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1.
Proc Natl Acad Sci U S A ; 114(33): 8853-8858, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28774955

RESUMO

Neurons in cortical layer 5B (L5B) connect the cortex to numerous subcortical areas. Possibly the best-studied L5B cortico-subcortical connection is that between L5B neurons in the rodent barrel cortex (BC) and the posterior medial nucleus of the thalamus (POm). However, the spatial organization of L5B giant boutons in the POm and other subcortical targets is not known, and therefore it is unclear if this descending pathway retains somatotopy, i.e., body map organization, a hallmark of the ascending somatosensory pathway. We investigated the organization of the descending L5B pathway from the BC by dual-color anterograde labeling. We reconstructed and quantified the bouton clouds originating from adjacent L5B columns in the BC in three dimensions. L5B cells target six nuclei in the anterior midbrain and thalamus, including the posterior thalamus, the zona incerta, and the anterior pretectum. The L5B subcortical innervation is target specific in terms of bouton numbers, density, and projection volume. Common to all target nuclei investigated here is the maintenance of projection topology from different barrel columns in the BC, albeit with target-specific precision. We estimated low cortico-subcortical convergence and divergence, demonstrating that the L5B corticothalamic pathway is sparse and highly parallelized. Finally, the spatial organization of boutons and whisker map organization revealed the subdivision of the posterior group of the thalamus into four subnuclei (anterior, lateral, medial, and posterior). In conclusion, corticofugal L5B neurons establish a widespread cortico-subcortical network via sparse and somatotopically organized parallel pathways.


Assuntos
Mesencéfalo , Rede Nervosa , Neurônios , Tálamo , Animais , Mesencéfalo/citologia , Mesencéfalo/fisiologia , Camundongos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Tálamo/citologia , Tálamo/fisiologia
2.
Proc Natl Acad Sci U S A ; 114(32): 8631-8636, 2017 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-28739891

RESUMO

Amyloid-ß (Aß) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aß is the ß-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aß levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aß surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aß, mechanistically linking Aß pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Neurônios/metabolismo , Inibidores de Proteases/farmacologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/patologia
3.
Cereb Cortex ; 28(8): 2763-2774, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28981591

RESUMO

In the vibrissal area of rodent somatosensory cortex, information on whisker stimulation is processed by neuronal networks in a corresponding cortical column. To understand how sensory stimuli are represented in a column, it is essential to identify cell types constituting these networks. Layer 6 (L6) comprises 25% of all neurons in a column. In rats, 430 of these are inhibitory interneurons (INs). Little is known about the axon projection of L6 INs with reference to columnar and laminar organization. We quantified axonal projections of L6 INs (n = 68) with reference to columns and layers in somatosensory cortex of rats. We found distinct projection types differentially targeting layers of a cortical column. The majority of L6 INs did not show a column-specific innervation, densely projecting to neighboring columns as well as the home column. However, a small fraction targeted granular and supragranular layers, where axon projections were confined to the home column. We also quantified putative innervation of pyramidal cells as a functional correlate of axonal distribution. Electrophysiological properties were not correlated to axon projection. The quantitative data on axonal projections and electrophysiological properties of L6 INs can guide future studies investigating cortical processing of sensory information at the single cell level.


Assuntos
Neurônios GABAérgicos/fisiologia , Inibição Neural/fisiologia , Vias Neurais/fisiologia , Córtex Somatossensorial/citologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/efeitos da radiação , Animais , Animais Recém-Nascidos , Dendritos , Feminino , Neurônios GABAérgicos/citologia , Glutamato Descarboxilase/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Vibrissas
4.
Proc Natl Acad Sci U S A ; 112(36): 11377-82, 2015 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-26305966

