Hippocampal activity is organized by a collection of network oscillators on multiple time scales. Of these, theta oscillations reflect rhythmic inputs, occurring typically during exploratory or memory-guided behaviour or REM sleep. Recent studies revealed an unexpected diversity of theta cycles. In rodents performing memory tasks, cycle-by-cycle variations were found based on beta-gamma frequency theta-nested spectral components (tSCs), likely related to distinct spiking dynamics with different contributions to memory processes.

The medial septum (MS) has been identified as responsible for generation of theta oscillations while gamma rhythms mostly have been associated with entorhinal cortex (EC) and CA3 inputs or local CA1 networks. To examine the possible contribution of the MS theta generator to the wave-by-wave spectral heterogeneity of theta, we recorded septal neurons simultaneously with the hippocampal local field potential in mice moving freely in a linear track and in anesthetized mice and rats, and used optogenetics to stimulate parvalbumin-expressing MS neurons in PV-IRES-Cre mice. We performed these experiments in collaboration with the Subcortical Modulation Research Group of the institute, the Research Centre for Natural Sciences and the University of Oxford.

We found that MS neurons’ firing rate and phase-locking to theta waves were correlated to the presence of different CA1 tSCs. Furthermore, most MS neurons not only showed strong phase-coupling to tSCs but also preceded them. Optogenetic activation of MS parvalbumin-expressing neurons with theta-modulated stimulation bursts proved that the MS is capable of eliciting theta-nested beta-gamma oscillations in the CA1.

In conclusion, these results suggest that septal firing is not only involved in the generation of the hippocampal theta oscillations but also modulate the higher frequency spectral components nested in individual theta cycles.