Introduction
Effective spatial learning and related navigation are essential skills
for humans and animals alike. These are, however, complex, multisensory
processes that require the integration of external visual cues with
internally generated movement-related cues (Johnsen & Rytter, 2021).
The mechanisms required to create a coherent representation of the
external environment have been intensively investigated, with the
hippocampal formation and parahippocampal region often providing the
start point (Eichenbaum, 2017; Moser et al., 2008; O’Keefe & Nadel,
1979). Within the hippocampal formation, the subiculum may make specific
contributions given its diverse spatial cells and its significance as a
route for the hippocampus proper to influence distal sites (Aggleton &
Christiansen, 2015; Kitanishi et al., 2021; Lever et al., 2009; O’Mara,
2005; Witter, 2006; Yamawaki et al., 2019a,b).
Both neurotoxic lesions of the hippocampus proper and lesions of the
subiculum impair location learning in the Morris Water Maze, suggesting
that together these hippocampal regions are necessary for successful
allocentric (world-centred) spatial learning (Morris et al., 1990).
Furthermore, the hippocampal formation is not uniform as is shows graded
anatomical and electrophysiological changes along its various axes. One
reflection is how the dorsal and ventral subiculum appear to be
functionally distinct in rodents. Based on a variety of evidence it
appears that the dorsal subiculum is the more critical for solving
spatial memory tasks (Bannerman et al., 2004; Burzynska et al., 2020;
Moser & Moser, 1998; O’Mara, 2005; O’Mara et al., 2009; Strange et al.,
2014; Witter et al., 1990). Consistent with this view, permanent lesions
of the dorsal subiculum are sufficient to impair T-maze alternation
(Potvin et al., 2007), a measure of spatial working memory. The pattern
of deficits suggested that the dorsal subiculum is essential for
processing idiothetic cues for navigation (Potvin et al., 2007). In
addition, dorsal subiculum lesions impaired both object-location memory
(Potvin et al., 2010) and the ability to distinguish adjacent-arm trials
in the radial-arm maze, pointing to a role in pattern-separation (Potvin
et al., 2009). These same lesion studies also indicated that the dorsal
hippocampus proper and the dorsal subiculum can contribute differently
to spatial memory (Potvin et al., 2007, 2009, 2010).
There are dense subiculum projections to the retrosplenial cortex that
in rodents preferentially target the granular subdivision (area 29).
These same projections principally arise from the dorsal subiculum
(Kinnavane et al., 2018; Sugar et al., 2011; van Groen & Wyss, 1992).
Like the hippocampus, retrosplenial cortex is repeatedly implicated in
spatial memory and navigation (Nelson et al., 2018; Nelson et al., 2015;
Harker & Whishaw, 2004; Vann et al., 2009; Wolbers & Büchel, 2005) as
well as episodic memory (Hayashi et al., 2020; Maguire, 2001; Nestor et
al., 2003; Vann et al., 2009). Furthermore, recent studies suggest that
these subiculum projections may facilitate the flow of contextual
information to retrosplenial cortex, thereby enabling memory formation
(Gao et al., 2021; Yamawaki et al., 2019b).
The effects of retrosplenial cortex lesions on spatial tasks appear to
be most pronounced when rats must rely on flexible cue integration, such
as when intra-maze and extra-maze cues are opposed (Pothuizen et al.,
2008, 2010; Vann & Aggleton, 2004; Vann et al., 2003) or when required
to choose between competing relevant and irrelevant spatial information
(Wesierska et al., 2009). Like the
dorsal subiculum, retrosplenial lesion deficits can also emerge when
visual stimuli are removed from spatial tasks (Cooper & Mizumori, 2001;
Elduayen & Save, 2014). Given the interconnectivity of retrosplenial
cortex with motor, sensory, and visual cortices (Miyashita & Rockland,
2007; Sugar et al., 2011; Yamawaki et al., 2016) this cortical area is
well placed to integrate information between different sensory
modalities to help navigation (Byrne et al., 2007; Mizumori et al.,
2000; Powell et al., 2020). However, it is unclear whether direct
hippocampal – retrosplenial connections are required for this process.
While much is known about the effects of permanent retrosplenial lesions
on learning and memory, far less is known when just the hippocampal
inputs to this area are disrupted. These more targeted studies have, so
far, been confined to showing the importance of mouse subiculum and CA1
inputs to retrosplenial cortex for contextual fear conditioning
(Yamawaki et al., 2019a,b). The present study sought to examine more
flexible forms of spatial learning involving working memory.
Consequently, rats were trained on a T-maze alternation task, followed
by multiple cue conditions. To disrupt the direct projections from the
dorsal subiculum to retrosplenial cortex, inhibitory designer-receptor
exclusively activated by designer drugs (iDREADDs) injections in the
dorsal subiculum were combined with intracerebral infusions of a ligand
(clozapine) at the target site (retrosplenial cortex) to inactivate
those projections locally (Gomez et al., 2017; Manvich et al., 2018;
Roth, 2016, 2017).