Stress Degrades Prefrontal Cortex Neuronal Coding of Goal-Directed Behavior

Abstract

Stress, pervasive in modern society, impairs prefrontal cortex (PFC)-dependent cognitive processes, an action implicated in multiple psychopathologies and estimated to contribute to nearly half of all work place accidents. However, the neurophysiological bases for stress-related impairment of PFC-dependent function remain poorly understood. The current studies examined the effects of stress on PFC neural coding during a working memory task in rats. Stress suppressed responses of medial PFC (mPFC) neurons strongly tuned to a diversity of task events, including delay and outcome (reward, error). Stress-related impairment of task-related neuronal activity included multidimensional coding by PFC neurons, an action that significantly predicted cognitive impairment. Importantly, the effects of stress on PFC neuronal signaling were highly conditional on tuning strength: stress increased task-related activity in the larger population of PFC neurons weakly tuned to task events. Combined, stress elicits a profound collapse of task representations across the broader population of PFC neurons.

Keywords: attention; cognition; multichannel recording; outcome-evaluation; prefrontal cortex; reward; working memory.

Figure 1.

Multiple task-related spiking activity profiles of single dmPFC neurons during T-maze task trials. (a) For each trial, the subject progresses through a sequence of events including a delay period in the start box (ai), hand-fed reward for a correct response (aii), and removal of the animal from the maze (aiii) to begin another trial. (b) Video tracking and infrared beams are used to timestamp maze events (trace = 7 trials). (c) Coronal section demonstrating recording site in dmPFC. Detail of electrode tip placement in adjacent section (400× inset). Arrow indicates recording surface location in Layer V. Scale bar, 150 µm; ACg, anterior cingulate; PL, prelimbic cortex; IL, infralimbic cortex. (d) Action potentials were classified as WS type (di; output neuron) or NS-type (dii; interneuron). (e) Stress impairs correct performance of this task (n = 13 sessions; mean ± SEM; **P < 0.001). Peri-event spike rasters (top) and time histograms (PETH; bottom) of a delay neuron (f), reward neuron (g), or pickup neuron (h) during left-correct (left) or right-correct (right) trials (Inset = spike waveforms). Shape of fiduciaries indicates the beginning of each event and used throughout all figures.

Figure 2.

Stress suppresses task-related spiking activity of strongly tuned WS-neurons. (a) Stress suppresses delay-related activity of strongly tuned dmPFC neurons (n = 57). ai, Spike rasters and PETHs of a delay neuron during correct or error trials from baseline and stress conditions. X-axes = time (seconds) before and after start of delay, Y-axes = spike probability, gray bar = delay interval (Inset = spike waveforms). (aii) Mean delay-related activity for correct or error trials was suppressed by stress. Chance level of performance = 50% correct. (aiii) Stress reduced the size of the population of delay-tuned neurons. (b) Stress suppresses reward responses (n = 55). (bi) Rasters and PETHs of a reward-tuned neuron demonstrating a robust stress-related suppression of reward-related signaling. PETH X-axes are aligned to delivery of reward. (bii) Stress suppressed mean reward-related responses. (biii) Stress suppressed the population size of reward-tuned neurons. NA = reward was not given on error trials. (c) Stress suppressed pickup-related spiking (n = 46). Rasters and PETHs of a pickup-tuned neuron are aligned to initial touch by the experimenter. The absence of initial response to touching animal (ci 1st panel) indicates that pickup response is not sensory mediated. Under Baseline conditions, this neuron exhibited a greater pickup response after error trials, indicative of an error-related signal. (cii) Stress suppressed mean pickup-related responses for both correct and error trials. Error trials demonstrated the highest sensitivity to stress. (ciii) The population size of pickup-tuned neurons was reduced during stress. Left and right trial activity was combined for population analyses. Probabilities >1 indicate that on average the interval contained >1 spike/bin/trial. Bar graphs = mean ± SEM. *P< 0.05; **P< 0.001.

Figure 3.

