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1.
J Neurophysiol ; 128(4): 763-777, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35975935

RESUMO

The spatiotemporal representation of neural activity during rest and upon sensory stimulation in cortical areas is highly dynamic and may be predominantly governed by cortical state. On the mesoscale level, intrinsic neuronal activity ranges from a persistent state, generally associated with a sustained depolarization of neurons, to a bimodal, slow wave-like state with bursts of neuronal activation alternating with silent periods. These different activity states are prevalent under certain types of sedatives or are associated with specific behavioral or vigilance conditions. Neurophysiological experiments assessing circuit activity usually assume a constant underlying state, yet reports of variability of neuronal responses under seemingly constant conditions are common in the field. Even when a certain type of neural activity or cortical state can be stably maintained over time, the associated response properties are highly relevant for explaining experimental outcomes. Here we describe the spatiotemporal characteristics of ongoing activity and sensory-evoked responses under two predominant functional states in the sensory cortices of mice: persistent activity (PA) and slow wave activity (SWA). Using electrophysiological recordings and local and wide-field calcium recordings, we examine whether spontaneous and sensory-evoked neuronal activity propagate throughout the cortex in a state-dependent manner. We find that PA and SWA differ in their spatiotemporal characteristics, which determine the cortical network's response to a sensory stimulus. During PA state, sensory stimulation elicits gamma-based short-latency responses that precisely follow each stimulation pulse and are prone to adaptation upon higher stimulation frequencies. Sensory responses during SWA are more variable, dependent on refractory periods following spontaneous slow waves. Although spontaneous slow waves propagated in anterior-posterior direction in a majority of observations, the direction of propagation of stimulus-elicited wave depends on the sensory modality. These findings suggest that cortical state explains variance and should be considered when investigating multiscale correlates of functional neurocircuit activity.NEW & NOTEWORTHY Here we dissect the cortical representation of brain states based on local photometry recordings and on mesoscale cortical calcium imaging, complemented by electrophysiological recordings in mice. We identify two distinct functional states in the sensory cortices, which differ in their spatiotemporal characteristics on the local and global cortical scales. We examine how intrinsic and stimulus-evoked neuronal activity propagates throughout the cortex in a state-dependent manner, supporting the notion that cortical state is a relevant variable to consider for a wide range of neurophysiological experiments.


Assuntos
Cálcio , Neurônios , Animais , Fenômenos Eletrofisiológicos , Hipnóticos e Sedativos , Camundongos , Neurônios/fisiologia , Vigília
2.
J Neurosci ; 34(11): 3854-63, 2014 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-24623764

RESUMO

Many structures of the mammalian CNS generate propagating waves of electrical activity early in development. These waves are essential to CNS development, mediating a variety of developmental processes, such as axonal outgrowth and pathfinding, synaptogenesis, and the maturation of ion channel and receptor properties. In the mouse cerebral cortex, waves of activity occur between embryonic day 18 and postnatal day 8 and originate in pacemaker circuits in the septal nucleus and the piriform cortex. Here we show that genetic knock-out of the major synthetic enzyme for GABA, GAD67, selectively eliminates the picrotoxin-sensitive fraction of these waves. The waves that remain in the GAD67 knock-out have a much higher probability of propagating into the dorsal neocortex, as do the picrotoxin-resistant fraction of waves in controls. Field potential recordings at the point of wave initiation reveal different electrical signatures for GABAergic and glutamatergic waves. These data indicate that: (1) there are separate GABAergic and glutamatergic pacemaker circuits within the piriform cortex, each of which can initiate waves of activity; (2) the glutamatergic pacemaker initiates waves that preferentially propagate into the neocortex; and (3) the initial appearance of the glutamatergic pacemaker does not require preceding GABAergic waves. In the absence of GAD67, the electrical activity underlying glutamatergic waves shows greatly increased tendency to burst, indicating that GABAergic inputs inhibit the glutamatergic pacemaker, even at stages when GABAergic pacemaker circuitry can itself initiate waves.


