| Anxiety-related disorders are highly prevalent and can cause great disability. However, a thorough understanding of the neurobiological underpinnings of anxiety is missing. In order to identify which brain areas may have a role in this behavior, several lesion studies have been conducted. Such studies have found that the ventral hippocampus (vHPC) and the medial prefrontal cortex (mPFC) are required for normal levels of avoidance of the aversive areas in these paradigms. We hypothesize that electrophysiological correlates of anxiety exist in the vHPC and the mPFC and that theta range synchrony between these areas is modulated by anxiety.;We initially sought to investigate whether we could detect evidence that the vHPC influences the mPFC awake-behaving mouse. To this end, we developed a method to detect the directionality of functional connectivity across brain areas using only LFP recordings. It is noteworthy that estimating the directionality of information flow in a circuit with LFP recordings is a problem of general interest among system neuroscientists. Current methods used to address this problem such as Granger causality and partial directed coherence are mathematically complex, which in turn creates difficulty for both implementing and interpreting such methods. Thus, we created a mathematically simple method to address this issue. Our method consists of crosscorrelating the amplitude envelopes of two signals filtered in a frequency band of interest. The position of the peak of the crosscorrelation provides an estimate of the lag between the two signals in the chosen frequency range. Applying this method to the vHPC-mPFC dataset revealed that theta range activity in the vHPC leads the mPFC with a lag comparable to the conduction delay of this pathway. Furthermore, a consistent lag between these two structures was found only in the theta range. Lastly, this method was found to be more robust than Granger causality and partial directed coherence to artifacts induced by noise. Importantly, these data are consistent with the hypothesis that theta range activity propagates from the vHPC to the mPFC.;We next used this approach to characterize synchrony in the theta range in this circuit and study its modulation during anxiety. Recordings from hippocampal and mPFC sites were obtained in the EPM, the open field and a control familiar environment that is not anxiogenic. Interestingly, theta-frequency activity in the mPFC and ventral, but not dorsal hippocampus was highly correlated at baseline, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power predicted avoidance of the aversive compartments of each arena, and were larger in serotonin 1A-receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are in line with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.;Lastly, we sought to characterize single unit activity in the mPFC while mice explored the EPM. As task-related firing modulated by behavioral demands has been found in the mPFC in other tasks, we hypothesized that task-related firing would also be present in anxiety paradigms that require the mPFC such as the EPM. Intriguingly, firing rates in arms of the same type were positively correlated, independently of the position of the arms relative to each other. Strikingly, cells with task-related firing were more robustly phase-locked to ventral hippocampal (vHPC) and mPFC, but not dHPC, theta (4-12 Hz) oscillations. Lastly, mPFC cells that were led by vHPC theta had more prominent task-related firing. These data show that mPFC unit activity is consistent with a role in anxiety, and suggest that neurons with anxiety task-related firing are preferentially integrated into a vHPC-mPFC circuit.;In summary, these data show that neural correlates of anxiety were found in mPFC single and multiunit activity, as well as in mPFC and vHPC LFPs. Intriguingly, higher coupling of mPFC activity to vHPC theta oscillations during anxiety was observed both in mPFC spike and LFP activity. Furthermore, measures of directionality show that vHPC activity in the theta range lead mPFC spikes and LFPs. These results are consistent with a model in which contextual information is propagated from the vHPC to the mPFC in the theta range. (Abstract shortened by UMI.)... |
