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Diego Contreras

Publications and source records attributed to Diego Contreras.

At least 19 recordsLinked to original sources
PubMed2006

Cellular mechanisms of suppressive interactions between somatosensory responses in vivo.

The neural integration of afferent inputs evoked by spatiotemporally distributed sensory stimuli is a critical step in the formation of coherent and continuous perceptual representations. Integration mechanisms in various systems include linear and nonlinear summation of sensory responses. One well-known example in the rat barrel system is the suppressive interaction between responses to the consecutive deflection of neighboring whiskers. The mechanism underlying cross-whisker suppression has long been postulated to rely on intracortical postsynaptic inhibition, although this hypothesis has been challenged by recent reports. Here we show, using intracellular and extracellular recordings in vivo, that cross-whisker suppression occurs in the absence of cortical activity. Instead, suppression arises from local circuit operations at multiple levels of the subcortical afferent pathway and is amplified by the nonlinear transformation of synaptic input into spike output in both the thalamus and cortex. Because these cellular processes are common to neural circuits subserving visual and auditory modalities, we propose that the suppressive mechanisms elucidated here are a general property of thalamocortical sensory systems.

Action Potentials↗
PubMed2006

Neuronal computations with stochastic network states.

Neuronal networks in vivo are characterized by considerable spontaneous activity, which is highly complex and intrinsically generated by a combination of single-cell electrophysiological properties and recurrent circuits. As seen, for example, during waking compared with being asleep or under anesthesia, neuronal responsiveness differs, concomitant with the pattern of spontaneous brain activity. This pattern, which defines the state of the network, has a dramatic influence on how local networks are engaged by inputs and, therefore, on how information is represented. We review here experimental and theoretical evidence of the decisive role played by stochastic network states in sensory responsiveness with emphasis on activated states such as waking. From single cells to networks, experiments and computational models have addressed the relation between neuronal responsiveness and the complex spatiotemporal patterns of network activity. The understanding of the relation between network state dynamics and information representation is a major challenge that will require developing, in conjunction, specific experimental paradigms and theoretical frameworks.

Anesthesia↗
PubMed2006

Integration of evoked responses in supragranular cortex studied with optical recordings in vivo.

Complex representations in sensory cortices rely on the integration of inputs that overlap temporally and spatially, particularly in supragranular layers, yet the spatiotemporal dynamics of this synaptic integration are largely unknown. The rodent somatosensory system offers an excellent opportunity to study these dynamics because of the overlapping functional representations of single-whisker inputs. We recorded responses in mouse primary somatosensory (barrel) cortex to single and paired whisker deflections using high-speed voltage-sensitive dye imaging. Responses to paired deflections at intervals of 0 and 10 ms summed sublinearly, producing a single transient smaller in amplitude than the sum of the component responses. At longer intervals of 50 and 100 ms, the response to the second deflection was reduced in amplitude and limited spatially relative to control. Between 100 and 200 ms, the response to the second deflection recovered and often showed areas of facilitation. With increasing interstimulus interval from 50 to 200 ms, recovery of the second response occurred from the second stimulated whisker's barrel column outward. In contrast to results with paired-whisker stimulation, when a whisker deflection was preceded by a weak electrical stimulus applied to the neighboring cortex, the summation of evoked responses was predominantly linear at all intervals tested. Thus under our conditions, the linearity of response summation in cortex was not predicted by the amplitudes of the component responses on a column-by-column basis, but rather by the timing and nature of the inputs.

Animals↗
PubMed2006

Balanced excitation and inhibition determine spike timing during frequency adaptation.

In layer 4 (L4) of the rat barrel cortex, a single whisker deflection evokes a stereotyped sequence of excitation followed by inhibition, hypothesized to result in a narrow temporal window for spike output. However, awake rats sweep their whiskers across objects, activating the cortex at frequencies known to induce short-term depression at both excitatory and inhibitory synapses within L4. Although periodic whisker deflection causes a frequency-dependent reduction of the cortical response magnitude, whether this adaptation involves changes in the relative balance of excitation and inhibition and how these changes might impact the proposed narrow window of spike timing in L4 is unknown. Here, we demonstrate for the first time that spike output in L4 is determined precisely by the dynamic interaction of excitatory and inhibitory conductances. Furthermore, we show that periodic whisker deflection results in balanced adaptation of the magnitude and timing of excitatory and inhibitory input to L4 neurons. This balanced adaptation mediates a reduction in spike output while preserving the narrow time window of spike generation, suggesting that L4 circuits are calibrated to maintain relative levels of excitation and inhibition across varying magnitudes of input.

