A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations

Abstract

Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing Ͻ4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15ϳ30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these "pro-arousal" neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation. medial septum; small-amplitude irregular activity, auditory response; theta oscillations; cholinergic THE MEDIAL SEPTUM-VERTICAL LIMB of the diagonal band of Broca (MSvDB) heavily innervates the hippocampus through cholinergic, GABAergic, and glutamatergic projections (Gritti et al. 2006;Kiss et al. 1990;Kohler et al. 1984;Lewis et al. 1967). These projections are essential for normal hippocampal functions. Lesion or inactivation of MSvDB recapitulates the memory deficit resulting from hippocampal lesions and eliminates hippocampal theta oscillations (Gray and McNaughton 1983;Green and Arduini 1954;Mahut 1972;Mizumori et al. 1990;Winson 1978).To achieve a mechanistic understanding of the critical role of MSvDB in hippocampal functioning, it is essential to elucidate how the neuronal activity in MSvDB modulates hippocampal activity, in particular its dynamic interactions on fine temporal scales. Indeed, this issue has been studied extensively at the electrophysiological level over the last few decades. Those studies have largely focused on the fast-firing, rhythmic-bursting MSvDB neurons and have demonstrated that these cells are the pacemaker of hippocampal theta oscillations (Ford et al. 1989;Hangya et al. 2009;Morales et al. 1971;Petsche et al. 1962).However, in parallel with their heterogeneity in terms of neurotransmitters, the physiological properties of MSvDB neurons are similarly diverse. In addition to the extensively studied fast-firing, rhythmic-bursting neurons, many MSvDB neurons are nonetheless slow-firing and do not fire theta-range rhythmic bursts (Ford et al. 1989;Gaztelu and Buno 1982;Stewart and Fox 1989). As such, these latter cells are unlikely candidates to participate in pacing theta oscillations. The function of these slow-firing neurons remains unknown, in ...

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

“…Half of the driven cells significantly increased their firing frequency in response to a tail pinch although they stayed within a slow-firing range (<4 Hz; Fig. 1B), consistent with the typical activity of cholinergic neurons (28,29).…”

“…Both cholinergic and GABAergic neurons, and a small fraction of VGlut2 immunoreactive neurons (25), are believed to play a critical role in such global coordination (26,27). Although GABAergic neurons of the MS were demonstrated to be entrained at theta frequency, identified cholinergic neurons did not show theta-related discharge pattern (28,29). Additionally, both GABAergic and cholinergic neurons are affected by the feedback long-range hippocampo-septal inhibitory connections (30).…”

Frequency-Dependent, Cell Type-Divergent Signaling in the Hippocamposeptal Projection

“…6) suggests that these changes may occur on a timescale of seconds, although shorter bursts of high-frequency HS activity, as seen physiologically during ripples, may cause briefer, nonsaturating effects. Intriguingly, recent in vivo recordings in awake animals identify a subpopulation of slow-firing, putative cholinergic cells that seem to promote hippocampal theta amplitude on a similarly slow timescale (Zhang et al, 2011). Therefore, although the hippocampus is capable of dynamically switching back and forth between theta and sharp wave/ripples following changes in animal behavior (Kramis et al, 1975), our results raise the possibility that the larger HS circuit is also subject to slow modulation, which may bias, although not dictate, the state of the network.…”

Central relaxin-3 receptor (RXFP3) activation increases ERK phosphorylation in septal cholinergic neurons and impairs spatial working memory

“…Septal cholinergic neurons are slow-firing neurons that promote hippocampal theta rhythm (Sotty et al 2003;Yoder and Pang 2005;Vandecasteele et al 2014) and are responsible for transient arousal states and hippocampal activation (Zhang et al 2011). Septal GABAergic parvalbumin (PV)-positive neurons are fast-firing (Sotty et al 2003;Yoder and Pang 2005;Vandecasteele et al 2014) and inhibit inhibitory hippocampal interneurons (Freund and Antal 1988;Toth et al 1997;Freund and Gulyas 1997;Hangya et al 2009).…”