Assuntos
Sinalização do Cálcio/fisiologia , Neurônios GABAérgicos/fisiologia , Glutamato Descarboxilase/genética , Neocórtex/embriologia , Neocórtex/fisiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Relógios Biológicos/fisiologia , Feminino , Feto , Glutamato Descarboxilase/fisiologia , Ácido Glutâmico/metabolismo , Proteínas de Fluorescência Verde/genética , Masculino , Camundongos , Camundongos Knockout , Inibição Neural/fisiologia , Técnicas de Cultura de Órgãos , Gravidez , Septo do Cérebro/embriologia , Septo do Cérebro/fisiologia , Transmissão Sináptica/genética , Ácido gama-Aminobutírico/genética
3.
PLoS Comput Biol ; 10(12): e1003962, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25474701

RESUMO

Diverse ion channels and their dynamics endow single neurons with complex biophysical properties. These properties determine the heterogeneity of cell types that make up the brain, as constituents of neural circuits tuned to perform highly specific computations. How do biophysical properties of single neurons impact network function? We study a set of biophysical properties that emerge in cortical neurons during the first week of development, eventually allowing these neurons to adaptively scale the gain of their response to the amplitude of the fluctuations they encounter. During the same time period, these same neurons participate in large-scale waves of spontaneously generated electrical activity. We investigate the potential role of experimentally observed changes in intrinsic neuronal properties in determining the ability of cortical networks to propagate waves of activity. We show that such changes can strongly affect the ability of multi-layered feedforward networks to represent and transmit information on multiple timescales. With properties modeled on those observed at early stages of development, neurons are relatively insensitive to rapid fluctuations and tend to fire synchronously in response to wave-like events of large amplitude. Following developmental changes in voltage-dependent conductances, these same neurons become efficient encoders of fast input fluctuations over few layers, but lose the ability to transmit slower, population-wide input variations across many layers. Depending on the neurons' intrinsic properties, noise plays different roles in modulating neuronal input-output curves, which can dramatically impact network transmission. The developmental change in intrinsic properties supports a transformation of a networks function from the propagation of network-wide information to one in which computations are scaled to local activity. This work underscores the significance of simple changes in conductance parameters in governing how neurons represent and propagate information, and suggests a role for background synaptic noise in switching the mode of information transmission.


Assuntos
Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/citologia , Biologia Computacional , Canais Iônicos/metabolismo , Neurônios/citologia , Ratos
4.
J Neurosci ; 33(30): 12154-70, 2013 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-23884925

RESUMO

Adaptation is a fundamental computational motif in neural processing. To maintain stable perception in the face of rapidly shifting input, neural systems must extract relevant information from background fluctuations under many different contexts. Many neural systems are able to adjust their input-output properties such that an input's ability to trigger a response depends on the size of that input relative to its local statistical context. This "gain-scaling" strategy has been shown to be an efficient coding strategy. We report here that this property emerges during early development as an intrinsic property of single neurons in mouse sensorimotor cortex, coinciding with the disappearance of spontaneous waves of network activity, and can be modulated by changing the balance of spike-generating currents. Simultaneously, developing neurons move toward a common intrinsic operating point and a stable ratio of spike-generating currents. This developmental trajectory occurs in the absence of sensory input or spontaneous network activity. Through a combination of electrophysiology and modeling, we demonstrate that developing cortical neurons develop the ability to perform nearly perfect gain scaling by virtue of the maturing spike-generating currents alone. We use reduced single neuron models to identify the conditions for this property to hold.


Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Córtex Somatossensorial/citologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Rede Nervosa/citologia , Rede Nervosa/embriologia , Rede Nervosa/fisiologia , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Córtex Somatossensorial/embriologia , Córtex Somatossensorial/fisiologia , Sinapses/fisiologia
5.
J Neurophysiol ; 112(12): 3033-45, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25185811

