent plasticity of V1b is mostly normal in the absence of C1q, even though C1q has previously been shown to be required for developmental synapse elimination in the mouse visual thalamus as well as sensorimotor cortex. The V1b phenotypes in mice lacking C1q are more similar to the mild defects previously observed in the hippocampus of these mice, emphasizing that the contribution of C1q to synapse elimination appears to be dependent on context.


Assuntos
Complemento C1q/metabolismo , Dominância Ocular/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Córtex Visual/metabolismo , Animais , Complemento C1q/genética , Dendritos/metabolismo , Espinhas Dendríticas/metabolismo , Camundongos , Camundongos Knockout , Sinapses/metabolismo
10.
Neuron ; 105(5): 799-812.e5, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-31883788

RESUMO

Sensory experiences cause long-term modifications of neuronal circuits by modulating activity-dependent transcription programs that are vital for regulation of long-term synaptic plasticity and memory. However, it has not been possible to precisely determine the interaction between neuronal activity patterns and transcription factor activity. Here we present a technique using two-photon fluorescence lifetime imaging (2pFLIM) with new FRET biosensors to chronically image in vivo signaling of CREB, an activity-dependent transcription factor important for synaptic plasticity, at single-cell resolution. Simultaneous imaging of the red-shifted CREB sensor and GCaMP permitted exploration of how experience shapes the interplay between CREB and neuronal activity in the neocortex of awake mice. Dark rearing increased the sensitivity of CREB activity to Ca2+ elevations and prolonged the duration of CREB activation to more than 24 h in the visual cortex. This technique will allow researchers to unravel the transcriptional dynamics underlying experience-dependent plasticity in the brain.


Assuntos
Cálcio/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Neocórtex/metabolismo , Plasticidade Neuronal , Neurônios/metabolismo , Animais , Escuridão , Transferência Ressonante de Energia de Fluorescência , Camundongos , Neocórtex/citologia , Vias Neurais , Neurônios/citologia , Estimulação Luminosa , Transdução de Sinais , Análise de Célula Única , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Córtex Visual/citologia , Córtex Visual/metabolismo
11.
Neurosci Bull ; 36(3): 277-288, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31768783

RESUMO

In the visual pathway, optic nerve (ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impairment in the visual cortex after ON injury remains unclear. The NOD-like receptor family pyrin domain containing 3 (NLRP3) is an important regulator of neuroinflammation. In this study, we established a mouse model of unilateral ON crush (ONC) and showed that the expression of NLRP3 was significantly increased in the primary visual cortex (V1) as a response to ONC and that the NLRP3 inflammasome was activated in the contralateral V1 1 days-14 days after ONC. Ablation of the NLRP3 gene significantly decreased the trans-neuronal degeneration within 14 days. Visual electrophysiological function was improved in NLRP3-/- mice. Taken together, these findings suggest that NLRP3 is a potential therapeutic target for protecting visual cortical neurons against degeneration after ON injury.


Assuntos
Potenciais Evocados Visuais , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Neurônios , Traumatismos do Nervo Óptico , Córtex Visual , Animais , Modelos Animais de Doenças , Potenciais Evocados Visuais/fisiologia , Inflamassomos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Neurônios/patologia , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Traumatismos do Nervo Óptico/fisiopatologia , Córtex Visual/metabolismo , Córtex Visual/patologia
12.
Neuron ; 105(3): 549-561.e5, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31810839

RESUMO

Paravascular drainage of solutes, including ß-amyloid (Aß), appears to be an important process in brain health and diseases such as Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aß accumulation in the brain.


Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Músculo Liso Vascular/irrigação sanguínea , Músculo Liso Vascular/metabolismo , Vigília/fisiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Capilares/metabolismo , Líquido Extracelular/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estimulação Luminosa/métodos , Sistema Vasomotor/metabolismo , Córtex Visual/irrigação sanguínea , Córtex Visual/metabolismo
13.
J Cereb Blood Flow Metab ; 40(3): 488-500, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-30755134

RESUMO

Negative blood oxygenation-level dependent (BOLD) signal observed during task execution in functional magnetic resonance imaging (fMRI) can be caused by different mechanisms, such as a blood-stealing effect or neuronal deactivation. Electrophysiological recordings showed that neuronal deactivation underlies the negative BOLD observed in the occipital lobe during visual stimulation. In this study, the metabolic demand of such a response was studied by measuring local metabolite concentration changes during a visual checkerboard stimulation using functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. The results showed increases of glutamate and lactate concentrations during the positive BOLD response, consistent with previous fMRS studies. In contrast, during the negative BOLD response, decreasing concentrations of glutamate, lactate and gamma-aminobutyric acid (GABA) were found, suggesting a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.


Assuntos
Imagem por Ressonância Magnética , Oxigênio/metabolismo , Estimulação Luminosa , Córtex Visual , Ácido gama-Aminobutírico/metabolismo , Adulto , Feminino , Ácido Glutâmico/metabolismo , Humanos , Ácido Láctico/metabolismo , Masculino , Córtex Visual/diagnóstico por imagem , Córtex Visual/metabolismo
14.
Elife ; 82019 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-31868167

RESUMO

Dark exposure (DE) followed by light reintroduction (LRx) reactivates robust synaptic plasticity in adult mouse primary visual cortex (V1), which allows subsequent recovery from amblyopia. Previously we showed that perisynaptic proteolysis by MMP9 mediates the enhancement of plasticity by LRx in binocular adult mice (Murase et al., 2017). However, it was unknown if a visual system compromised by amblyopia could engage this pathway. Here we show that LRx to adult amblyopic mice induces perisynaptic MMP2/9 activity and extracellular matrix (ECM) degradation in deprived and non-deprived V1. Indeed, LRx restricted to the amblyopic eye is sufficient to induce robust MMP2/9 activity at thalamo-cortical synapses and ECM degradation in deprived V1. Two-photon live imaging demonstrates that the history of visual experience regulates MMP2/9 activity in V1, and that DE lowers the threshold for the proteinase activation. The homeostatic reduction of the MMP2/9 activation threshold by DE enables visual input from the amblyopic pathway to trigger robust perisynaptic proteolysis.


Assuntos
Ambliopia/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteostase/fisiologia , Córtex Visual/metabolismo , Ambliopia/embriologia , Ambliopia/patologia , Animais , Biomarcadores , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Feminino , Luz , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Estimulação Luminosa , Lectinas de Plantas , Proteólise , Receptores de N-Acetilglucosamina , Sinapses , Visão Binocular/fisiologia , Córtex Visual/embriologia , Córtex Visual/patologia
15.
Curr Biol ; 29(24): 4268-4275.e7, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31786063

RESUMO

Neuronal response to sensory stimuli depends on the context. The response in primary visual cortex (V1), for instance, is reduced when a stimulus is surrounded by a similar stimulus [1-3]. The source of this surround suppression is partially known. In mouse, local horizontal integration by somatostatin-expressing interneurons contributes to surround suppression [4]. In primates, however, surround suppression arises too quickly to come from local horizontal integration alone, and myelinated axons from higher visual areas, where cells have larger receptive fields, are thought to provide additional surround suppression [5, 6]. Silencing higher visual areas indeed decreased surround suppression in the awake primate by increasing responses to large stimuli [7, 8], although not under anesthesia [9, 10]. In smaller mammals, like mice, fast surround suppression could be possible without feedback. Recent studies revealed a small reduction in V1 responses when silencing higher areas [11, 12] but have not investigated surround suppression. To determine whether higher visual areas contribute to V1 surround suppression, even when this is not necessary for fast processing, we inhibited the areas lateral to V1, particularly the lateromedial area (LM), a possible homolog of primate V2 [13], while recording in V1 of awake and anesthetized mice. We found that part of the surround suppression depends on activity from lateral visual areas in the awake, but not anesthetized, mouse. Inhibiting the lateral visual areas specifically increased responses in V1 to large stimuli. We present a model explaining how excitatory feedback to V1 can have these suppressive effects for large stimuli.


