118 research outputs found
Estimation of Thalamocortical and Intracortical Network Models from Joint Thalamic Single-Electrode and Cortical Laminar-Electrode Recordings in the Rat Barrel System
A new method is presented for extraction of population firing-rate models for
both thalamocortical and intracortical signal transfer based on stimulus-evoked
data from simultaneous thalamic single-electrode and cortical recordings using
linear (laminar) multielectrodes in the rat barrel system. Time-dependent
population firing rates for granular (layer 4), supragranular (layer 2/3), and
infragranular (layer 5) populations in a barrel column and the thalamic
population in the homologous barreloid are extracted from the high-frequency
portion (multi-unit activity; MUA) of the recorded extracellular signals. These
extracted firing rates are in turn used to identify population firing-rate
models formulated as integral equations with exponentially decaying coupling
kernels, allowing for straightforward transformation to the more common
firing-rate formulation in terms of differential equations. Optimal model
structures and model parameters are identified by minimizing the deviation
between model firing rates and the experimentally extracted population firing
rates. For the thalamocortical transfer, the experimental data favor a model
with fast feedforward excitation from thalamus to the layer-4 laminar population
combined with a slower inhibitory process due to feedforward and/or recurrent
connections and mixed linear-parabolic activation functions. The extracted
firing rates of the various cortical laminar populations are found to exhibit
strong temporal correlations for the present experimental paradigm, and simple
feedforward population firing-rate models combined with linear or mixed
linear-parabolic activation function are found to provide excellent fits to the
data. The identified thalamocortical and intracortical network models are thus
found to be qualitatively very different. While the thalamocortical circuit is
optimally stimulated by rapid changes in the thalamic firing rate, the
intracortical circuits are low-pass and respond most strongly to slowly varying
inputs from the cortical layer-4 population
Spatial characterization of interictal high frequency oscillations in epileptic neocortex
Interictal high frequency oscillations (HFOs), in particular those with frequency components in excess of 200 Hz, have been proposed as important biomarkers of epileptic cortex as well as the genesis of seizures. We investigated the spatial extent, classification and distribution of HFOs using a dense 4 × 4 mm2 two dimensional microelectrode array implanted in the neocortex of four patients undergoing epilepsy surgery. The majority (97%) of oscillations detected included fast ripples and were concentrated in relatively few recording sites. While most HFOs were limited to single channels, ∼10% occurred on a larger spatial scale with simultaneous but morphologically distinct detections in multiple channels. Eighty per cent of these large-scale events were associated with interictal epileptiform discharges. We propose that large-scale HFOs, rather than the more frequent highly focal events, are the substrates of the HFOs detected by clinical depth electrodes. This feature was prominent in three patients but rarely seen in only one patient recorded outside epileptogenic cortex. Additionally, we found that HFOs were commonly associated with widespread interictal epileptiform discharges but not with locally generated ‘microdischarges’. Our observations raise the possibility that, rather than being initiators of epileptiform activity, fast ripples may be markers of a secondary local response
Astrocytes convert network excitation to tonic inhibition of neurons
<p>Abstract</p> <p>Background</p> <p>Glutamate and γ-aminobutyric acid (GABA) transporters play important roles in balancing excitatory and inhibitory signals in the brain. Increasing evidence suggest that they may act concertedly to regulate extracellular levels of the neurotransmitters.</p> <p>Results</p> <p>Here we present evidence that glutamate uptake-induced release of GABA from astrocytes has a direct impact on the excitability of pyramidal neurons in the hippocampus. We demonstrate that GABA, synthesized from the polyamine putrescine, is released from astrocytes by the reverse action of glial GABA transporter (GAT) subtypes GAT-2 or GAT-3. GABA release can be prevented by blocking glutamate uptake with the non-transportable inhibitor DHK, confirming that it is the glutamate transporter activity that triggers the reversal of GABA transporters, conceivably by elevating the intracellular Na<sup>+ </sup>concentration in astrocytes. The released GABA significantly contributes to the tonic inhibition of neurons in a network activity-dependent manner. Blockade of the Glu/GABA exchange mechanism increases the duration of seizure-like events in the low-[Mg<sup>2+</sup>] <it>in vitro </it>model of epilepsy. Under <it>in vivo </it>conditions the increased GABA release modulates the power of gamma range oscillation in the CA1 region, suggesting that the Glu/GABA exchange mechanism is also functioning in the intact hippocampus under physiological conditions.</p> <p>Conclusions</p> <p>The results suggest the existence of a novel molecular mechanism by which astrocytes transform glutamat<it>ergic </it>excitation into GABA<it>ergic </it>inhibition providing an adjustable, <it>in situ </it>negative feedback on the excitability of neurons.</p
Nuclear envelope protein Lem2 is required for mouse development and regulates MAP and AKT kinases
The nuclear lamina, along with associated nuclear membrane proteins, is a nexus for regulating signaling in the nucleus. Numerous human diseases arise from mutations in lamina proteins, and experimental models for these disorders have revealed aberrant regulation of various signaling pathways. Previously, we reported that the inner nuclear membrane protein Lem2, which is expressed at high levels in muscle, promotes the differentiation of cultured myoblasts by attenuating ERK signaling. Here, we have analyzed mice harboring a disrupted allele for the Lem2 gene (Lemd2). No gross phenotypic defects were seen in heterozygotes, although muscle regeneration induced by cardiotoxin was delayed. By contrast, homozygous Lemd2 knockout mice died by E11.5. Although many normal morphogenetic hallmarks were observed in E10.5 knockout embryos, most tissues were substantially reduced in size. This was accompanied by activation of multiple MAP kinases (ERK1/2, JNK, p38) and AKT. Knockdown of Lem2 expression in C2C12 myoblasts also led to activation of MAP kinases and AKT. These findings indicate that Lemd2 plays an essential role in mouse embryonic development and that it is involved in regulating several signaling pathways. Since increased MAP kinase and AKT/mTORC signaling is found in other animal models for diseases linked to nuclear lamina proteins, LEMD2 should be considered to be another candidate gene for human disease
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