The Effects of Short-Term Synaptic Depression at Thalamocortical Synapses on Orientation Tuning in Cat V1

We examine the effects of short-term synaptic depression on the orientation tuning of the LGN input to simple cells in cat primary visual cortex (V1). The total LGN input has an untuned component as well as a tuned component, both of which grow with stimulus contrast. The untuned component is not visible in the firing rate responses of the simple cells. The suppression of the contribution of the untuned input component to firing rate responses is key to establishing orientation selectivity and its invariance with stimulus contrast. It has been argued that synaptic depression of LGN inputs could contribute to the selective suppression of the untuned component and thus contribute to the tuning observed in simple cells. We examine this using a model fit to the depression observed at thalamocortical synapses in-vivo, and compare this to an earlier model fit based on in-vitro observations. We examine the tuning of both the conductance and the firing rate induced in simple cells by the net LGN input. We find that depression causes minimal suppression of the untuned component. The primary effect of depression is to cause the contrast response curve to saturate at lower contrasts without differentially affecting the tuned vs. untuned components. This effect is slightly weaker for in-vivo vs. in-vitro parameters. Thus, synaptic depression of LGN inputs does not appreciably contribute to the orientation tuning of V1 simple cells

Methylphenidate Actively Induces Emergence from General Anesthesia

Background: Although accumulating evidence suggests that arousal pathways in the brain play important roles in emergence from general anesthesia, the roles of monoaminergic arousal circuits are unclear. In this study, the authors tested the hypothesis that methylphenidate (an inhibitor of dopamine and norepinephrine transporters) induces emergence from isoflurane general anesthesia. Methods: Using adult rats, the authors tested the effect of intravenous methylphenidate on time to emergence from isoflurane general anesthesia. They then performed experiments to test separately for methylphenidate-induced changes in arousal and changes in minute ventilation. A dose–response study was performed to test for methylphenidate-induced restoration of righting during continuous isoflurane general anesthesia. Surface electroencephalogram recordings were performed to observe neurophysiological changes. Plethysmography recordings and arterial blood gas analysis were performed to assess methylphenidate-induced changes in respiratory function. Intravenous droperidol was administered to test for inhibition of methylphenidate's actions. Results: Methylphenidate decreased median time to emergence from 280 to 91 s. The median difference in time to emergence without methylphenidate compared with administration of methylphenidate was 200 [155–331] s (median, [95% CI]). During continuous inhalation of isoflurane, methylphenidate induced return of righting in a dose-dependent manner, induced a shift in electroencephalogram power from delta (less than 4 Hz) to theta (4–8 Hz), and induced an increase in minute ventilation. Administration of intravenous droperidol (0.5 mg/kg) before intravenous methylphenidate (5 mg/kg) largely inhibited methylphenidate-induced emergence behavior, electroencephalogram changes, and changes in minute ventilation. Conclusions: Methylphenidate actively induces emergence from isoflurane general anesthesia by increasing arousal and respiratory drive, possibly through activation of dopaminergic and adrenergic arousal circuits. The authors' findings suggest that methylphenidate may be useful clinically as an agent to reverse general anesthetic-induced unconsciousness and respiratory depression at the end of surgery.National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant K08-GM094394)National Institutes of Health (U.S.) (Grant K08-GM083216)Massachusetts General Hospital. Dept. of Anesthesia and Critical Car

Bayesian analysis of trinomial data in behavioral experiments and its application to human studies of general anesthesia

Accurate quantification of loss of response to external stimuli is essential for understanding the mechanisms of loss of consciousness under general anesthesia. We present a new approach for quantifying three possible outcomes that are encountered in behavioral experiments during general anesthesia: correct responses, incorrect responses and no response. We use a state-space model with two state variables representing a probability of response and a conditional probability of correct response. We show applications of this approach to an example of responses to auditory stimuli at varying levels of propofol anesthesia ranging from light sedation to deep anesthesia in human subjects. The posterior probability densities of model parameters and the response probability are computed within a Bayesian framework using Markov Chain Monte Carlo methods.National Institutes of Health (U.S.) (Grant DP2-OD006454)National Institutes of Health (U.S.) (Grant K25-NS057580)National Institutes of Health (U.S.) (Grant DP1-OD003646)National Institutes of Health (U.S.) (Grant R01-EB006385)National Institutes of Health (U.S.) (Grant R01-MH071847

Half-width of tuning curves at half-height (i.e., difference between orientation giving peak response and orientation giving 50% of peak response) obtained from the tuning curves of total LGN input: A) Conductance B) Firing Rate.

<p>Each half-width is calculated at a specific contrast (<i>x-axis</i>; 3%, 6%, 12%, 24%, 48%, 72% and 96%). Half-widths are averaged over the experimentally measured LGN cells, mean ± std error (<i>y-axis</i>). If null-orientation response was greater than 50% of the peak response, the half-width is undetermined (half-width >90°, See Supplementary Fig. 2 of [17); in such cases we set the half-width to 90°. Four different response measures are shown, as described in legend of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone-0106046-g007" target="_blank">Fig. 7</a>. Conventions as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone-0106046-g007" target="_blank">Fig. 7</a>.</p

Ratio of the amplitude of the tuning curve in Fig. 3 (normalized conductance) at the null orientation (the orientation orthogonal to the preferred) at 96% contrast to that at the preferred orientation (<i>x-axis</i>; 3%, 6%, 12%, 24%, 48%, 72% and 96%).