RESUMO

In vivo Ca2+ imaging of neuronal populations in deep cortical layers has remained a major challenge, as the recording depth of two-photon microscopy is limited because of the scattering and absorption of photons in brain tissue. A possible strategy to increase the imaging depth is the use of red-shifted fluorescent dyes, as scattering of photons is reduced at long wavelengths. Here, we tested the red-shifted fluorescent Ca2+ indicator Cal-590 for deep tissue experiments in the mouse cortex in vivo. In experiments involving bulk loading of neurons with the acetoxymethyl (AM) ester version of Cal-590, combined two-photon imaging and cell-attached recordings revealed that, despite the relatively low affinity of Cal-590 for Ca2+ (Kd=561 nM), single-action potential-evoked Ca2+ transients were discernable in most neurons with a good signal-to-noise ratio. Action potential-dependent Ca2+ transients were recorded in neurons of all six layers of the cortex at depths of up to -900 µm below the pial surface. We demonstrate that Cal-590 is also suited for multicolor functional imaging experiments in combination with other Ca2+ indicators. Ca2+ transients in the dendrites of an individual Oregon green 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-1 (OGB-1)-labeled neuron and the surrounding population of Cal-590-labeled cells were recorded simultaneously on two spectrally separated detection channels. We conclude that the red-shifted Ca2+ indicator Cal-590 is well suited for in vivo two-photon Ca2+ imaging experiments in all layers of mouse cortex. In combination with spectrally different Ca2+ indicators, such as OGB-1, Cal-590 can be readily used for simultaneous multicolor functional imaging experiments.


Assuntos
Cálcio/metabolismo , Fluorometria/métodos , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Neuroimagem/métodos , Potenciais de Ação/fisiologia , Animais , Cálcio/análise , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Dendritos/metabolismo , Dendritos/fisiologia , Ácido Egtázico/análogos & derivados , Ácido Egtázico/química , Ácido Egtázico/metabolismo , Feminino , Corantes Fluorescentes/química , Corantes Fluorescentes/metabolismo , Indicadores e Reagentes/química , Indicadores e Reagentes/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-Clamp , Reprodutibilidade dos Testes
5.
Proc Natl Acad Sci U S A ; 112(45): 14072-7, 2015 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-26512104

RESUMO

Cortical inhibitory interneurons (INs) are subdivided into a variety of morphologically and functionally specialized cell types. How the respective specific properties translate into mechanisms that regulate sensory-evoked responses of pyramidal neurons (PNs) remains unknown. Here, we investigated how INs located in cortical layer 1 (L1) of rat barrel cortex affect whisker-evoked responses of L2 PNs. To do so we combined in vivo electrophysiology and morphological reconstructions with computational modeling. We show that whisker-evoked membrane depolarization in L2 PNs arises from highly specialized spatiotemporal synaptic input patterns. Temporally L1 INs and L2-5 PNs provide near synchronous synaptic input. Spatially synaptic contacts from L1 INs target distal apical tuft dendrites, whereas PNs primarily innervate basal and proximal apical dendrites. Simulations of such constrained synaptic input patterns predicted that inactivation of L1 INs increases trial-to-trial variability of whisker-evoked responses in L2 PNs. The in silico predictions were confirmed in vivo by L1-specific pharmacological manipulations. We present a mechanism-consistent with the theory of distal dendritic shunting-that can regulate the robustness of sensory-evoked responses in PNs without affecting response amplitude or latency.


Assuntos
Córtex Cerebral/citologia , Dendritos/fisiologia , Potenciais Somatossensoriais Evocados/fisiologia , Modelos Neurológicos , Células Piramidais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Córtex Cerebral/fisiologia , Simulação por Computador , Interneurônios/fisiologia , Técnicas de Patch-Clamp , Ratos , Vibrissas/fisiologia
6.
Exp Physiol ; 102(5): 489-521, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28139019

