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).