RESUMO

Spontaneous synchronous activity (SSA) that propagates as electrical waves is found in numerous central nervous system structures and is critical for normal development, but the mechanisms of generation of such activity are not clear. In previous work, we showed that the ventrolateral piriform cortex is uniquely able to initiate SSA in contrast to the dorsal neocortex, which participates in, but does not initiate, SSA (Lischalk JW, Easton CR, Moody WJ. Dev Neurobiol 69: 407-414, 2009). In this study, we used Ca(2+) imaging of cultured embryonic day 18 to postnatal day 2 coronal slices (embryonic day 17 + 1-4 days in culture) of the mouse cortex to investigate the different activity patterns of individual neurons in these regions. In the piriform cortex where SSA is initiated, a higher proportion of neurons was active asynchronously between waves, and a larger number of groups of coactive cells was present compared with the dorsal cortex. When we applied GABA and glutamate synaptic antagonists, asynchronous activity and cellular clusters remained, while synchronous activity was eliminated, indicating that asynchronous activity is a result of cell-intrinsic properties that differ between these regions. To test the hypothesis that higher levels of cell-autonomous activity in the piriform cortex underlie its ability to initiate waves, we constructed a conductance-based network model in which three layers differed only in the proportion of neurons able to intrinsically generate bursting behavior. Simulations using this model demonstrated that a gradient of intrinsic excitability was sufficient to produce directionally propagating waves that replicated key experimental features, indicating that the higher level of cell-intrinsic activity in the piriform cortex may provide a substrate for SSA generation.


Assuntos
Ondas Encefálicas , Córtex Cerebral/fisiologia , Sincronização Cortical , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Sinalização do Cálcio , Células Cultivadas , Córtex Cerebral/embriologia , Sinapses Elétricas/fisiologia , Camundongos , Modelos Neurológicos , Rede Nervosa/embriologia , Córtex Piriforme/embriologia , Córtex Piriforme/fisiologia , Sinapses/fisiologia , Canais de Sódio Disparados por Voltagem/fisiologia
6.
Dev Neurobiol ; 82(7-8): 596-612, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36250606

RESUMO

Spontaneous electrical activity plays major roles in the development of cortical circuitry. This activity can occur highly localized regions or can propagate over the entire cortex. Both types of activity coexist during early development. To investigate how different forms of spontaneous activity might be temporally segregated, we used wide-field trans-cranial calcium imaging over an entire hemisphere in P1-P8 mouse pups. We found that spontaneous waves of activity that propagate to cover the majority of the cortex (large-scale waves; LSWs) are generated at the end of the first postnatal week, along with several other forms of more localized activity. We further found that LSWs are segregated into sleep cycles. In contrast, cortical activity during wake states is more spatially restricted and the few large-scale forms of activity that occur during wake can be distinguished from LSWs in sleep based on their initiation in the motor cortex and their correlation with body movements. This change in functional cortical circuitry to a state that is permissive for large-scale activity may temporally segregate different forms of activity during critical stages when activity-dependent circuit development occurs over many spatial scales. Our data also suggest that LSWs in early development may be a functional precursor to slow sleep waves in the adult, which play critical roles in memory consolidation and synaptic rescaling.


Assuntos
Córtex Cerebral , Sono , Animais , Camundongos , Animais Recém-Nascidos , Eletroencefalografia
7.
J Physiol ; 589(Pt 10): 2529-41, 2011 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-21486817

RESUMO

Waves of spontaneous electrical activity propagate across many regions of the central nervous system during specific stages of early development. The patterns of wave propagation are critical in the activation of many activity-dependent developmental programs. It is not known how the mechanisms that initiate and propagate spontaneous waves operate during periods in which major changes in neuronal structure and function are taking place. We have recently reported that spontaneous waves of activity propagate across the neonatal mouse cerebral cortex and that these waves are initiated at pacemaker sites in the septal nucleus and ventral cortex. Here we show that spontaneous waves occur between embryonic day 18 (E18) and postnatal day 12 (P12), and that during that period they undergo major changes in transmitter dependence and propagation patterns. At early stages, spontaneous waves are largely GABA dependent and are mostly confined to the septum and ventral cortex. As development proceeds, wave initiation depends increasingly on AMPA-type glutamate receptors, and an ever increasing fraction of waves propagate into the dorsal cortex. The initiation sites and restricted propagation of waves at early stages are highly correlated with the position of GABAergic neurons in the cortex. The later switch to a glutamate-based mechanism allows propagation of waves into the dorsal cortex, and appears to be a compensatory mechanism that ensures continued wave generation even as GABA transmission becomes inhibitory.