RESUMO

Although patch pipettes were initially designed to record extracellularly the elementary current events from muscle and neuron membranes, the whole-cell and loose cell-attached recording configurations proved to be useful tools for examination of signalling within and between nerve cells. In this Paton Prize Lecture, I will initially summarize work on electrical signalling within single neurons, describing communication between the dendritic compartments, soma and nerve terminals via forward- and backward-propagating action potentials. The newly discovered dendritic excitability endows neurons with the capacity for coincidence detection of spatially separated subthreshold inputs. When these are occurring during a time window of tens of milliseconds, this information is broadcast to other cells by the initiation of bursts of action potentials (AP bursts). The occurrence of AP bursts critically impacts signalling between neurons that are controlled by target-cell-specific transmitter release mechanisms at downstream synapses even in different terminals of the same neuron. This can, in turn, induce mechanisms that underly synaptic plasticity when AP bursts occur within a short time window, both presynaptically in terminals and postsynaptically in dendrites. A fundamental question that arises from these findings is: 'what are the possible functions of active dendritic excitability with respect to network dynamics in the intact cortex of behaving animals?' To answer this question, I highlight in this review the functional and anatomical architectures of an average cortical column in the vibrissal (whisker) field of the somatosensory cortex (vS1), with an emphasis on the functions of layer 5 thick-tufted cells (L5tt) embedded in this structure. Sensory-evoked synaptic and action potential responses of these major cortical output neurons are compared with responses in the afferent pathway, viz. the neurons in primary somatosensory thalamus and in one of their efferent targets, the secondary somatosensory thalamus. Coincidence-detection mechanisms appear to be implemented in vivo as judged from the occurrence of AP bursts. Three-dimensional reconstructions of anatomical projections suggest that inputs of several combinations of thalamocortical projections and intra- and transcolumnar connections, specifically those from infragranular layers, could trigger active dendritic mechanisms that generate AP bursts. Finally, recordings from target cells of a column reveal the importance of AP bursts for signal transfer to these cells. The observations lead to the hypothesis that in vS1 cortex, the sensory afferent sensory code is transformed, at least in part, from a rate to an interval (burst) code that broadcasts the occurrence of whisker touch to different targets of L5tt cells. In addition, the occurrence of pre- and postsynaptic AP bursts may, in the long run, alter touch representation in cortex.


Assuntos
Potenciais de Ação/fisiologia , Dendritos/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Córtex Somatossensorial/fisiologia , Transmissão Sináptica/fisiologia , Vias Aferentes/fisiologia , Animais , Neurônios/fisiologia , Sinapses/fisiologia
7.
Cereb Cortex ; 26(8): 3461-75, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27178196

RESUMO

The cortex connects to the thalamus via extensive corticothalamic (CT) pathways, but their function in vivo is not well understood. We investigated "top-down" signaling from cortex to thalamus via the cortical layer 5B (L5B) to posterior medial nucleus (POm) pathway in the whisker system of the anesthetized mouse. While L5B CT inputs to POm are extremely strong in vitro, ongoing activity of L5 neurons in vivo might tonically depress these inputs and thereby block CT spike transfer. We find robust transfer of spikes from the cortex to the thalamus, mediated by few L5B-POm synapses. However, the gain of this pathway is not constant but instead is controlled by global cortical Up and Down states. We characterized in vivo CT spike transfer by analyzing unitary PSPs and found that a minority of PSPs drove POm spikes when CT gain peaked at the beginning of Up states. CT gain declined sharply during Up states due to frequency-dependent adaptation, resulting in periodic high gain-low gain oscillations. We estimate that POm neurons receive few (2-3) active L5B inputs. Thus, the L5B-POm pathway strongly amplifies the output of a few L5B neurons and locks thalamic POm sub-and suprathreshold activity to cortical L5B spiking.