Action Potentials↗
PubMed2006

The role of T-channels in the generation of thalamocortical rhythms.

The presence of T-channels in thalamic cells allows for the generation of rhythmic bursts of spikes and the existence of two firing modes in thalamic cells: tonic and bursting. This intrinsic electrophysiological property has fundamental consequences for the functional properties of the thalamus across waking and sleep stages and is centrally implicated in a growing number of pathological states. Rhythmic bursting brings about highly synchronized activity throughout corticothalamic circuits which is incompatible with the relay of information through the thalamus. Understanding the conditions that determine the change in firing mode of thalamic cells as well as the role of bursting in the generation of synchronized oscillations is critical to understand the function of the thalamus. The functional properties of T-channels and the resulting low threshold spike are discussed here with emphasis on the differences in the bursting properties of reticular thalamic and thalamocortical neurons. The role of thalamic bursting in the generation of sleep oscillations and their specific sequence during slow wave sleep will also be discussed.

Animals↗
PubMed2005

NMDA/AMPA ratio impacts state transitions and entrainment to oscillations in a computational model of the nucleus accumbens medium spiny projection neuron.

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an "up" state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of "up" and "down" state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be approximately 20% of the "up" state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

Animals↗
PubMed2005

Dynamics of excitation and inhibition underlying stimulus selectivity in rat somatosensory cortex.

Neurons in sensory systems respond to stimuli within their receptive fields, but the magnitude of the response depends on specific stimulus features. In the rodent whisker system, the response magnitude to the deflection of a particular whisker is, in most cells, dependent on the direction of deflection. Here we use in vivo intracellular recordings from thalamorecipient neurons in layers 3 and 4 of the rat barrel cortex to elucidate the dynamics of the synaptic inputs underlying direction selectivity. We show that cells are direction selective despite a broadly tuned excitatory and inhibitory synaptic input. Selectivity emerges from a direction-dependent temporal shift of excitation relative to inhibition. For preferred direction deflections, excitation precedes inhibition, but as the direction diverges from the preferred, this separation decreases. Our results illustrate a mechanism by which the timing of the synaptic inputs, and not their relative peak amplitudes, primarily determine feature selectivity.

Action Potentials↗
PubMed2005

Stimulus-dependent gamma (30-50 Hz) oscillations in simple and complex fast rhythmic bursting cells in primary visual cortex.

Oscillatory activity is generated by many neural systems. gamma band (approximately 40 Hz) oscillations in the thalamus and cortex occur spontaneously and in response to sensory stimuli. Fast rhythmic bursting (FRB) cells (also called chattering cells) comprise a unique class of cortical neurons that, during depolarization by current injection, intrinsically generate bursts of high-frequency action potentials with an interburst frequency between 30 and 50 Hz. In the present study, we show for the first time that FRB cells in the primary visual cortex can be either simple or complex and are distributed throughout all cortical layers. Strikingly, both simple and complex FRB cells generate spike bursts at gamma frequencies in response to depolarizing current pulses, but only simple FRB cells exhibit a selective, stimulus feature-dependent increase in gamma oscillations in response to visual stimulation. In addition, we find that hyperpolarization does not reduce the relative power of visually evoked gamma oscillations in the V(m) response of FRB cells. Our results thus indicate that visually evoked gamma activity in individual simple and complex FRB cells is generated in large part by rhythmic synaptic input, rather than by depolarization-dependent activation of intrinsic properties. Finally, the presence of FRB cells in layer 6 suggests a role for corticothalamic feedback in potentiating thalamic oscillations and facilitating the generation of a corticothalamocortical oscillatory loop. We propose that rather than functioning as pacemakers, FRB cells amplify and distribute stimulus-driven gamma oscillations in the neocortex.

Action Potentials↗
PubMed2005

Stimulus-dependent changes in spike threshold enhance feature selectivity in rat barrel cortex neurons.