Effects of stress on task-related spiking activity of dmPFC putative interneurons. (a) Stress significantly suppressed spiking activity of strongly tuned delay-related NS neurons (n = 10). Exemplar delay neuron rasters and PETHs from correct or error trials during baseline and stress conditions. X-axes = time (s) before and after start of delay, Y-axes = spike probability, gray bar = delay interval (Inset = spike waveforms). (aii) Average delay-related activity during correct and error trials was suppressed by stress. (aiii) Stress completely eliminated the population of strongly delay-tuned NS neurons. (b) Reward-related responses were not effected by stress (n = 12). (bi) Reward-tuned neuron rasters and PETHs demonstrating a moderate suppression of reward-related signaling. PETH X-axes are aligned to delivery of reward. (bii) The average of reward-related responses was not affected by stress. (biii) Stress did not affect the population size of reward-tuned NS neurons. NA = reward was not given on error trials. (c) Stress did not significantly suppress pickup-related spiking (n = 14). (ci) Rasters and PETHs of a pickup-tuned neuron are aligned to initial touch by the experimenter. During baseline conditions, this pickup neuron exhibited a greater pickup response after correct trials. (cii) Stress did not significantly suppress the mean pickup-related responses for both correct and error trials. (ciii) The population size of pickup-tuned neurons was slightly reduced during stress. Bar graphs = mean ± SEM.

Figure 4.

Stress suppresses multiplexed task-related spiking activity. (a) Multiplexed responses of delay-tuned neurons. (ai) Spiking rasters and PETHs of a delay-tuned neuron also responsive to pickup (PETH aligned to pickup). (aii) Overall, stress suppressed pickup-related spiking activity of delay-tuned neurons suggesting that PFC neuron error signals carried by delay neurons are suppressed by stress (n = 17). Multiplexed reward (aiii, n = 18) and choice-related (aiv, n = 21) responses of delay-tuned neurons were also suppressed by stress. (b) Choice-related responses of reward-tuned multiplexing neurons are suppressed during stress (n = 27). *P < 0.05; **P < 0.01.

Figure 5.

Behavioral relevance of task-related spiking activity. Pareto plots of multiple linear regression coefficients when predicting trial outcome (rewarded vs. error) and overall performance. (a) Pickup multiplexed responses of delay-tuned neurons are most predictive of successful trial outcome and overall performance. (b) Delay and choice multiplexed responses of reward-tuned neurons are most predictive of trial-by-trial outcome. Y-axis = P value. Insets = t values. Spiking activity during reward intervals could not be included in this analysis given there is no reward-related activity following error trials.

Figure 6.

CRF effects T-maze performance and task-related spiking activity of dmPFC WS neurons. (a) CRF (ICV 200 ng) impairs correct performance of this task (n = 9 sessions; mean ± SEM; **P < 0.001). (b) CRF significantly suppressed strongly tuned delay-related activity (n = 59), (c) reward-related responses (n = 114), and (d) pickup-related spiking (n = 115). Similar to the stress cohort, delay-related activity prior to errors was greater than correct trials, whereas pickup-related responses following errors were smaller. Left and right trial activity was combined for population analyses. Probabilities >1 indicate that on average the interval contained >1 spike/bin/trial. Bar graphs = mean ± SEM. **P< 0.001.

Figure 7.

CRF impairs multiplexed task-related spiking activity. (a) Multiplexed responses of delay-tuned neurons. Similar to the effects of stress, CRF suppresses (ai) pickup-related spiking activity of delay-tuned neurons suggesting that PFC neuron error signals are suppressed by CRF and (aii) reward-related responses. (aiii) CRF additionally suppressed choice-related spiking activity of delay-tuned neurons. (b) Similar to the actions of stress, choice-related multiplexed responses of reward-tuned neurons are suppressed by CRF. **P < 0.01.

Figure 8.

Stress enhances responses of weakly tuned dmPFC WS neurons. (a) Weak delay-related spiking activity is increased during stress. (ai) Raster and PETHs of an illustrative weakly tuned delay neuron. X-axes = time (seconds) before and after start of delay, Y-axes = spike probability, gray bar = delay interval (Inset = spike waveforms). (aii) Stress significantly increased weakly tuned responses of delay neurons for correct and error trials. (b) Reward responses and (c) pickup responses were also enhanced during stress. Left and right trial activity was combined for population analyses. Probabilities >1 indicate that on average the interval contained >1 spike/bin/trial. Bar graphs = mean ± SEM. **P < 0.01.