Assuntos
Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Potenciais de Ação , Anestesia , Animais , Simulação por Computador , Potenciais Pós-Sinápticos Excitadores , Agonistas de Receptores de GABA-A/farmacologia , Camundongos Transgênicos , Microeletrodos , Modelos Neurológicos , Muscimol/farmacologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Técnicas de Rastreamento Neuroanatômico , Neurônios/citologia , Optogenética , Córtex Somatossensorial/citologia , Córtex Somatossensorial/efeitos dos fármacos , Tálamo/citologia , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Vibrissas/inervação , Vibrissas/fisiologia
8.
Cereb Cortex ; 26(8): 3534-43, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27230219

RESUMO

Cortical layer 5B (L5B) thick-tufted pyramidal neurons have reliable responses to whisker stimulation in anesthetized rodents. These cells drive a corticothalamic pathway that evokes spikes in thalamic posterior medial nucleus (POm). While a subset of POm has been shown to integrate both cortical L5B and paralemniscal signals, the majority of POm neurons are suggested to receive driving input from L5B only. Here, we test this possibility by investigating the origin of whisker-evoked responses in POm and specifically the contribution of the L5B-POm pathway. We compare L5B spiking with POm spiking and subthreshold responses to whisker deflections in urethane anesthetized mice. We find that a subset of recorded POm neurons shows early (<50 ms) spike responses and early large EPSPs. In these neurons, the early large EPSPs matched L5B input criteria, were blocked by cortical inhibition, and also interacted with spontaneous Up state coupled large EPSPs. This result supports the view of POm subdivisions, one of which receives whisker signals predominantly via L5B neurons.


Assuntos
Células Piramidais/fisiologia , Córtex Somatossensorial/fisiologia , Tálamo/fisiologia , Percepção do Tato/fisiologia , Vibrissas/fisiologia , Potenciais de Ação , Animais , Potenciais Pós-Sinápticos Excitadores , Camundongos Transgênicos , Vias Neurais/citologia , Vias Neurais/fisiologia , Optogenética , Células Piramidais/citologia , Córtex Somatossensorial/citologia , Tálamo/citologia
9.
Proc Natl Acad Sci U S A ; 111(25): 9277-82, 2014 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-24927564

RESUMO

Sensory information reaches the cortex through synchronously active thalamic axons, which provide a strong drive to layer 4 (L4) cortical neurons. Because of technical limitations, the dendritic signaling processes underlying the rapid and efficient activation of L4 neurons in vivo remained unknown. Here we introduce an approach that allows the direct monitoring of single dendritic spine Ca(2+) signals in L4 spiny stellate cells of the vibrissal mouse cortex in vivo. Our results demonstrate that activation of N-methyl-D-aspartate (NMDA) receptors is required for sensory-evoked action potential (AP) generation in these neurons. By analyzing NMDA receptor-mediated Ca(2+) signaling, we identify whisker stimulation-evoked large responses in a subset of dendritic spines. These sensory-stimulation-activated spines, representing predominantly thalamo-cortical input sites, were denser at proximal dendritic regions. The amplitude of sensory-evoked spine Ca(2+) signals was independent of the activity of neighboring spines, without evidence for cooperativity. Furthermore, we found that spine Ca(2+) signals evoked by back-propagating APs sum linearly with sensory-evoked synaptic Ca(2+) signals. Thus, our results identify in sensory information-receiving L4 cortical neurons a linear mode of dendritic integration that underlies the rapid and reliable transfer of peripheral signals to the cortical network.


Assuntos
Sinalização do Cálcio/fisiologia , Córtex Cerebral/metabolismo , Dendritos/metabolismo , Rede Nervosa/fisiologia , Medula Espinal/metabolismo , Animais , Córtex Cerebral/citologia , Camundongos , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/citologia
10.
Cereb Cortex ; 25(4): 849-58, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24165834

