Characterization of the Spatiotemporal Network in Prefrontal Cortex-Hippocampal Synchronization: The Role of the Thalamic Nucleus Reuniens and Delta Band 2-5 Hz Oscillations

Abstract

Background: Schizophrenia is a devastating mental health illness in which our pharmacologic options do not treat the cognitive deficits that largely contribute to long-term disability. Problems with cognition likely arise from dysfunctional neural networks in which spatially distinct brain regions are unable to temporally coordinate electrical activity accurately. More specifically, the hippocampus (HC) normally achieves long-range, temporal coordination through generation of theta (4-8 Hz) oscillations by which the prefrontal cortex (PFC) can synchronize its activity. This synchronization occurs through direct HC-to-PFC monosynaptic projections, and disruptions in this pathway can replicate key features of schizophrenia. Although prior research has concentrated heavily on HC-to-PFC theta oscillatory synchronization, the neural network by which PFC exerts “top-down” influence back to HC is largely unknown for at least two reasons. For one, unlike direct HC-to-PFC projections, PFC-to-HC projections are indirect, mainly occurring through a synapse in the thalamic nucleus reunions (nRe). Secondly, the oscillatory band utilized by PFC to synchronize HC activity is largely unknown, although limited evidence suggests a 2-5 Hz oscillation as a potential candidate. The overall aim of this thesis was to characterize the circuitry by which PFC coordinates HC activity. We hypothesized PFC-to-HC synchronization occurs through a 2-5 Hz oscillation that is mediated through nRe.

Methods: Local field potentials (LFPs) were recorded in PFC, HC, and nRe in normal rats (n= 15) under urethane anesthesia. The nucleus reticularis pontis oralis (RPO) was stimulated at five intensity levels to induce theta oscillations in HC. LFPs during RPO stimulation were extracted and underwent fast Fourier transform. Linear regression analysis (Pearson’s correlation coefficient, r) was performed to analyze the relationship between peak oscillatory frequency and power spectrum density in PFC and HC as a function of RPO stimulus intensity. Peak frequencies for theta and 2-5 Hz were identified in HC and PFC spectra, respectively, and spectral power at these frequencies were identified for each signal. Pairwise correlations were calculated between power spectrum density in PFC, HC, and nRe within the 2-5 Hz and theta bands to assess synchronization. Partial correlational analysis was performed between HC-PFC to statically remove the influence of nRe signal to characterize its role in PFC-HC synchronization. In the second set of experiments, LFPs were recorded in PFC and HC during local lidocaine in vivo inactivation of nRe (n=4 rats). Coherence between HC-PFC was calculated before and after lidocaine injections to assess influence of nRe.

Results: As previously described, theta oscillations were the prominent signal in HC during RPO stimulation. In comparison, a narrow-band oscillation within the 2-5 Hz range (distinct from wide-band delta) dominated PFC signals at low RPO stimulus intensities. Oscillatory frequency increased linearly with RPO stimulus intensity for theta (r = 0.64, p<0.001) and 2-5 Hz (r =0.37, p<0.01) frequency bands. However, these two oscillations followed an opposite trend with respect to power density: theta power increased (r = 0.63, p <0.001), whereas 2-5 Hz power decreased (r = -0.60, p<0.001) with RPO stimulus intensity, suggesting a negative coupling between the two signals. PFC-HC signals were significantly correlated for both theta and 2-5 Hz oscillations in 7 out of the 15 rats (47%). For this subgroup, PFC-HC partial correlation, controlling for nRe signal, eliminated residual PFC-HC correlations for the 2-5 Hz oscillation (correlation r=0.81, partial correlation r=0.13, p<0.001), but had no significant effect on HC-PFC correlations for theta oscillation (correlation r=0.65, partial correlation r=0.61, p=0.53). PFC-HC coherence of 2-5 Hz oscillation significantly decreased after lidocaine injection (coherence pre-lidocaine 0.73, post-lidocaine 0.34, p<0.01), but had little effect on coherence for theta oscillation (coherence pre-lidocaine =0.52, post-lidocaine =0.48, p=0.19).

Discussion: Our results support that HC-PFC synchronization occurs not only by previously reported HC theta rhythm, but also by a second narrow-band oscillation in the 2-5 Hz range that dominates PFC activity. Importantly, removal of nRe influence, either statistically (using partial correlation) or experimentally (by in vivo lidocaine inactivation) significantly reduces PFC-HC coupling within the 2-5 Hz band, but has minimal effect on HC-PFC theta coupling, suggesting that nRe mediates PFC-HC 2-5 Hz but not theta oscillatory synchronization. In summary, this thesis proposes a novel thalamo-cortical (nRe-PFC) network by which PFC-HC synchronization occurs through a 2-5 Hz oscillation that is mediated through nRe. In contrast, reciprocal HC-to-PFC synchronization occurs through the theta band via a direct, monosynaptic projection. This network is likely dynamic by which the strength of PFC-HC coupling between theta and 2-5 Hz oscillatory bands vary depending on RPO stimulation intensity level. In the future, continued elucidation of this neural network will likely offer a deeper understanding of the cognitive dysfunction in schizophrenia, and thus the potential for improved treatment options.