Assuntos
Ondas Encefálicas/fisiologia , Córtex Cerebral/fisiologia , Neurotransmissores/fisiologia , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Córtex Cerebral/crescimento & desenvolvimento , Feminino , Ácido Glutâmico/fisiologia , Camundongos , Camundongos Endogâmicos , Neurônios/fisiologia , Ácido gama-Aminobutírico/fisiologia
8.
J R Soc Interface ; 18(181): 20210523, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34428947

RESUMO

Widefield calcium imaging has recently emerged as a powerful experimental technique to record coordinated large-scale brain activity. These measurements present a unique opportunity to characterize spatiotemporally coherent structures that underlie neural activity across many regions of the brain. In this work, we leverage analytic techniques from fluid dynamics to develop a visualization framework that highlights features of flow across the cortex, mapping wavefronts that may be correlated with behavioural events. First, we transform the time series of widefield calcium images into time-varying vector fields using optic flow. Next, we extract concise diagrams summarizing the dynamics, which we refer to as FLOW (flow lines in optical widefield imaging) portraits. These FLOW portraits provide an intuitive map of dynamic calcium activity, including regions of initiation and termination, as well as the direction and extent of activity spread. To extract these structures, we use the finite-time Lyapunov exponent technique developed to analyse time-varying manifolds in unsteady fluids. Importantly, our approach captures coherent structures that are poorly represented by traditional modal decomposition techniques. We demonstrate the application of FLOW portraits on three simple synthetic datasets and two widefield calcium imaging datasets, including cortical waves in the developing mouse and spontaneous cortical activity in an adult mouse.


Assuntos
Encéfalo , Cálcio , Animais , Encéfalo/diagnóstico por imagem , Camundongos
9.
Dev Neurobiol ; 76(6): 661-72, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26385616

RESUMO

Spontaneous activity in the developing brain helps refine neuronal connections before the arrival of sensory-driven neuronal activity. In mouse neocortex during the first postnatal week, waves of spontaneous activity originating from pacemaker regions in the septal nucleus and piriform cortex propagate through the neocortex. Using high-speed Ca(2+) imaging to resolve the spatiotemporal dynamics of wave propagation in parasagittal mouse brain slices, we show that the hippocampus can act as an additional source of neocortical waves. Some waves that originate in the hippocampus remain restricted to that structure, while others pause at the hippocampus-neocortex boundary and then propagate into the neocortex. Blocking GABAergic neurotransmission decreases the likelihood of wave propagation into neocortex, whereas blocking glutamatergic neurotransmission eliminates spontaneous and evoked hippocampal waves. A subset of hippocampal and cortical waves trigger Ca(2+) waves in astrocytic networks after a brief delay. Hippocampal waves accompanied by Ca(2+) elevation in astrocytes are more likely to propagate into the neocortex. Finally, we show that two structures in our preparation that initiate waves-the hippocampus and the piriform cortex-can be electrically stimulated to initiate propagating waves at lower thresholds than the neocortex, indicating that the intrinsic circuit properties of those regions are responsible for their pacemaker function.


Assuntos
Córtex Cerebral/citologia , Hipocampo/citologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Animais , Animais Recém-Nascidos , Astrócitos/metabolismo , Cálcio/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Estimulação Elétrica , Agonistas de Aminoácidos Excitatórios/farmacologia , Glutamato Descarboxilase/metabolismo , Hipocampo/crescimento & desenvolvimento , Técnicas In Vitro , Camundongos , Rede Nervosa/crescimento & desenvolvimento , Picrotoxina/farmacologia , Potássio/farmacologia , Valina/análogos & derivados , Valina/farmacologia
10.
J Neurosci ; 24(7): 1719-25, 2004 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-14973256