RESUMO

This computational study integrates anatomical and physiological data to assess the functional role of the lateral excitatory connections between layer 2/3 (L2/3) pyramidal cells (PCs) in shaping their response during early stages of intracortical processing of a whisker deflection (WD). Based on in vivo and in vitro recordings, and 3D reconstructions of connected pairs of L2/3 PCs, our model predicts that: 1) AMPAR and NMDAR conductances/synapse are 0.52 ± 0.24 and 0.40 ± 0.34 nS, respectively; 2) following WD, connection between L2/3 PCs induces a composite EPSPs of 7.6 ± 1.7 mV, well below the threshold for action potential (AP) initiation; 3) together with the excitatory feedforward L4-to-L2/3 connection, WD evoked a composite EPSP of 16.3 ± 3.5 mV and a probability of 0.01 to generate an AP. When considering the variability in L4 spiny neurons responsiveness, it increased to 17.8 ± 11.2 mV; this 3-fold increase in the SD yielded AP probability of 0.35; 4) the interaction between L4-to-L2/3 and L2/3-to-L2/3 inputs is highly nonlinear; 5) L2/3 dendritic morphology significantly affects L2/3 PCs responsiveness. We conclude that early stages of intracortical signaling of WD are dominated by a combination of feedforward L4-L2/3 and L2/3-L2/3 lateral connections.


Assuntos
Córtex Cerebral/anatomia & histologia , Córtex Cerebral/fisiologia , Células Piramidais/citologia , Células Piramidais/fisiologia , Vibrissas/fisiologia , Potenciais de Ação/fisiologia , Animais , Simulação por Computador , Potenciais Pós-Sinápticos Excitadores/fisiologia , Imageamento Tridimensional , Modelos Neurológicos , Ratos , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/fisiologia
11.
Cereb Cortex ; 25(11): 4415-29, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25761638

RESUMO

Stimulation of a principal whisker yields sparse action potential (AP) spiking in layer 2/3 (L2/3) pyramidal neurons in a cortical column of rat barrel cortex. The low AP rates in pyramidal neurons could be explained by activation of interneurons in L2/3 providing inhibition onto L2/3 pyramidal neurons. L2/3 interneurons classified as local inhibitors based on their axonal projection in the same column were reported to receive strong excitatory input from spiny neurons in L4, which are also the main source of the excitatory input to L2/3 pyramidal neurons. Here, we investigated the remaining synaptic connection in this intracolumnar microcircuit. We found strong and reliable inhibitory synaptic transmission between intracolumnar L2/3 local-inhibitor-to-L2/3 pyramidal neuron pairs [inhibitory postsynaptic potential (IPSP) amplitude -0.88 ± 0.67 mV]. On average, 6.2 ± 2 synaptic contacts were made by L2/3 local inhibitors onto L2/3 pyramidal neurons at 107 ± 64 µm path distance from the pyramidal neuron soma, thus overlapping with the distribution of synaptic contacts from L4 spiny neurons onto L2/3 pyramidal neurons (67 ± 34 µm). Finally, using compartmental simulations, we determined the synaptic conductance per synaptic contact to be 0.77 ± 0.4 nS. We conclude that the synaptic circuit from L4 to L2/3 can provide efficient shunting inhibition that is temporally and spatially aligned with the excitatory input from L4 to L2/3.


Assuntos
Interneurônios/citologia , Condução Nervosa/fisiologia , Inibição Neural/fisiologia , Células Piramidais/citologia , Córtex Somatossensorial/citologia , Sinapses/fisiologia , Animais , Animais Recém-Nascidos , Simulação por Computador , Estimulação Elétrica , Humanos , Imageamento Tridimensional , Potenciais Pós-Sinápticos Inibidores , Lisina/análogos & derivados , Lisina/metabolismo , Modelos Neurológicos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Vibrissas/inervação , Adulto Jovem
12.
Cereb Cortex ; 25(11): 4450-68, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25838038

RESUMO

Vertical thalamocortical afferents give rise to the elementary functional units of sensory cortex, cortical columns. Principles that underlie communication between columns remain however unknown. Here we unravel these by reconstructing in vivo-labeled neurons from all excitatory cell types in the vibrissal part of rat primary somatosensory cortex (vS1). Integrating the morphologies into an exact 3D model of vS1 revealed that the majority of intracortical (IC) axons project far beyond the borders of the principal column. We defined the corresponding innervation volume as the IC-unit. Deconstructing this structural cortical unit into its cell type-specific components, we found asymmetric projections that innervate columns of either the same whisker row or arc, and which subdivide vS1 into 2 orthogonal [supra-]granular and infragranular strata. We show that such organization could be most effective for encoding multi whisker inputs. Communication between columns is thus organized by multiple highly specific horizontal projection patterns, rendering IC-units as the primary structural entities for processing complex sensory stimuli.


