BEHAVIOR-DEPENDENT FREQUENCY INTERFERENCE BETWEEN SUBCORTICAL THETA OSCILLATORS SHAPES PREFRONTAL-HIPPOCAMPAL COUPLING

The brain’s computational capacity relies on distributed and parallel processing across regions, and coordinated oscillatory rhythms are thought to modulate these interactions (Singer, 1999). Theta oscillations (6–12 Hz), in particular, dynamically coordinate activity between the hippocampus and medial prefrontal cortex (mPFC) during trajectory decisions (Jones & Wilson, 2005; Ito et al., 2018). However, how such inter-regional synchrony is flexibly and adaptively controlled remains unclear. The medial septum (MS) and supramammillary nucleus (SuM) are two subcortical sources of theta oscillations, and we hypothesized that modulation of these oscillators could enable dynamic interregional coupling.
To test this hypothesis, we performed simultaneous recordings from the SuM, MS, mPFC, and hippocampal CA1 while rats performed a goal-directed alternation task in a modified T-maze. We found that SuM theta oscillated at a higher frequency than MS theta, creating a baseline frequency mismatch between the two oscillators. However, before trajectory decisions at the T-junction, SuM theta frequency significantly decreased, reducing this mismatch. Concurrently, CA1 theta frequency also slowed, and theta-rhythm coupling between mPFC and CA1 was enhanced.
To probe the mechanism underlying this behavior-dependent modulation of SuM theta, we examined a potential causal role for direct projections from mPFC to SuM. Consistent with this idea, optogenetic silencing of mPFC axons in SuM disrupted the decision-related modulation of SuM theta frequency and impaired mPFC–CA1 coupling. Together, these findings reveal a top-down mPFC influence on interactions between subcortical theta oscillators, enabling behavior-dependent theta synchrony between cortical regions.