<p>Black horizontal line indicates amplitude ratio 1. The cases shown are: No Depression (red), Depression using <i>in-vivo</i> (green) fit parameters, Depression using <i>in-vitro</i> (blue) fit parameters. A) Amplitude ratios for Cell I of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone-0106046-g002" target="_blank">Fig. 2</a>; B) Amplitude ratios for Cell II of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone-0106046-g002" target="_blank">Fig. 2</a>; C) Amplitude ratios averaged over all 7 experimentally measured LGN cells (mean ± std error). In C, four different response measures are shown: either the actual experimental PSTH is used (“data”) or a linear rectified approximation to it (see Materials and Methods); and there are two different measures of the size of this response (maximum amplitude over a cycle or DC+F1, where DC is mean over a cycle and F1 is Fourier amplitude of the first harmonic); see inset for colors corresponding to these 4 measures. All points between each pair of vertical bars represent the same contrast: for different response measures, results for each contrast are offset relative to each other for ease of visualization.</p

Orientation tuning of the peak LGN input to the simple cell (in terms of conductance) over a cycle in response to drifting grating stimuli of varying contrasts.

<p>Results are shown for two different models of LGN response time course, each based on the response time course of a measured LGN cell: Cell I (A–C) and Cell II (D–F). In each figure, the colored circles show peak input for 6 different contrast levels (3%, 6%, 12%, 24%, 48%, 72% and 96%) and 19 orientation angles (from −90° to 90° with steps of 10°). The colored smooth curves show fits of a Gaussian plus baseline to these tuning curves at the different contrasts. Each fit is normalized to the value of the fit at the preferred orientation at highest contrast (96%), which is set to 1. Orientation tuning curves are calculated for the cases: No Depression (A, D), Depression using <i>in-vivo</i> (B, E) fit parameters, Depression using <i>in-vitro</i> (C, F) fit parameters.</p

Results from our model of synaptic depression at visual thalamocortical synapses <i>in-vivo</i>, based on the model of Dittman and Regehr (1998).

<p>A) Model behavior: Dynamics of the normalized PSP’s evoked in response to stimulation of a model synapse with different frequencies. Average responses are shown to delivery of 20 Hz, 50 Hz and 100 Hz trains of electrical stimuli to LGN following the background activity. The response is normalized to equal 1 at 90% of the peak value (see Materials and Methods). Note that peaks are aligned and the response to the first stimulus is identical to all three frequencies. The <i>x-axis</i> is scaled so that inter-stimulus interval is shown as equal at all frequencies. In units of time, inter-stimulus intervals are 50 msec, 20 msec and 10 msec for the red, green and blue curves. B) Comparison with experimental data: Smooth curves show model response amplitudes (90% of peak value from panel A) as a function of stimulus number at stimulation frequencies of 20 (red), 50 (green) and 100 (blue) Hz. Mean <i>in-vivo</i> response amplitudes measured by Boudreau and Ferster <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone.0106046-Boudreau1" target="_blank">[34]</a> are indicated by colored dots; error bars show the size of the data points in their figures, which they state are larger than the error bars and thus serve as an upper bound of the experimental error bars. For comparison, results obtained by using <i>in-vitro</i> depression parameters ( model) are shown for the case of 100 Hz stimulation (brown circles and line). C) Effect of increased intraocular pressure. Green: control response to 50 Hz stimulation, identical to green line in (B). Black: responses when background LGN firing rates were reduced before stimulation from a mean value of 11.8 Hz for control condition to a mean value of 4.1 Hz, modeling effects of increase in intraocular pressure (see Materials and Methods). The response to the first stimulus when the LGN firing rates were low is 1.5 times the value when the LGN firing rates were high. The corresponding ratio from Boudreau and Ferster <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone.0106046-Boudreau1" target="_blank">[34]</a> is 1.45±0.11.</p

Tuning of the standard deviation of the peak membrane potential normalized to the mean peak membrane potential at 64% contrast preferred orientation.

<p>A) Data from Finn et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone.0106046-Finn1" target="_blank">[17]</a> (data points and error bars) and our fits to them (smooth curves). Observed normalized standard deviation for the background (0% contrast) is 0.21. For 4% and 64% contrasts observed values are shown as error bars at orientations −90°,–30°,0°,30° and 90°. Estimated normalized standard deviation values are shown as smooth curves that are fit to the data by considering a single function, , (Eq. 12), which is constrained to give observed experimental values (see Materials and Methods). is shown here for 0% contrast (black curve), 4% contrast (blue curve) and 64% contrast (red curve). B) The estimated normalized standard deviation values, <i>f</i>(<i>contrast</i>, <i>orientation</i>), that we use in our simulations for contrasts 0%, 3%, 6%, 12%, 24%, 48%, 72% and 96%.</p

Ratio of the null orientation DC input to preferred orientation DC input averaged over LGN cells, across contrasts.

<p>Only cells for which both DC’s were greater than 0.05 are included in the calculation; mean ratios (squares) and the standard deviations (error bars) are shown. The cases shown are: No Depression (red), Depression using <i>in-vivo</i> (green) or <i>in-vitro</i> (blue) fit parameters. For each case, two different response measures are shown: either the actual experimental PSTH is used (“data”) or a linear rectified approximation to it (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0106046#pone-0106046-g007" target="_blank">Fig. 7</a> legend and Materials and Methods). For a given response measure and contrast (3%, 6%, 12%, 24%, 48%, 72% or 96%), ratio of number of cells that have both DC inputs >0.05 to total number of cells is shown as gray bars.</p