What is the Functional Relevance of Prefrontal Cortex Entrainment to Hippocampal Theta Rhythms?

Abstract

There has been considerable interest in the importance of oscillations in the brain and in how these oscillations relate to the firing of single neurons. Recently a number of studies have shown that the spiking of individual neurons in the medial prefrontal cortex (mPFC) become entrained to the hippocampal (HPC) theta rhythm. We recently showed that theta-entrained mPFC cells lost theta-entrainment specifically on error trials even though the firing rates of these cells did not change (Hyman et al., 2010). This implied that the level of HPC theta-entrainment of mPFC units was more predictive of trial outcome than differences in firing rates and that there is more information encoded by the mPFC on working memory tasks than can be accounted for by a simple rate code. Nevertheless, the functional meaning of mPFC entrainment to HPC theta remains a mystery. It is also unclear as to whether there are any differences in the nature of the information encoded by theta-entrained and non-entrained mPFC cells. In this review we discuss mPFC entrainment to HPC theta within the context of previous results as well as provide a more detailed analysis of the Hyman et al. (2010) data set. This re-analysis revealed that theta-entrained mPFC cells selectively encoded a variety of task-relevant behaviors and stimuli while never theta-entrained mPFC cells were most strongly attuned to errors or the lack of expected rewards. In fact, these error responsive neurons were responsible for the error representations exhibited by the entire ensemble of mPFC neurons. A theta reset was also detected in the post-error period. While it is becoming increasingly evident that mPFC neurons exhibit correlates to virtually all cues and behaviors, perhaps phase-locking directs attention to the task-relevant representations required to solve a spatially based working memory task while the loss of theta-entrainment at the start of error trials may represent a shift of attention away from these representations. The subsequent theta reset following error commission, when coupled with the robust responses of never theta-entrained cells, could produce a potent error-evoked signal used to alert the rat to changes in the relationship between task-relevant cues and reward expectations.

Keywords: hippocampus; oscillations; prefrontal cortex; theta rhythm; working memory.

Figure 1

Information encoding and post-error activity of mPFC units. In all plots black bars are for “never theta” cells and striped bars are theta cells. (A) Behavioral selectivity indices for “never theta” and theta cells. “Never theta” cells were significantly more selective for erroneous test LP's over inter-trial intervals, and theta cells were more selective for correct trial sample and test phases and left and right LPs (*p < 0.05 t-test and Wilcoxon rank sum for grouped animal means; y-axis: group mean d′ values and error bars: SEM). (B) Pre- vs. post-test LP selectivity by cell and trial type. There was a significant interaction between cell and trial types (p < 0.05; two-way ANOVA). Both theta and “never theta” cells were equally selective for the periods before and after correct test LP's, while for error trials “never theta” cells more strongly differentiated these periods (*p < 0.05 t-test and Wilcoxon rank sum for grouped animal means; y-axis: group mean d′ values and error bars: SEM). Furthermore, while theta cells were similarly selective for these periods on correct and error trials (ns; p > 0.05), “never theta” cells selectivity significantly differed by trial type (*p < 0.01 t-test and Wilcoxon rank sum for grouped animal means). (C) Error trial firing rates before and after test LP's. The y-axis shows the average of each cell's mean post-LP response divided by pre-LP firing rates, and accordingly values near 1.0 indicate similar firing rates before and after error LP's. “Never theta” firing rates increased (mean = 1.57 ± 0.24) but theta cell activity was stable (mean = 1.01 ± 0.09; *p < 0.05 t-test and Wilcoxon rank sum for grouped animal means; error bars: SEM).

Figure 2

Ensemble MSUA separation. (A) Example of 3D representation of MSUA space for the DNMS task. Population vectors are colored corresponding to the different task phase LP's and trial outcomes. The axes of this 3D projection correspond to different combinations of the single-unit firing rates. This plot shows clear clustering and separation of sample and test phase LP's on both error and correct trials, however only error trial test LP's separate from correct trials. (B) Mean MSUA separation distances for ensembles with (solid bars) and without “never theta” cells (striped bars). Full population ensembles had significantly greater separation of test LP's between error and correct trials than ensembles excluding “never theta” cells (*p < 0.05; t-test and Wilcoxon rank sum test for grouped animal means; y-axis: percentage of session mean Mahalanobis distance; error bars: SEM).

Figure 3

Hippocampal theta phase reset after error responses. (A) Power spectral density distributions for 1 s before (black) and 1 s after (gray) erroneous test LP's (error bars: 95% confidence intervals). The mean LFP theta power was significantly greater after the response (p < 0.01; paired t-test). (B) Spectrogram of erroneous test LP averaged LFPs. A clear increase in theta frequency power appears ~400 ms following the response (shown by the arrow-timepoint = 0). (C) Averaged normalized LFP signal for all error trials. Plot begins at the time of the LP. Averaged LFP (solid line) and ±SEM (dotted lines) are shown. At ~400 ms after the LP an obviously visible theta oscillation arises which is indicative aligned theta phases across the LFP's from each error trial and signifies that a theta phase reset occurred around the time of the LP. (D) Instantaneous theta phases of LFP's at 535 ms after error trial. Theta phases were not uniformly distributed (p < 0.01; Rayleigh's test of uniformity; bold number indicates the number of samples). (E) Spectrogram of correct trial test LP averaged LFP. There is a period of high theta power between 1.5 and 2 s before the LP (approximately the time locomotor trajectories split between right and left levers), indicating theta phase alignment at the decision point on correct trials. (F) Correct trial averaged normalized LFP. There are no signs of significant theta reset following correct LP's. (G) Instantaneous theta phases of LFP's at 535 ms after correct trial. Phases were distributed uniformly (Rayleigh's test of uniformity).