Feature selectivity is a fundamental property of sensory cortex neurons, yet the mechanisms underlying its genesis are not fully understood. Using intracellular recordings in vivo from layers 2-6 of rat barrel cortex, we studied the selectivity of neurons to the angular direction of whisker deflection. The spike output and the underlying synaptic response decreased exponentially in magnitude as the direction of deflection diverged from the preferred. However, the spike output was more sharply tuned for direction than the underlying synaptic response amplitude. This difference in selectivity was attributable to the rectification imposed by the spike threshold on the input-output function of cells. As in the visual system, spike threshold was not constant and showed trial-to-trial variability. However, here we show that the mean spike threshold was direction dependent and increased as the direction diverged from the preferred. Spike threshold was also related to the rate of rise of the synaptic response, which was direction dependent and steepest for the preferred direction. To assess the impact of the direction-dependent changes in spike threshold on direction selectivity, we applied a fixed threshold to the synaptic responses and calculated a predicted spike output. The predicted output was more broadly tuned than the obtained spike response, demonstrating for the first time that the regulation of the spike threshold by the properties of the synaptic response effectively enhances the selectivity of the spike output.

Action Potentials↗
PubMed2005

Combined experimental/simulation studies of cellular and network mechanisms of epileptogenesis in vitro and in vivo.

The electrical correlates of clinical seizures, and of experimental models of seizures, are recognized because neurons behave differently than normal. Individual neurons do unusual things, and neuronal activities become correlated with each other in ways that are not observed under physiologic conditions. Single neurons may fire bursts of action potentials superimposed on large depolarizations, and the bursts may recur rhythmically over a wide range of frequencies (<1 Hz to 25 Hz); periods of noisy subthreshold activity can occur; and firing can even be suppressed in some neurons. At the population level, nearby neurons tend to fire action potentials, or generate bursts, that are temporally locked together on a few-milliseconds time scale, so that large voltage transients are generated in extracellular fields. Very fast oscillations (>80 Hz) in neuronal aggregates may occur before, during, or after such large field potentials. Finally, cellular activities may even be correlated across large brain regions. The authors review some of the means by which cellular intrinsic properties, synaptic interactions, and electrical coupling via gap junctions, all contribute to the anomalous population activities characteristic of seizures. Also reviewed are some of the data suggesting that the requisite gap junctions are located on the axons of glutamatergic neurons.

Action Potentials↗
PubMed2004

Integration of synaptic responses to neighboring whiskers in rat barrel cortex in vivo.

Characterizing input integration at the single-cell level is a critical step to understanding cortical function, particularly when sensory stimuli are represented over wide cortical areas and single cells exhibit large receptive fields. To study synaptic integration of sensory inputs, we made intracellular recordings from the barrel cortex of anesthetized rats in vivo. For each cell, we deflected the principal whisker (PW) either alone or preceded by the deflection of a single adjacent whisker (AW) at an interval of 20 or 3 ms. At the 20-ms interval in all cases, prior AW deflection significantly suppressed the PW-evoked spike output and caused the underlying synaptic response to reach a peak Vm less depolarized than that arising from PW deflection alone. The decrease in peak Vm was not attributed to hyperpolarizing inhibition but to a divisive reduction in PW-evoked PSP amplitude. The reduction in amplitude was not a result of shunting inhibition but was mostly a result of removal of the synaptic drive, or disfacilitation. When the AW-PW interval was shortened to 3 ms, spike suppression was observed in a subset of the cells studied. In most cases, a divisive reduction in synaptic response amplitude was offset by summation with the preceding AW-evoked depolarization. To determine whether suppression is a general feature of synaptic integration by barrel cortex neurons, we also characterized the interaction of responses evoked by local electrical stimulation. In contrast to the whisker data, we found that responses to paired stimulation at the same intervals produced more spikes and reached a peak Vm more depolarized than the individual responses alone, suggesting that whisker-evoked suppression is not a result of postsynaptic mechanisms. Instead, we propose that cross-whisker response suppression depends on sensory-specific mechanisms at cortical and subcortical levels.

Action Potentials↗
PubMed2004

Single-column thalamocortical network model exhibiting gamma oscillations, sleep spindles, and epileptogenic bursts.