Assuntos
Rede Nervosa/fisiologia , Neurônios/classificação , Neurônios/fisiologia , Córtex Somatossensorial/citologia , Vibrissas/inervação , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Simulação por Computador , Dendritos/fisiologia , Lisina/análogos & derivados , Lisina/metabolismo , Modelos Neurológicos , Vias Neurais/fisiologia , Neurônios/citologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar
13.
Proc Natl Acad Sci U S A ; 110(33): 13618-23, 2013 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-23904480

RESUMO

Layer 5 pyramidal neurons process information from multiple cortical layers to provide a major output of cortex. Because of technical limitations it has remained unclear how these cells integrate widespread synaptic inputs located in distantly separated basal and tuft dendrites. Here, we obtained in vivo two-photon calcium imaging recordings from the entire dendritic field of layer 5 motor cortex neurons. We demonstrate that during subthreshold activity, basal and tuft dendrites exhibit spatially localized, small-amplitude calcium transients reflecting afferent synaptic inputs. During action potential firing, calcium signals in basal dendrites are linearly related to spike activity, whereas calcium signals in the tuft occur unreliably. However, in both dendritic compartments, spike-associated calcium signals were uniformly distributed throughout all branches. Thus, our data support a model of widespread, multibranch integration with a direct impact by basal dendrites and only a partial contribution on output signaling by the tuft.


Assuntos
Sinalização do Cálcio/fisiologia , Dendritos/metabolismo , Córtex Motor/citologia , Células Piramidais/metabolismo , Sinapses/fisiologia , Animais , Eletroporação , Camundongos , Córtex Motor/metabolismo , Técnicas de Patch-Clamp
14.
Proc Natl Acad Sci U S A ; 109(22): 8740-5, 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22592800

RESUMO

Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-ß (Aß) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca(2+) imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of Aß may underlie this impairment. Indeed, we found that acute treatment with the γ-secretase inhibitor LY-411575 reduces soluble Aß levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Aß can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble Aß is crucial for hippocampal hyperactivity.


Assuntos
Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/fisiologia , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Fatores Etários , Alanina/análogos & derivados , Alanina/farmacologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Azepinas/farmacologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Região CA1 Hipocampal/fisiopatologia , Cálcio/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência por Excitação Multifotônica , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia
15.
Proc Natl Acad Sci U S A ; 108(37): 15420-5, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21876170

RESUMO

Single cortical neurons in the mammalian brain receive signals arising from multiple sensory input channels. Dendritic integration of these afferent signals is critical in determining the amplitude and time course of the neurons' output signals. As of yet, little is known about the spatial and temporal organization of converging sensory inputs. Here, we combined in vivo two-photon imaging with whole-cell recordings in layer 2 neurons of the mouse vibrissal cortex as a means to analyze the spatial pattern of subthreshold dendritic calcium signals evoked by the stimulation of different whiskers. We show that the principle whisker and the surrounding whiskers can evoke dendritic calcium transients in the same neuron. Distance-dependent attenuation of dendritic calcium transients and the corresponding subthreshold depolarization suggest feed-forward activation. We found that stimulation of different whiskers produced multiple calcium hotspots on the same dendrite. Individual hotspots were activated with low probability in a stochastic manner. We show that these hotspots are generated by calcium signals arising in dendritic spines. Some spines were activated uniquely by single whiskers, but many spines were activated by multiple whiskers. These shared spines indicate the existence of presynaptic feeder neurons that integrate and transmit activity arising from multiple whiskers. Despite the dendritic overlap of whisker-specific and shared inputs, different whiskers are represented by a unique set of activation patterns within the dendritic field of each neuron.