Assuntos
Inibição Neural/fisiologia , Córtex Visual/metabolismo , Vigília/fisiologia , Animais , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Orientação/fisiologia , Estimulação Luminosa/métodos , Córtex Visual/fisiologia , Campos Visuais , Vias Visuais/fisiologia , Percepção Visual/fisiologia
16.
Neural Plast ; 2019: 6804575, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772567

RESUMO

The perineuronal net (PNN) is a mesh-like proteoglycan structure on the neuronal surface which is involved in regulating plasticity. The PNN regulates plasticity via multiple pathways, one of which is direct regulation of synapses through the control of AMPA receptor mobility. Since neuronal pentraxin 2 (Nptx2) is a known regulator of AMPA receptor mobility and Nptx2 can be removed from the neuronal surface by PNN removal, we investigated whether Nptx2 has a function in the PNN. We found that Nptx2 binds to the glycosaminoglycans hyaluronan and chondroitin sulphate E in the PNN. Furthermore, in primary cortical neuron cultures, the addition of NPTX2 to the culture medium enhances PNN formation during PNN development. These findings suggest Nptx2 as a novel PNN binding protein with a role in the mechanism of PNN formation.


Assuntos
Proteína C-Reativa/metabolismo , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Células Satélites Perineuronais/metabolismo , Córtex Visual/metabolismo , Animais , Células Cultivadas , Feminino , Rede Nervosa/química , Rede Nervosa/citologia , Plasticidade Neuronal/fisiologia , Neurônios/química , Neurônios/metabolismo , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Células Satélites Perineuronais/química , Córtex Visual/química , Córtex Visual/citologia
17.
eNeuro ; 6(6)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31767573

RESUMO

Environmental enrichment (EE) has been shown to improve neural function via the regulation of cortical plasticity. Its capacity to induce functional and/or anatomical repair of miswired circuits is unknown. Ten-m3 knock-out (KO) mice exhibit a highly stereotyped and profound miswiring of ipsilateral retinogeniculate axons and associated deficits in binocularly-mediated visual behavior. We determined whether, and when, EE can drive the repair of subcortical wiring deficits by analyzing Ten-m3 KO and wild-type (WT) mice that were enriched for six weeks from adulthood, weaning or birth in comparison to standard-housed (SE) controls. Six weeks of EE initiated from birth, but not later, induced a significant reduction in the area occupied by ipsilateral retinogeniculate terminals in KOs. No EE-induced correction of mistargeted axons was observed at postnatal day (P)7, indicating that this intervention impacts pruning rather than initial targeting of axons. This reduction was most prominent in the ventrolateral region of the dorsal lateral geniculate nucleus (dLGN), suggesting a preferential pruning of the most profoundly mistargeted axons. EE can thus partially repair a specific, subcortical axonal wiring deficit, but only during an early, developmentally-restricted time window.


Assuntos
Axônios/metabolismo , Encéfalo/crescimento & desenvolvimento , Período Crítico Psicológico , Meio Ambiente , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Vias Visuais/crescimento & desenvolvimento , Animais , Encéfalo/metabolismo , Abrigo para Animais , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/genética , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/metabolismo , Vias Visuais/metabolismo
18.
Nat Commun ; 10(1): 5055, 2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699994

