Figure 1: Causal evidence for a speed circuit upstream of
the hippocampal-entorhinal complex
A: The medial septum/diagonal band of Broca (MSDB) directly innervates
the hippocampal formation (“HPF” in figure; Swanson and Cowan, 1979;
Alonso and Köhler), while receiving projections from the mesencephalic
locomotor region (MLR), and specifically two of its associated nuclei,
the pedunculopontine tegmental nucleus (PPN) and cuneiform nucleus
(Cun), among other regions (Nauta and Kuypers, 1958; Lee et al., 2014).
The MSDB neuronal population is comprised of three major cell types:
glutamatergic (Glut.) (24.5%), GABAergic (GABA) (27.8%), and
cholinergic (ACh) (47%) (Colom et al., 2005). All three cell types can
increase their firing rates with increased speed (Fuhrmann et al., 2015;
Justus et al., 2017; King et al., 1998; Davidson et al., unpublished),
although together, the MSDB population has been shown to have both
positively and negatively speed-modulated activity (Justus, 2017).
Optogenetic-mediated stimulation of gluamatergic and GABAergic cells can
also influence rate and/or temporal coding in the hippocampal-entorhinal
complex in a manner analogous to that of speed (Fuhrmann et al., 2015;
Robinson et al., 2016; Bender et al., 2015), implicating these
septohippocampal or -entorhinal projections in speed signal
transmission, although recent evidence shows the glutamatergic effects
may be primarily mediated by local stimulation of the other cell types
(Robinson et al., 2016). The specific role of cholinergic projections in
mediating downstream speed-like effects remains less well-defined, and
indeed seems more complex in nature (Carpenter et al., 2017;
Vandecasteele et al., 2014; Nagode et al., 2011). Interestingly,
optogenetic activation of the MSDB glutamatergic population has also
been shown to initiate locomotion and increase running speed (Fuhrmann
et al., 2015).
B: The MLR is historically implicated in initiating and controlling
locomotive behavior through its descending projections (Shik et al.,
1966; Mori et al., 1978; Takakusaki, 2008), but also sends ascending
projections to MSDB, among other regions (Nauta and Kuypers, 1958; Lee
et al., 2014). It receives locomotion-associated input from the basal
ganglia (Garcia-Rill, 1986; Roseberry et al., 2016). The PPN population
contains the same cell types as the MSDB population, albeit in different
proportions (43% Glut., 31% GABA, 27% ACh) (Wang and Morales, 2009).
Glutamatergic MLR cells scale their firing rates with running speed
while GABAergic PPN cells show more heterogeneous responses to speed
(Roseberry et al., 2016); the cholinergic population’s rate-speed
relationship has yet to be reported. Optogenetic activation of
glutamatergic cells initiates locomotion and increases speed, while
activation of GABAergic cells decreases speed and terminates locomotion
(Roseberry et al., 2016). Activation of cholinergic cells seems to have
minor effects on locomotion (Roseberry et al., 2016). Note that while
the figure shows population proportions for PPN only, the optogenetic
response results reflect a more general MLR population (Roseberry et
al., 2016). While the MLR has been indirectly implicated in stimulating
speed and locomotive signaling in MSDB and thus indirectly in the
hippocampal-entorhinal complex (Lee et al., 2014; Fu et al., 2014),
direct evidence for this relationship has only yet been reported in
unpublished work (Carvalho et al., unpublished; Tanke et al.,
unpublished).
C: Basal ganglia cells also encode speed, particularly in the striatum
(Kim et al., 2014; Bartholomew et al., 2016) and the substantia nigra
(Barter et al., 2015). The basal ganglia has various monosynaptic
outputs to the MLR (Garcia-Rill, 1986; Roseberry et al., 2016), and the
PPN has been shown to project back to the striatum (Wall et al., 2013).
A recent study (Roseberry et al., 2016) showed that medium spiny neurons
in the direct (dMSNs) and indirect (iMSNs) striatal pathways increase
their firing rates with speed and, furthermore, that
optogenetic-mediated stimulation of these cells differentially
controlled both running speed and MLR firing rates as depicted here.