Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus

Abstract

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...

Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm

“…Recent studies based on genetic mutations in mice, however, provide strong support for theta rhythm heterogeneity (20,21). Furthermore, recent experiments by Vandecasteel et al demonstrated that optogenetic stimulation of cholinergic MS neurons selectively enhances cholinergic type 2 theta rhythm without affecting noncholinergic type 1 theta rhythm (22). In the present study, we revealed a neural mechanism involved in object exploration distinct from open-field exploration behavior.…”

“…Moreover, the MS is also the nodal point for ascending afferent systems involved in the generation of hippocampal theta rhythms, the largest synchronous oscillatory signals in the mammalian brain, which are implicated in diverse brain functions (17,18). Although the heterogeneity of hippocampal theta rhythms has long been under debate (19), recent studies based on genetic mutations in mice and optogenetics provide strong support for theta rhythm heterogeneity (20)(21)(22). However, their exact behavioral correlates are still debated.…”

Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms

“…Recent evidence using optogenetic activation of MS-DBB cholinergic neurons suggests that ACh neurons may not significantly take part in theta generation in the hippocampus (Vandecasteele et al, 2014). As for MS-DBB GABAergic neurons, these neurons have unique connectivity to GABAergic interneurons in the hippocampus and strongly fire phase-locked to theta, suggesting that they play an important role in theta generation (Petsche et al, 1962;Freund and Antal, 1988;Stewart and Fox, 1990;Hangya et al, 2009;Bender et al, 2015).…”

“…Recent evidence suggests that the MS-DBB provides an important input for cell assembly formation in the hippocampus and grid cell organization in the entorhinal cortex (Brandon et al, 2011;Wang et al, 2015). Whereas the traditional model of the septum consists of GABAergic and cholinergic neurons, a third population of glutamatergic neurons expressing Type 2 vesicular glutamate transporters (VGLUT2) was described more recently (Sotty et al, 2003;.…”

Ripple-triggered stimulation of the locus coeruleus during post-learning sleep disrupts ripple/spindle coupling and impairs memory consolidation

“…The septalhippocampal circuit, which supports exploratory and attentive behaviors (Vertes and Kocsis 1997), could be one of the competing networks. It has been shown that firing of the medial septal neurons is suppressed around ripples (Dragoi et al 1999;Vandecasteele et al 2014); in turn, activation of the septo-hippocampal pathway suppresses ripple generation (Vandecasteele et al 2014). The medial septum is a major hippocampal afferent and both structures are heavily innervated by NE fibers (Loy et al 1980).…”