To better understand population phenomena in thalamocortical neuronal ensembles, we have constructed a preliminary network model with 3,560 multicompartment neurons (containing soma, branching dendrites, and a portion of axon). Types of neurons included superficial pyramids (with regular spiking [RS] and fast rhythmic bursting [FRB] firing behaviors); RS spiny stellates; fast spiking (FS) interneurons, with basket-type and axoaxonic types of connectivity, and located in superficial and deep cortical layers; low threshold spiking (LTS) interneurons, which contacted principal cell dendrites; deep pyramids, which could have RS or intrinsic bursting (IB) firing behaviors, and endowed either with nontufted apical dendrites or with long tufted apical dendrites; thalamocortical relay (TCR) cells; and nucleus reticularis (nRT) cells. To the extent possible, both electrophysiology and synaptic connectivity were based on published data, although many arbitrary choices were necessary. In addition to synaptic connectivity (by AMPA/kainate, NMDA, and GABA(A) receptors), we also included electrical coupling between dendrites of interneurons, nRT cells, and TCR cells, and--in various combinations--electrical coupling between the proximal axons of certain cortical principal neurons. Our network model replicates several observed population phenomena, including 1) persistent gamma oscillations; 2) thalamocortical sleep spindles; 3) series of synchronized population bursts, resembling electrographic seizures; 4) isolated double population bursts with superimposed very fast oscillations (>100 Hz, "VFO"); 5) spike-wave, polyspike-wave, and fast runs (about 10 Hz). We show that epileptiform bursts, including double and multiple bursts, containing VFO occur in rat auditory cortex in vitro, in the presence of kainate, when both GABA(A) and GABA(B) receptors are blocked. Electrical coupling between axons appears necessary (as reported previously) for persistent gamma and additionally plays a role in the detailed shaping of epileptogenic events. The degree of recurrent synaptic excitation between spiny stellate cells, and their tendency to fire throughout multiple bursts, also appears critical in shaping epileptogenic events.

Action Potentials↗
PubMed2004

Synaptic responses to whisker deflections in rat barrel cortex as a function of cortical layer and stimulus intensity.

To study the synaptic and spike responses of barrel cortex neurons as a function of cortical layer and stimulus intensity, we recorded intracellularly in vivo from barbiturate anesthetized rats while increasing the velocity-acceleration of the whisker deflection. Granular (Gr; layer 4) cells had the EPSP with the shortest peak and onset latency, whereas supragranular (SGr; layers 2-3) cells had the EPSP with longest duration and slowest rate of rise. Infragranular (Igr; layers 5-6) cells had intermediate values, and thus each layer was unique. The spike response peak of Gr cells was followed by IGr and then by SGr cells. In all cells, depolarization reduced the duration and amplitude of the response, but only in Gr cells did it reveal an early IPSP that cut short the EPSP. This early IPSP was associated with a large decrease in input resistance and an apparent reversal potential below spike threshold; consequently, synaptic integration in Gr cells was limited to the initial 5-7 msec of the response. In contrast, in SGr and IGr cells, results suggest an overlap in time of the EPSP and IPSP, with a small drop in input resistance and an apparent reversal potential above spike threshold, facilitating input integration for up to 20 msec. Decreasing stimulus intensity (velocity-acceleration) reduced the amplitude and increased the peak latency of the response without altering its synaptic composition. We propose that layer 4 circuits are better suited to perform coincidence detection, whereas supra and infragranular circuits are better designed for input integration.

Action Potentials↗
PubMed2004

In vivo fluorescence microscopy of neuronal activity in three dimensions by use of voltage-sensitive dyes.

We report in vivo imaging of neuronal electrical activity from superficial layers of the mouse barrel cortex. The measurements have approximately 16-microm spatial and 3-ms temporal resolution and reach depths of 150 microm below the cortical surface. The depth-dependent differential-fluorescence optical sections of activity are consistent with known cortical architecture and represent an important step toward in vivo measurement of functioning complex neural networks. Our observations employ a custom gradient-index lens probe and voltage-sensitive dye fluorescence; the use of epi-illumination rather than dark-field illumination provides the dramatic signal-to-noise improvement necessary for fast three-dimensional imaging.

Animals↗
PubMed2003

Nonlinear integration of sensory responses in the rat barrel cortex: an intracellular study in vivo.