Assuntos
Córtex Cerebral/fisiologia , Dendritos/fisiologia , Sensação/fisiologia , Animais , Cálcio/metabolismo , Espinhas Dendríticas/fisiologia , Estimulação Elétrica , Camundongos , Camundongos Endogâmicos C57BL , Estimulação Física , Fatores de Tempo , Vibrissas/fisiologia
16.
Proc Natl Acad Sci U S A ; 108(40): 16807-12, 2011 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-21949377

RESUMO

Although physiological data on microcircuits involving a few inhibitory neurons in the mammalian cerebral cortex are available, data on the quantitative relation between inhibition and excitation in cortical circuits involving thousands of neurons are largely missing. Because the distribution of neurons is very inhomogeneous in the cerebral cortex, it is critical to map all neurons in a given volume rather than to rely on sparse sampling methods. Here, we report the comprehensive mapping of interneurons (INs) in cortical columns of rat somatosensory cortex, immunolabeled for neuron-specific nuclear protein and glutamate decarboxylase. We found that a column contains ~2,200 INs (11.5% of ~19,000 neurons), almost a factor of 2 less than previously estimated. The density of GABAergic neurons was inhomogeneous between layers, with peaks in the upper third of L2/3 and in L5A. IN density therefore defines a distinct layer 2 in the sensory neocortex. In addition, immunohistochemical markers of IN subtypes were layer-specific. The "hot zones" of inhibition in L2 and L5A match the reported low stimulus-evoked spiking rates of excitatory neurons in these layers, suggesting that these inhibitory hot zones substantially suppress activity in the neocortex.


Assuntos
Mapeamento Encefálico/métodos , Interneurônios/fisiologia , Inibição Neural/fisiologia , Córtex Somatossensorial/citologia , Animais , Fluorescência , Glutamato Descarboxilase , Imuno-Histoquímica , Microscopia Confocal , Ratos , Ratos Wistar , Córtex Somatossensorial/fisiologia
17.
Proc Natl Acad Sci U S A ; 108(10): 4188-93, 2011 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-21368112

RESUMO

The cortical output layer 5 contains two excitatory cell types, slender- and thick-tufted neurons. In rat vibrissal cortex, slender-tufted neurons carry motion and phase information during active whisking, but remain inactive after passive whisker touch. In contrast, thick-tufted neurons reliably increase spiking preferably after passive touch. By reconstructing the 3D patterns of intracortical axon projections from individual slender- and thick-tufted neurons, filled in vivo with biocytin, we were able to identify cell type-specific intracortical circuits that may encode whisker motion and touch. Individual slender-tufted neurons showed elaborate and dense innervation of supragranular layers of large portions of the vibrissal area (total length, 86.8 ± 5.5 mm). During active whisking, these long-range projections may modulate and phase-lock the membrane potential of dendrites in layers 2 and 3 to the whisking cycle. Thick-tufted neurons with soma locations intermingling with those of slender-tufted ones display less dense intracortical axon projections (total length, 31.6 ± 14.3 mm) that are primarily confined to infragranular layers. Based on anatomical reconstructions and previous measurements of spiking, we put forward the hypothesis that thick-tufted neurons in rat vibrissal cortex receive input of whisker motion from slender-tufted neurons onto their apical tuft dendrites and input of whisker touch from thalamic neurons onto their basal dendrites. During tactile-driven behavior, such as object location, near-coincident input from these two pathways may result in increased spiking activity of thick-tufted neurons and thus enhanced signaling to their subcortical targets.


