How do speed signals get to the hippocampus and entorhinal cortex?
The speed-dependent increases in firing rate of CA1 and CA3 place cells are, at least partially, driven by the aforementioned inputs from MEC cells, which themselves are speed-modulated (Sargolini et al., 2006; Wills et al., 2012; Buetfering et al. 2014; Hinman et al., 2016). But what causes MEC cells to increase their rates at faster running speeds? Among the regions projecting to the entorhinal-hippocampal complex, the medial septum emerges as the strongest candidate as the critical supplier of this speed signal. The role of this circuit in speed processing has been recently reviewed (Campbell and Giocomo, 2018), but here we expand upon this discussion. The medial septum has heavy reciprocal connections with both the MEC and the hippocampus (Swanson and Cowan, 1979; Alonso and Köhler, 1984), and its role in regulating the hippocampal theta rhythm is extremely well established (Winson, 1978; Kramis and Vanderwolf, 1980; Stewart and Vanderwolf, 1987, Bland and Colom, 1993; Bland et al., 2006; for review, see Colgin 2013; 2016; but see Goutagny et al., 2009). Furthermore, pharmacological inactivation of the medial septum has been shown to strongly impact hippocampal-entorhinal temporal and rate speed encoding (Mizumori et al., 1990; Hinman et al., 2016).
Neurons in the medial septum (often combined with the related diagonal band of Broca to form the acronym ‘MSDB’) generally fire at higher theta-modulated rates at increased running speeds (King et al., 1998; Zhou et al., 1999; Justus et al., 2017). These neurons can be divided into three distinct subpopulations, all of which target the entorhinal-hippocampal complex: glutamatergic, GABAergic, and cholinergic (Fig. 1A) (Sotty et al., 2003; Colom et al., 2005). Glutamatergic cells, the most recently characterized subpopulation (Manns et al., 2001; Sotty et al., 2003; Colom et al., 2005), display linear activity increases with speed (Fig. 1A) (Furhmann et al., 2015, Justus et al., 2017), as do septal glutamatergic axons in the MEC (Justus et al., 2017). These projections have been shown to target various cell types throughout the MEC and hippocampus, including pyramidal cells and inhibitory interneurons (Huh et al., 2010; Sun et al., 2014) and, upon optogenetic-based activation, increase the firing rates of many of these cells (Fuhrmann et al., 2015; Justus et al., 2017). These results implicate septal projections in mediating the various rate and temporal codes for speed in the hippocampal-entorhinal complex, an idea further supported by the finding that optogenetic stimulation of these projections at theta frequencies successfully elicits CA1 theta at matching frequencies (Fig. 1A) (Fuhrmann et al., 2015; Robinson et al., 2016). However, the specific mechanisms these projections might utilize to facilitate downstream speed encoding remain unclear, as septal glutamatergic innervation has been suggested to be most effectively integrated by pyramidal cells in MEC (Justus et al., 2017), while alternatively, initiating a disinhibitory circuit in CA1 (Fuhrmann et al., 2015). Importantly, optogenetic activation of these projections can also induce locomotion at a speed that is correlated to the stimulation frequency (Fig. 1A). Moreover, when local MSDB glutamatergic transmission is pharmacologically blocked during the same optogenetic manipulation, locomotion persists despite the termination of hippocampal signaling effects, indicating that the basal forebrain may somehow discriminate between descending motor commands and efference copy-like metrics (i.e. speed) of those same commands utilized by the spatial representation circuit (Fuhrmann et al., 2015).
GABAergic and cholinergic MSDB cells have been studied extensively for much longer, the former having a well-characterized role in ‘pacing’ theta in the hippocampal-entorhinal complex (Mitchell et al., 1982; Freund and Antal, 1988; Hangya et al., 2009; Unal et al., 2015). Septal GABAergic projections directly target hippocampal interneurons (Freund and Antal, 1988; Tóth et al., 1997; Sun et al., 2014), while cholinergic cells project to interneurons and pyramidal cells (Cole and Nicoll, 1983; Widmer et al., 2006; Sun et al., 2014). Such features position these cell types well to meaningfully contribute to entorhinal-hippocampal speed encoding, an idea corroborated by both cell types’ reported rate increases with speed (King et al., 1998; Davidson et al., unpublished) (Fig. 1A). In agreement with this concept, optogenetic activation of GABAergic cells has been reported to override the effects of locomotion on theta, and, as seen in the glutamatergic population, possibly influence locomotion itself, although the latter conclusion is less clear (Bender et al., 2015) (Fig. 1A). MSDB cholinergic projections modulate hippocampal cellular membrane potentials and firing rates (Ropert, 1985; Haam et al., 2018), and possibly play important roles in hippocampal theta generation (Smythe et al., 1992; Buzsáki, 2002; Haam et al., 2018; Mikulovic et al., 2018). Blocking MEC muscarinic transmission disrupts the local theta frequency-speed relationship (Newman et al., 2013), However, investigations directly and selectively activating the MSDB cholinergic population have yet to elucidate a clear, causal role in either speed-like signaling in the entorhinal-hippocampal complex or locomotion (Nagode et al., 2011; Vandecasteele et al., 2014; Carpenter et al., 2017; Haam et al., 2018) (Fig. 1A).
This evidence points towards a role for basal forebrain nuclei in delivering and controlling the hippocampal-entorhinal speed signal while possibly somehow simultaneously initiating a related locomotive command. This idea is further supported by results from studies manipulating speed signaling in the entorhinal-hippocampal complex through local pharmacological disruptions of all three kinds of transmission (Bouwman et al., 2005; Hinman et al., 2013; Jacobson et al., 2013; Newman et al., 2013).