PROJECT SUMMARY Efforts to improve cognitive function by harnessing endogenous brain rhythms have yielded promising results in both humans and experimental animals. However, this approach has not yet been extended to use interregional oscillatory synchrony for cognitive enhancement. Rodent neurophysiology studies have shown that oscillations within the theta band coordinate interactions between the hippocampus (HC) and the medial prefrontal cortex (mPFC) during the performance of spatial working memory (SWM) tasks. These tasks require the rat to use the memory of a previous traversal to guide an upcoming behavioral choice. Although recent work shows that disruptions of HC-mPFC theta synchrony result in SWM deficits, it is not yet known if HC- mPFC theta synchrony can be used to enhance SWM. Recently, new tools have been developed that not only allow real-time monitoring of neural synchrony, but also are capable of driving interregional synchrony with millisecond precision. Therefore, the goal of the current project is to facilitate SWM by first harnessing (Aim 1), then manipulating (Aim 2) HC-mPFC theta synchrony using a combination of in vivo recording and optogenetic techniques in freely moving rats during SWM task performance. The scientific premise of the proposed project is based on published work that shows a strong link between HC-mPFC synchrony and SWM. The overarching hypothesis is that SWM can be enhanced by ensuring that memory-guided decisions are accompanied by high HC-mPFC theta synchrony. For Aim 1, HC-mPFC theta coherence will be monitored in real time while rats perform a SWM-dependent delayed alternation (DA) task. A trial will be initiated when coherence exceeds or falls below values that have been shown previously to be associated with good or poor SWM performance. It is predicted that choice accuracy on the DA task will be highest for sessions in which trials were initiated based on high HC-mPFC theta coherence. This finding would be the first to demonstrate a working memory improvement simply by timing trials to coincide with strong HC-mPFC theta synchrony. For Aim 2, theta frequency optical stimulation using the excitatory opsin, channelrhodopsin (ChR2) will be delivered to mPFC triggered by real-time detection of HC theta. It is predicted that choice accuracy will be higher on stimulation trials compared to light-off trials. These results would demonstrate for the first time that SWM can be improved through direct induction of HC-mPFC theta synchrony. The success of this exploratory grant will direct future work by setting the stage for experiments that will (1) use HC-mPFC theta synchrony to rescue cognitive deficits in animal models of developmental insults and neuropsychiatric disorders, and (2) explore the specific mechanisms that drive synchrony within the extended HC-mPFC circuit.