To study integration of converging sensory inputs on single cortical neurons, we performed intracellular recordings in vivo in the barrel cortex of the barbiturate-anesthetized rat. We deflected the principal whisker (PW) for each cell either alone or preceded (at 20, 50, and 100 msec) by the deflection of a small number of remote whiskers (RWs) far from the PW. The synaptic responses to both the PW and the RW were similar qualitatively and consisted of excitation followed by inhibition that comprised an early and a late component. The RW response was of smaller amplitude and more often subthreshold for action potential generation. The main effect of the RW deflection was a suppression of the subsequent response to the PW that was most pronounced at the 20 msec interval and decreased progressively at the 50 and 100 msec intervals. Suppression of the spike output of the cell was not caused by hyperpolarization (subtractive inhibition) but by a reduction in the EPSP amplitude (divisive inhibition), resulting in a highly sublinear summation of the two responses. The small decrease in input resistance caused by the RW responses is not consistent with synaptic shunting as the main cause of the reduction of the EPSP amplitude. Instead, our results suggest that suppression results from a decrease in the amount of synaptic input triggered by the PW, particularly the early excitation. We suggest that this process involves a reduction in reverberant granular cell excitation that is induced by PW deflection.

Action Potentials↗
PubMed2003

Response to contrast of electrophysiologically defined cell classes in primary visual cortex.

Information processing in the visual cortex is critically dependent on the input-output relationships of its component neurons. The transformation of synaptic inputs into spike trains depends in turn on the host of intrinsic membrane properties expressed by neurons, which define established electrophysiological cell classes in the neocortex. Here we studied, with intracellular recordings in vivo, how the electrophysiological cell classes in the primary visual cortex transform an increasing input, represented by stimulus contrast, into membrane depolarization and trains of action potentials. We used contrast as input because, regardless of their stimulus selectivity, primary visual cortical cells increase their firing rates in response to increases in luminance contrast. We found that both the spike rate response and the membrane potential response are best described by the hyperbolic ratio function when compared with linear, power, and logarithmic functions. In addition, both responses show similar parameter values and similar residual variance from the fits to all four functions. We also found that changes in membrane potential are similar, but firing rates differ strongly, between the established electrophysiological cell classes: fast spiking neurons show the highest firing rates, followed by fast rhythmic bursting, and regular spiking (RS) cells. In addition, among complex cells, RS cells from supragranular layers fired at higher rates than RS cells from infragranular layers. Finally, we show that the differences in firing rates between cell classes arise from differences in the slope of the relationship between membrane potential and spike rate.

Action Potentials↗
PubMed2003

Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain.

The analgesic efficacy and safety of dexketoprofen trometamol (the active enantiomer of the racemic compound ketoprofen) (25mg q.i.d.) vs. ketorolac (10mg q.i.d.) was assessed in 115 patients with bone cancer pain included in a multicenter, randomized, double-blind, parallel group study. A level of >/=40 mm on the 100 mm visual analog scale (VAS) and >/=10 in the pain rating index were required for inclusion. At the end of treatment on day 7 (+1 day), mean values of VAS were 32+/-24 mm for dexketoprofen and 40+/-30 mm for ketorolac (P=0.12) but the pain rating index was significantly lower in patients given dexketoprofen (8.5+/-2.3 vs. 9.7+/-2.9, P=0.04). Moreover, most of the patients reached a pain intensity difference from baseline >/=20 mm (75% of patients for dexketoprofen and 65% of patients for ketorolac). Around half of patients in both treatments had a pain intensity <30 mm on VAS at the end of treatment (55% for dexketoprofen and 47% for ketorolac). In the overall assessment of efficacy, a higher percentage of both patients and physicians rated dexketoprofen as 'quite effective' or 'very effective' compared to ketorolac. The percentage of patients withdrawn from the study for any reason as well as for insufficient therapeutic effect or due to adverse events was lower in the dexketoprofen group than in the ketorolac group. Treatment-related adverse events occurred in 16% of patients given dexketoprofen and in 24% given ketorolac. Serious adverse events occurred in 3.5% of patients from both groups but only one case of gastrointestinal hemorrhage was considered related to ketorolac. We conclude that dexketoprofen trometamol 25 mg q.i.d. oral route is a good analgesic therapy in the treatment of bone cancer pain, comparable to ketorolac 10 mg q.i.d., with a good tolerability profile.

Administration, Oral↗