RESUMO

Rewards influence plasticity of early sensory representations, but the underlying changes in circuitry are unclear. Recent experimental findings suggest that inhibitory circuits regulate learning. In addition, inhibitory neurons are highly modulated by diverse long-range inputs, including reward signals. We, therefore, hypothesise that inhibitory plasticity plays a major role in adjusting stimulus representations. We investigate how top-down modulation by rewards interacts with local plasticity to induce long-lasting changes in circuitry. Using a computational model of layer 2/3 primary visual cortex, we demonstrate how interneuron circuits can store information about rewarded stimuli to instruct long-term changes in excitatory connectivity in the absence of further reward. In our model, stimulus-tuned somatostatin-positive interneurons develop strong connections to parvalbumin-positive interneurons during reward such that they selectively disinhibit the pyramidal layer henceforth. This triggers excitatory plasticity, leading to increased stimulus representation. We make specific testable predictions and show that this two-stage model allows for translation invariance of the learned representation.


Assuntos
Interneurônios/metabolismo , Inibição Neural/fisiologia , Plasticidade Neuronal/fisiologia , Recompensa , Córtex Visual/metabolismo , Animais , Simulação por Computador , Modelos Neurológicos , Vias Neurais/metabolismo , Células Piramidais/metabolismo
19.
Nat Commun ; 10(1): 5277, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754099

RESUMO

Mitochondrial calcium ([Ca2+]mito) dynamics plays vital roles in regulating fundamental cellular and organellar functions including bioenergetics. However, neuronal [Ca2+]mito dynamics in vivo and its regulation by brain activity are largely unknown. By performing two-photon Ca2+ imaging in the primary motor (M1) and visual cortexes (V1) of awake behaving mice, we find that discrete [Ca2+]mito transients occur synchronously over somatic and dendritic mitochondrial network, and couple with cytosolic calcium ([Ca2+]cyto) transients in a probabilistic, rather than deterministic manner. The amplitude, duration, and frequency of [Ca2+]cyto transients constitute important determinants of the coupling, and the coupling fidelity is greatly increased during treadmill running (in M1 neurons) and visual stimulation (in V1 neurons). Moreover, Ca2+/calmodulin kinase II is mechanistically involved in modulating the dynamic coupling process. Thus, activity-dependent dynamic [Ca2+]mito-to-[Ca2+]cyto coupling affords an important mechanism whereby [Ca2+]mito decodes brain activity for the regulation of mitochondrial bioenergetics to meet fluctuating neuronal energy demands as well as for neuronal information processing.


Assuntos
Encéfalo/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Citosol/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Córtex Visual/metabolismo , Animais , Encéfalo/citologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Microscopia de Fluorescência por Excitação Multifotônica , Mitocôndrias/ultraestrutura , Córtex Motor/citologia , Córtex Motor/metabolismo , Córtex Visual/citologia
20.
Nat Neurosci ; 22(11): 1936-1944, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31570865

RESUMO

Recent work examining astrocytic physiology centers on fluorescence imaging, due to development of sensitive fluorescent indicators and observation of spatiotemporally complex calcium activity. However, the field remains hindered in characterizing these dynamics, both within single cells and at the population level, because of the insufficiency of current region-of-interest-based approaches to describe activity that is often spatially unfixed, size-varying and propagative. Here we present an analytical framework that releases astrocyte biologists from region-of-interest-based tools. The Astrocyte Quantitative Analysis (AQuA) software takes an event-based perspective to model and accurately quantify complex calcium and neurotransmitter activity in fluorescence imaging datasets. We apply AQuA to a range of ex vivo and in vivo imaging data and use physiologically relevant parameters to comprehensively describe the data. Since AQuA is data-driven and based on machine learning principles, it can be applied across model organisms, fluorescent indicators, experimental modes, and imaging resolutions and speeds, enabling researchers to elucidate fundamental neural physiology.


Assuntos
Astrócitos/metabolismo , Cálcio/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Neurotransmissores/metabolismo , Imagem Óptica/métodos , Adenoviridae , Algoritmos , Animais , Animais Recém-Nascidos , Vetores Genéticos , Camundongos , Software , Transfecção , Córtex Visual/metabolismo
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