Electrode contact localization.

<p>Placements of macrocontacts (gray) relative to amygdala subnuclei and ventral surface of the frontal lobe for each subject (color coded). Coronal plane drawings of the medial temporal lobe (MTL) (anterior [A], posterior [P], left [L] and right [R]) are shown for all three subjects. All three orthogonal planes are shown for PT258.</p

Hilbert-Huang Transform analysis.

<p>(A) Illustration of a typical single trial of instantaneous frequency in the alpha range and its amplitude derived from the Hilbert-Huang transform of a recorded LFP on the interval −1 to +2 s from stimulus onset. (B, C, D) Instantaneous amplitude averaged over OFC and amygdala contacts conditioned on valence of choice. Colored lines show mean (+/− s.e.). Green horizontal line denotes significant differences at p<.05 FDR corrected.</p

Spectral conditional Granger causality comparisons.

<p>(A–C) Spectral CGC between amygdala and OFC contacts, computed over all trials for the interval −1 s to +1 s relative to stimulus onset. The CGC magnitudes as a function of frequency were computed using all contacts shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109689#pone-0109689-g002" target="_blank">Figure 2</a>. Amygdala-to-OFC is shown in red, and OFC-to-amygdala is shown in black. A two-sided cluster-based permutation test for net CGC was performed for each subject by random rearrangement of trials for each contact. For each subject, the null permutation distribution was used to determine the largest-to-smallest net CGC statistic with FWER controlled at.05. Net CGC is given by the CGC from amygdala-to-OFC (red) minus the CGC from OFC-to-amygdala (black). Significant (p<.05) clusters are denoted by *. The maximum cluster (joint contact-pair and frequency) was identified for each subject and is depicted by the gray bar.</p

Experimental procedure and behavioral analysis.

<p>(A) Task summary. On every trial subjects were shown an image of a snack food for 1 s, at which time they were prompted to indicate whether or not they would be willing to eat the food using a four-item response scale (Strong-Yes, Yes, No, Strong-No). At the end of the experiment one trial was selected at random and the subject's choice was implemented using the actual food. Snacks could be appetitive or aversive, as measured by independent continuous liking-ratings provided by each subject. (B) Scatter plots (jittered) showing the association between prior continuous liking-ratings and choices for each food and subject. Lines correspond to least square fits. Correlation coefficients and p-values were: PT258: 0.73, p<10⁻²⁷; PT206: 0.91, p<10⁻⁶³, PT180: 0.58, p<10⁻¹⁵ (C) Estimated cumulative transition probabilities from an ordinal multinomial GLM that conditions choices in trial <i>t</i> on the response on the previous trial <i>t -1</i>. Dotted lines correspond to the best estimates from a restricted model without the autoregressive (i.e., history independent) component.</p

Time-frequency spectral conditional Granger causality.

<p>(A, B, C) Net CGC, computed on the interval −1 s to +2 s from stimulus onset and 5 Hz to 40 Hz for each subject. Net CGC is given by the CGC from amygdala-to-OFC minus the CGC from OFC-to-amygdala. The spectral density used to compute CGC was calculated using a sliding 300 ms window and a multitaper technique with a step size of 10 ms. (D, E, F) The contact-pair net direction of influence was analyzed between each of the amygdala-OFC pairs, and then aggregated over all of the amygdala-OFC contacts for each subject. A two-sided cluster-based permutation test was performed for each subject by random rearrangement of trials for each contact. The cluster suprathreshold maximum was identified over a (time, frequency) grid composed of 280 ms by 2.5 Hz tiles for a total of 154 frequency-time clusters. The FWER was controlled using the same method as described for time-frequency coherence, and non-significant clusters masked in an equivalent fashion. A one-sided cluster-based permutation test was also performed on the absolute OFC-to-amygdala CGC to establish its contribution to the net CGC. The red contours define the borders of the clusters, internal to which represents the areas statistically significantly greater than zero, with an internal maximum CGC of 0.010, 0.006, and 0.010 for panels D, E, and F respectively.</p

Characterization of generalized linear models of task-related activity.

<p>Plot of 80 seconds of spike train data, spanning three trials and fit with a GLM using (<b>A</b>) a homogeneous Poisson model, (<b>B</b>) an inhomogeneous Poisson model, and (<b>C</b>) an a conditional intensity model (Model 1b, during baseline conditions only). Spike counts of the original spike train are plotted with black dots against lambda (<i>λ</i>; green line with red confidence intervals). X-axis = experimental time. <b>D</b>) Kolmogorov–Smirnov (K-S) goodness-of-fit plot demonstrates that incorporation of spike history improves performance of the CI-GLM (blue vs. green line). The K-S plot of the final model (blue line; model from panel C) falls within equivalency confidence intervals of the K-S test (diagonal solid and dotted lines) for all quantiles, indicating that inclusion of spike history with behavioral intervals in the CI-GLM is critical to appropriately model _plPFC spiking activity. Inhomogeneous Poisson models using solely the behavioral states of the task overestimate neuron interspike intervals (green line; model from panel B). Models of neuronal activity (1–3; main text) also passed K-S goodness-of-fit tests (<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002681#pcbi.1002681.s003" target="_blank">Fig. S3</a>).</p

Peri-stimulus time histograms (PSTHs) illustrate the effects of stress on _plPFC neuron task-related spiking activity.