RESUMO

In mouse, the first neurons are generated at embryonic day (E) 12 and form the preplate (PP), which contains a mix of future marginal zone cells, including Cajal-Retzius cells, and subplate cells. To detect developmental changes in channel populations in these earliest-generated neurons of the cerebral cortex, we studied the electrophysiological properties of proliferative cells of the ventricular zone and postmitotic neurons of the PP at E12 and E13, using whole-cell patch-clamp recordings. We found an inward sodium current in 55% of PP cells. To determine whether sodium currents occur in a specific cell type, we stained recorded cells with an antibody for calretinin, a calcium-binding protein found specifically in Cajal-Retzius cells. All calretinin-positive cells had sodium currents, although so did some calretinin-negative cells. To correlate the Na current expression to Na channel gene expression with the Cajal-Retzius cell phenotype, we performed single-cell reverse transcription-PCR on patch-clamp recorded cells to detect expression of the Cajal-Retzius cell marker reelin and the Na channel isoforms SCN 1, 2, and 3. These results showed that virtually all Cajal-Retzius cells (97%), as judged by reelin expression, express the SCN transcript identified as the SCN3 isoform. Of these, 41% presented a functional Na current. There is, however, a substantial SCN-positive population in the PP (27% of SCN-positive cells) that does not express reelin. These results raise the possibility that populations of pioneer neurons of the PP, including Cajal-Retzius cells, gain neuronal physiological properties early in development via expression of the Na(v)1.3 (SCN3) Na channel isoform.


Assuntos
Neocórtex/metabolismo , Neurônios/metabolismo , RNA Mensageiro/biossíntese , Canais de Sódio/genética , Canais de Sódio/metabolismo , Sódio/metabolismo , Animais , Calbindina 2 , Diferenciação Celular/fisiologia , Idade Gestacional , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/citologia , Neocórtex/embriologia , Neurônios/classificação , Neurônios/citologia , Técnicas de Patch-Clamp , Potássio/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Reelina , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína G de Ligação ao Cálcio S100/biossíntese
11.
Lab Chip ; 13(4): 527-35, 2013 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-23042571

RESUMO

In order to understand information processing in neural circuits, it is necessary to detect both electrical and chemical signaling with high spatial and temporal resolution. Although the primary currency of neural information processing is electrical, many of the downstream effects of the electrical signals on the circuits that generate them are dependent on activity-dependent increases in intracellular calcium concentration. It is therefore of great utility to be able to record electrical signals in neural circuits at multiple sites, while at the same time detecting optical signals from reporters of intracellular calcium levels. We describe here a microfluidic multi-electrode array (MMEA) capable of high-resolution extracellular recording from brain slices that is optically compatible with calcium imaging at single cell resolution. We show the application of the MMEA device to record waves of spontaneous activity in developing cortical slices and to perform multi-site extracellular recordings during simultaneous calcium imaging of activity. The MMEA has the unique capability to simultaneously allow focal electrical and chemical stimuli at different locations of the surface of a brain slice.


Assuntos
Encéfalo/fisiologia , Eletrofisiologia , Técnicas Analíticas Microfluídicas , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Sinalização do Cálcio , Eletrofisiologia/instrumentação , Feminino , Camundongos , Microeletrodos , Técnicas Analíticas Microfluídicas/instrumentação , Estimulação Química
12.
Dev Neurobiol ; 70(10): 679-92, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20506182

