All-optical electrophysiology reveals behavior-dependent dynamics of excitation and inhibition in the hippocampus

Understanding how neuronal integration is modulated by behavior is a fundamental goal in neuroscience. We combined voltage imaging with optogenetic depolarization to reveal how changes in excitatory (E) and inhibitory (I) inputs, modulate the spiking output, subthreshold dynamics, and gain of key genetically defined cell types in the CA1 region of the hippocampus. We imaged pyramidal cells (PCs), vasoactive intestinal peptide (VIP), somatostatin (SST), and parvalbumin (PV) interneurons (INs) and found that locomotion reduced firing in PCs and VIP INs while increasing activity in SST and PV cells. Prolonged optical depolarization experiments and simulations revealed that intracellular theta oscillations are predominantly driven by inhibitory inputs in PCs and VIP cells. Firing rate-laser intensity (F-I) curves revealed distinct gain modulation across cell types, with a divisive gain reduction in PC bursting during locomotion, while simple spikes are unaffected. A two-compartment model suggested that this results from a balanced E/I input increase to somatic and dendritic compartments. These findings reveal how behavioral state-dependent coordination of excitation and inhibition governs hippocampal neuronal dynamics and output-specific gain modulation.