Theta oscillations in the limbic system depend on the integrity of the medial septum. The different populations of medial septal neurons (cholinergic and GABAergic) are assumed to affect different aspects of theta oscillations. Using optogenetic stimulation of cholinergic neurons in ChAT-Cre mice, we investigated their effects on hippocampal local field potentials in both anesthetized and behaving mice. Cholinergic stimulation completely blocked sharp wave ripples and strongly suppressed the power of both slow oscillations (0.5-2 Hz in anesthetized, 0.5-4 Hz in behaving animals) and supratheta (6-10 Hz in anesthetized, 10-25 Hz in behaving animals) bands. The same stimulation robustly increased both the power and coherence of theta oscillations (2-6 Hz) in urethane-anesthetized mice. In behaving mice, cholinergic stimulation was less effective in the theta (4-10 Hz) band yet it also increased the ratio of theta/slow oscillation and theta coherence. The effects on gamma oscillations largely mirrored those of theta. These findings show that medial septal cholinergic activation can both enhance theta rhythm and suppress peri-theta frequency bands, allowing theta oscillations to dominate.S ubcortical neuromodulators play a critical role in shifting states of the brain (1, 2). State changes can occur both during sleep and in the waking animal and are instrumental in affecting local circuit computation that supports various functions, including attention, learning, memory, and action (3-5). The septo-hippocampal cholinergic system has been hypothesized to play a critical role in setting network states in the limbic system (4, 6). ACh can affect both short-and long-term plasticity of synaptic connections and provide favorable conditions for encoding information (7-9). These plastic states are associated with hippocampal theta oscillations (10). High theta states are characterized by increased release of ACh that varies in a task-dependent manner on the time scale of seconds (11-13). In contrast, reduced cholinergic activity allows effective spread of excitation in the recurrent CA3 network, giving rise to synchronous sharp wave ripples (SPW-R) (14-16).Inactivation of the medial septum (MS)/diagonal band of Broca abolishes theta oscillations in the hippocampus and entorhinal cortex (17) and results in severe learning deficit (18,19). Similarly, selective toxin lesion of septal cholinergic neurons produces a several-fold decrease of theta power but not its frequency (20). The phase of the local field potentials (LFP) theta oscillations shifts from the septal to the temporal pole and in the CA3-CA1 axis by ∼180° (21, 22). Thus, at each point in time neurons residing at different locations of the three-dimensional structure of the hippocampus spike at different theta phases yet are bound together by the global theta signal. These numerous sources of theta generators are believed to be coordinated by the reciprocal connections between the septum and hippocampus (23), but the nature of this spatial-temporal coordination is n...

No abstract