RESUMO

Spontaneous waves of activity that propagate across large structures during specific developmental stages play central roles in CNS development. To understand the genesis and functions of these waves, it is critical to understand the spatial and temporal patterns of their propagation. We recently reported that spontaneous waves in the neonatal cerebral cortex originate from a ventrolateral pacemaker region. We have now analyzed a large number of spontaneous waves using calcium imaging over the entire area of coronal slices from E18-P1 mouse brains. In all waves, the first cortical region active is this ventrolateral pacemaker. In half of the waves, however, the cortical pacemaker activity is itself triggered by preceding activity in the septal nuclei. Most waves are restricted to the septum and/or ventral cortex, with only some invading the dorsal cortex or the contralateral hemisphere. Waves fail to propagate at very stereotyped locations at the boundary between ventral and dorsal cortex and at the dorsal midline. Waves that cross these boundaries pause at these same locations. Waves at these stages are blocked by both picrotoxin and CNQX, indicating that both GABA(A) and AMPA receptors are involved in spontaneous activity.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/fisiologia , Potenciais Evocados/fisiologia , Núcleos Septais/embriologia , Núcleos Septais/fisiologia , Animais , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/fisiologia , Sinalização do Cálcio/fisiologia , Potenciais Evocados/efeitos dos fármacos , Feminino , Lateralidade Funcional/fisiologia , Camundongos , Vias Neurais/embriologia , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Imagens com Corantes Sensíveis à Voltagem/métodos
13.
Dev Neurobiol ; 69(7): 407-14, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19263415

RESUMO

Spontaneous electrical activity that moves in synchronized waves across large populations of neurons plays widespread and important roles in nervous system development. The propagation patterns of such waves can encode the spatial location of neurons to their downstream targets and strengthen synaptic connections in coherent spatial patterns. Such waves can arise as an emergent property of mutually excitatory neural networks, or can be driven by a discrete pacemaker. In the mouse cerebral cortex, spontaneous synchronized activity occurs for approximately 72 h of development centered on the day of birth. It is not known whether this activity is driven by a discrete pacemaker or occurs as an emergent network property. Here we show that this activity propagates as a wave that is initiated at either of two homologous pacemakers in the temporal region, and then propagates rapidly across both sides of the brain. When these regions of origin are surgically isolated, waves do not occur. Therefore, this cortical spontaneous activity is a bilateral wave that originates from a discrete subset of pacemaker neurons.


Assuntos
Potenciais de Ação/fisiologia , Córtex Cerebral/fisiologia , Rede Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Tempo de Reação/fisiologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/citologia , Eletrofisiologia/métodos , Camundongos , Técnicas de Cultura de Órgãos
14.
Dev Neurobiol ; 69(4): 255-66, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19172658

RESUMO

The second messenger cyclic guanosine monophosphate (cGMP) plays many roles during nervous system development. Consequently, cGMP production shows complex patterns of regulation throughout early development. Elevated glutamate levels are known to increase cGMP levels in the mature nervous system. A number of clinical conditions including ischemia and perinatal asphyxia can result in elevated glutamate levels in the developing brain. To investigate the effects of elevated glutamate levels on cGMP in the developing cortex we exposed mouse brain slices to glutamate or N-methyl D-aspartate (NMDA). We find that at early postnatal stages when the endogenous production of cGMP is high, glutamate or NMDA exposure results in a significant lowering of the overall production of cGMP in the cortex, unlike the situation in the mature brain. However, this response pattern is complex with regional and cell-type specific exceptions to the overall lowered cGMP production. These data emphasize that the response of the developing brain to physiological disturbances can be different from that of the mature brain, and must be considered in the context of the developmental events occurring at the time of disturbance.


Assuntos
Córtex Cerebral/efeitos dos fármacos , GMP Cíclico/metabolismo , Ácido Glutâmico/farmacologia , N-Metilaspartato/farmacologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/metabolismo , Imuno-Histoquímica , Camundongos , Técnicas de Cultura de Órgãos
15.
Dev Neurobiol ; 67(12): 1574-88, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17542015

RESUMO

Spontaneous, synchronized electrical activity (SSA) plays important roles in nervous system development, but it is not clear what causes it to start and stop at the appropriate times. In previous work, we showed that when SSA in neonatal mouse cortex is blocked by TTX in cultured slices during its normal time of occurrence (E17-P3), it fails to stop at P3 as it does in control cultured slices, but instead persists through at least P10. This indicates that SSA is self-extinguishing. Here we use whole-cell recordings and [Ca2+]i imaging to compare control and TTX-treated slices to isolate the factors that normally extinguish SSA on schedule. In TTX-treated slices, SSA bursts average 4 s in duration, and have two components. The first, lasting about 1 s, is mediated by AMPA receptors; the second, which extends the burst to 4 s and is responsible for most of the action potential generation during the burst, is mediated by NMDA receptors. In later stage (P5-P9) control slices, after SSA has declined to about 4% of its peak frequency, bursts lack this long NMDA component. Blocking this NMDA component in P5-P9 TTX-treated slices reduces SSA frequency, but not to the low values found in control slices, implying that additional factors help extinguish SSA. GABA(A) inhibitors restore SSA in control slices, indicating that the emergence of GABA(A)-mediated inhibition is another major factor that helps terminate SSA.