<p><b>A</b>) T-maze schematic and associated peri-event raster and histogram analysis illustrates prototypic (i) delay- (ii) run- (iii) branch- (iv) choice- (v) reward- and (vi) pickup-related activity observed from _plPFC neurons (0 sec. = start of respective behavioral interval; n = 40 correct trials of a baseline recording session; Delay length = 20 sec.; 5 msec. bins). Colored fiduciaries indicate beginning of each major event of the T-maze task (Red, Start Box; Green, Gate; Magenta, Branch; Grey, Choice; Cyan, Reward; Yellow, Pickup). <b>B</b>) Task-related discharge of a single WS-type _plPFC neuron during correctly executed trials with a left arm entry during the baseline recording session (17 trials; top) and subsequent stress session (11 trials; bottom). Delay-related spiking of this delay neuron was enhanced during stress. Inset illustrates recorded spike waveforms. PSTH y-axis represents spiking probability/bin normalizing for different numbers of trials (5 msec. bins). <b>C</b>) Run-related activity suppressed during stress conditions. <b>D</b>) Suppression of choice-related activity during stress. Labeling conventions of C–D are identical to B.</p

Stress-related changes in _plPFC neuron spike-history predicted discharge (SHPD) throughout baseline or acute stress conditions.

<p><b>A</b>) Spiking gain (rate-ratio exp<i>^α,η</i>) measures of the contribution of spike history at different points back in time for a small (n = 50) ensemble of neurons. The SHPD gain of one exemplar neuron is highlighted. <b>B</b>) SHPD gain at different points back in time decay exponentially under baseline and stress conditions (Model 1a). Described in the main text, stress produced an overall reduction in SHPD gains (inset; *p<0.005), but did not significantly alter the decay of gains at any spike history time bin. <b>C</b>) Schematic of recurrent pathways within the PFC of connectivity within layers II/III or V as well as connectivity between II/III and V represents one putative mechanism supporting SHPD. Adopted from: <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002681#pcbi.1002681-Gabbott1" target="_blank">[72]</a>–<a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002681#pcbi.1002681-Zhang1" target="_blank">[74]</a>.</p

Stress-related changes in delay- and response-related _plPFC neuron spike-history predicted discharge (SHPD).

<p><b>A</b>) Delay-specific gains of SHPD interaction terms from the CI-GLM (Model 2; <i>α, η</i>) were averaged across _plPFC neurons and plotted. <b>B</b>) Response interval-specific gains of SHPD interaction terms (Model 3). Stress suppressed delay-specific SHPD gains and increased the impact of the most recent spiking history during the response period. (*p<0.05 FDR corrected compared to baseline; x<0.05 FDR corrected compared to 1.0).</p

Stress-Induced Impairment of a Working Memory Task: Role of Spiking Rate and Spiking History Predicted Discharge

<div><p>Stress, pervasive in society, contributes to over half of all work place accidents a year and over time can contribute to a variety of psychiatric disorders including depression, schizophrenia, and post-traumatic stress disorder. Stress impairs higher cognitive processes, dependent on the prefrontal cortex (<b>PFC</b>) and that involve maintenance and integration of information over extended periods, including working memory and attention. Substantial evidence has demonstrated a relationship between patterns of PFC neuron spiking activity (action-potential discharge) and components of delayed-response tasks used to probe PFC-dependent cognitive function in rats and monkeys. During delay periods of these tasks, persistent spiking activity is posited to be essential for the maintenance of information for working memory and attention. However, the degree to which stress-induced impairment in PFC-dependent cognition involves changes in task-related spiking rates or the ability for PFC neurons to retain information over time remains unknown. In the current study, spiking activity was recorded from the medial PFC of rats performing a delayed-response task of working memory during acute noise stress (93 db). Spike history-predicted discharge (<b>SHPD</b>) for PFC neurons was quantified as a measure of the degree to which ongoing neuronal discharge can be predicted by past spiking activity and reflects the degree to which past information is retained by these neurons over time. We found that PFC neuron discharge is predicted by their past spiking patterns for nearly one second. Acute stress impaired SHPD, selectively during delay intervals of the task, and simultaneously impaired task performance. Despite the reduction in delay-related SHPD, stress increased delay-related spiking rates. These findings suggest that neural codes utilizing SHPD within PFC networks likely reflects an additional important neurophysiological mechanism for maintenance of past information over time. Stress-related impairment of this mechanism is posited to contribute to the cognition-impairing actions of stress.</p> </div