Assuntos
Axônios , Córtex Cerebral/fisiologia , Neurônios/citologia , Vibrissas/fisiologia , Potenciais de Ação , Animais , Córtex Cerebral/citologia , Ratos , Ratos Wistar
18.
J Neurosci ; 32(26): 8952-68, 2012 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-22745495

RESUMO

The GluA1 subunit of AMPA receptors (AMPARs) is critical for hippocampal synaptic transmission and plasticity. Here, we measured the activity of single units from the CA1 region of the hippocampus while GluA1 knock-out (GluA1⁻/⁻) and wild-type (WT) mice traversed a linear track. Although overall firing rates were similar, GluA1⁻/⁻ neurons were more likely to spike in bursts, but at lower burst frequencies, compared with WT neurons. GluA1⁻/⁻ neurons showed large reductions in all measures of spatial and directional selectivity compared with WT neurons. Consistent with these alterations of single-neuron properties, the accuracy of the population code for position was substantially reduced in GluA1⁻/⁻, yet it is predicted to approach the accuracy of WT with increasing population size. The absolute representation of space, independent of movement direction, was greatly diminished in GluA1⁻/⁻ mice and is predicted to remain reduced even for larger populations. Finally, we found that the rate maps of GluA1⁻/⁻ neurons showed increased trial-by-trial variability but reduced experiential plasticity compared with the WT. These results reveal the critical contribution of GluA1-containing AMPARs to individual place cells and the hippocampal population code for space, which could explain the selective behavioral impairments observed in these mice.


Assuntos
Potenciais de Ação/genética , Hipocampo/citologia , Movimento/fisiologia , Neurônios/fisiologia , Receptores de AMPA/deficiência , Comportamento Espacial/fisiologia , Potenciais de Ação/fisiologia , Animais , Mapeamento Encefálico , Eletrodos Implantados , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Recompensa , Percepção Espacial
19.
Cereb Cortex ; 22(10): 2375-91, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22089425

RESUMO

Soma location, dendrite morphology, and synaptic innervation may represent key determinants of functional responses of individual neurons, such as sensory-evoked spiking. Here, we reconstruct the 3D circuits formed by thalamocortical afferents from the lemniscal pathway and excitatory neurons of an anatomically defined cortical column in rat vibrissal cortex. We objectively classify 9 cortical cell types and estimate the number and distribution of their somata, dendrites, and thalamocortical synapses. Somata and dendrites of most cell types intermingle, while thalamocortical connectivity depends strongly upon the cell type and the 3D soma location of the postsynaptic neuron. Correlating dendrite morphology and thalamocortical connectivity to functional responses revealed that the lemniscal afferents can account for some of the cell type- and location-specific subthreshold and spiking responses after passive whisker touch (e.g., in layer 4, but not for other cell types, e.g., in layer 5). Our data provides a quantitative 3D prediction of the cell type-specific lemniscal synaptic wiring diagram and elucidates structure-function relationships of this physiologically relevant pathway at single-cell resolution.


Assuntos
Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/fisiologia , Córtex Somatossensorial/citologia , Córtex Somatossensorial/fisiologia , Tálamo/citologia , Tálamo/fisiologia , Vibrissas/fisiologia , Animais , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Ratos , Ratos Wistar , Células Receptoras Sensoriais/classificação , Tato/fisiologia , Vibrissas/citologia , Vibrissas/inervação
20.
J Hist Neurosci ; 32(2): 198-217, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34129431

RESUMO

Dr. Bert Sakmann (b. 1942) studied at the Universities of Tuebingen, Freiburg, Berlin, Paris, and Munich, graduating in 1967. Much of his professional life has been spent in various institutes of the Max Planck Society. In 1971, a British Council Fellowship took him to the Department of Biophysics of University College London to work with Bernard Katz (1911-2003). In 1974, he obtained his Ph.D. from the University of Goettingen and, with Erwin Neher (b. 1944) at the Max Planck Institute for Biophysical Chemistry, began work that would transform cellular biology and neuroscience, resulting in the 1991 Nobel Prize for Physiology or Medicine. In 2008, Dr. Sakmann returned to Munich, where he headed the research group "Cortical Columns in Silico" at the Max Planck Institute of Neurobiology in Martinsried. Here, their group discovered the cell-type specific sensory activation patterns in different layers of a column in the vibrissal area of rodents' somatosensory cortices.


Assuntos
Medicina , Neurociências , Masculino , Humanos , História do Século XX , Alemanha , Prêmio Nobel , Neurobiologia
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