Assuntos
Potenciais de Ação/fisiologia , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo , Potenciais de Ação/efeitos dos fármacos , Animais , Córtex Cerebral/efeitos dos fármacos , Processamento de Imagem Assistida por Computador , Camundongos , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp , Venenos/farmacologia , Receptores de AMPA/efeitos dos fármacos , Receptores de AMPA/metabolismo , Receptores de GABA/efeitos dos fármacos , Receptores de Glutamato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Tetrodotoxina/farmacologia
16.
Dev Dyn ; 235(6): 1668-77, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16518821

RESUMO

The second messenger cyclic guanosine monophosphate (cGMP) regulates multiple aspects of both structural development and physiological function in the developing nervous system. Recent in vitro experiments have shown that cGMP also modulates the response of developing vertebrate neurons to guidance molecules. This has led to the proposal that in vivo cGMP plays a critical role in directing the outgrowth of the apical dendrites of developing neurons in the cerebral cortex. Despite this proposed role, the onset, localization, and dynamics of cGMP production in the embryonic cortex are unknown. To investigate the potential contribution of cGMP in the embryo, we have used a pharmacological and immunohistochemical approach to test whether the endogenous production of cGMP, and the capacity to produce cGMP in response to nitric oxide (NO), in the cerebral cortex is compatible with the proposed developmental roles for cGMP. We find that cortical cGMP production and NO sensitivity are regionally and developmentally regulated. Cortical cGMP production begins at E15, later than in the ganglionic eminences, becomes high in the cortical plate but not the ventricular zone, and is dependent on nitric oxide synthase activity. Furthermore, although radially migrating neurons were not NO responsive until they reached the cortical plate, NO exposure revealed an additional population of tangentially migrating presumptive interneurons from the ganglionic eminences with the capacity to produce cGMP. These results provide a new level of understanding of the stage and cell type specific regulation of the NO/cGMP pathway during embryonic development.


Assuntos
Córtex Cerebral/embriologia , Corpo Estriado/embriologia , GMP Cíclico/biossíntese , Óxido Nítrico/fisiologia , Animais , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
17.
J Physiol ; 577(Pt 1): 155-67, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-16945966

RESUMO

Waves of spontaneous electrical activity that are highly synchronized across large populations of neurones occur throughout the developing mammalian central nervous system. The stages at which this activity occurs are tightly regulated to allow activity-dependent developmental programmes to be initiated correctly. What determines the onset and cessation of spontaneous synchronous activity (SSA) in a particular region of the nervous system, however, remains unclear. We have tested the hypothesis that activity itself triggers developmental changes in intrinsic and circuit properties that determine the stages at which SSA occurs. To do this we exposed cultured slices of mouse neocortex to tetrodotoxin (TTX) to block SSA, which normally occurs between embryonic day 17 (E17) and postnatal day 3 (P3). In control cultured slices, SSA rarely occurs after P3. In TTX-treated slices, however, SSA was generated from P3 (the day of TTX removal) until at least P10. This indicates that in the absence of spontaneous activity, the mechanisms that normally determine the timing of SSA are not initiated, and that a compensatory response occurs that shifts the time of SSA occurrence to later developmental stages.


