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).