Assuntos
Potenciais de Ação/fisiologia , Relógios Biológicos/fisiologia , Córtex Cerebral/embriologia , Córtex Cerebral/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Animais , Retroalimentação/fisiologia , Camundongos
18.
Physiol Rev ; 85(3): 883-941, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15987798

RESUMO

At specific stages of development, nerve and muscle cells generate spontaneous electrical activity that is required for normal maturation of intrinsic excitability and synaptic connectivity. The patterns of this spontaneous activity are not simply immature versions of the mature activity, but rather are highly specialized to initiate and control many aspects of neuronal development. The configuration of voltage- and ligand-gated ion channels that are expressed early in development regulate the timing and waveform of this activity. They also regulate Ca2+ influx during spontaneous activity, which is the first step in triggering activity-dependent developmental programs. For these reasons, the properties of voltage- and ligand-gated ion channels expressed by developing neurons and muscle cells often differ markedly from those of adult cells. When viewed from this perspective, the reasons for complex patterns of ion channel emergence and regression during development become much clearer.


Assuntos
Canais Iônicos/fisiologia , Músculos/citologia , Músculos/fisiologia , Neurônios/fisiologia , Animais , Encéfalo/fisiologia , Humanos , Ativação do Canal Iônico/fisiologia , Ligantes , Músculo Esquelético/citologia , Músculo Esquelético/fisiologia
19.
Cereb Cortex ; 13(3): 239-51, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12571114

RESUMO

We measured dye coupling, electrical coupling, and voltage-gated currents using whole-cell voltage clamp in slices of mouse sensorimotor cortex at embryonic day 14 (E14). As in rat ventricular zone (VZ), cells of the VZ were extensively dye coupled, often in clusters of >100 cells. In mouse VZ, however, cells were much less electrically coupled, making measurement of voltage-gated currents more accurate. All VZ cells expressed delayed K(+) currents (I(K)), and 30%, including morphologically identified radial glia, also expressed inward Na(+) currents (I(Na)). This fraction is consistent with I(Na) expression being an early event following cell cycle exit. Intermediate zone (IZ) cells also expressed I(K) and I(Na). Na(+) current amplitude distributions indicated three populations of IZ cells: those without I(Na), those with I(Na) similar in amplitude to VZ cells, and those with I(Na) being almost 10 times larger than in VZ cells. Cells of the cortical plate (CP) expressed both I(K) and I(Na), with I(Na) being almost 10-fold larger than in VZ cells. No cell in any zone expressed detectable hyperpolarization-activated currents. Our data suggest that the distribution and density of I(Na) may be related to early events of cell cycle exit and migration.


Assuntos
Embrião de Mamíferos/fisiologia , Corantes Fluorescentes/análise , Canais Iônicos/fisiologia , Neocórtex/fisiologia , Potenciais de Ação/fisiologia , Animais , Embrião de Mamíferos/química , Feminino , Canais Iônicos/análise , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/química , Gravidez
20.
J Neurophysiol ; 89(4): 1761-73, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12611962

RESUMO

Voltage- and current-clamp recordings were made from acute slices of mouse cerebral cortex from embryonic day 14 to postnatal day 17. We targeted cells in the migratory population of the embryonic intermediate zone (IZ) and in deep layers of embryonic and postnatal cortical plate (CP). IZ neurons maintain fairly consistent properties through the embryonic period, all expressing high-input resistance, inward Na(+) currents and outward K(+) currents, and none showing any hyperpolarization-activated currents. In CP neurons, several changes in physiological properties occur in the late embryonic and early postnatal period: inward Na(+) current density is strongly upregulated while outward K(+) current density remains almost unchanged, input resistance drops dramatically, and a hyperpolarization-activated current resembling I(h) appears. As a result of these changes, the action potential becomes larger, shorter in duration, and its threshold shifts to more negative potentials. In addition, CP cells become capable of firing repetitively and an increasing fraction show spontaneous action potentials. This coordinated development of ion channel properties may help to time the occurrence of developmentally relevant spontaneous activity in the immature cortex.


Assuntos
Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Canais de Potássio/fisiologia , Células Piramidais/fisiologia , Canais de Sódio/fisiologia , Potenciais de Ação/fisiologia , Animais , Córtex Cerebral/citologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Patch-Clamp , Gravidez
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