Review articleRetrosplenial cortex and its role in cue-specific learning and memory
Graphical abstract
Introduction
The retrosplenial cortex (RSC) has become the focus of increased research interest over the past two decades (Fig. 1), due in part to the discovery that structural and functional changes in RSC are associated with several common forms of mental illness. For example, the RSC is among the first cortical regions to exhibit signs of neurodegeneration and pathology associated with Alzheimer’s Disease (Buckner et al., 2005; Ma et al., 1994). Additionally, heightened excitability of RSC neurons has been linked to age-related cognitive decline (Bucci et al., 1998; Haberman et al., 2017) and alterations in RSC function and connectivity are associated with schizophrenia (Bluhm et al., 2009) and autism (Hogeveen et al., 2018). Accordingly, in 2009, Vann, Aggleton, and Maguire aptly asked, “What does the retrosplenial cortex do?” These authors reviewed findings from neuroanatomical and animal studies, as well as human imaging studies, demonstrating a role for the RSC in a range of cognitive functions. In particular, however, they described a role for the RSC in spatial navigation as “incontrovertible” (pg. 799). Considering the reciprocal connections between the RSC and other regions involved in spatial navigation (e.g., hippocampal formation, anterior and lateral-dorsal thalamic nuclei), and that single-unit recording studies have identified spatial correlates within the RSC, it is no surprise that recent studies have continued to emphasize the RSC’s important role in spatial navigation (Alexander and Nitz, 2015; 2017; Czajkowski et al., 2014; Vedder et al., 2017; for a review see Mitchell et al., 2018). Nevertheless, a growing body of research, carried out primarily in laboratory animals, has also demonstrated a role for the RSC in a variety of non-spatial learning and memory paradigms. It is thus worth asking if the RSC contributes more to learning and memory than simply “space” and “place”.
The purpose of this review is to consider the role of the RSC in cue-specific learning and memory. We use the term cue-specific learning and memory to refer to putatively non-spatial conditioning paradigms that involve discrete cues, typically visual or auditory stimuli. Thus, we will not explicitly review experiments that examine RSC contributions to spatial navigation, even if discrete cues are involved (e.g., Vedder et al., 2017). In addition, we recognize that in any learning and memory experiment, discrete cues are necessarily presented against a background of other cues, often referred to as the “context” (Bouton, 2010). We will only briefly review RSC contributions to contextual learning and memory, in and of itself (for a review, see Corcoran et al., 2018). We will, however, emphasize the role of the context when it may be especially important for influencing responding to discrete cues. Indeed, as will be described, we suggest that RSC contributions to cue learning are intimately tied to contextual processing.
In the first portion of this review we will briefly describe the connectivity of RSC in rats, with an emphasis on connections that may be particularly important for cue-specific learning. Next, with a specific focus on Pavlovian and instrumental conditioning experiments, we will review and assess the role of the RSC in associative learning and memory for discrete visual and auditory cues. These experiments fall into three general categories (each with its own sub-categories): 1) first-order conditioning, 2) discrimination learning, and 3) higher-order conditioning. We then review several ways in which contextual stimuli can influence learning and responding to discrete cues, and suggest a role for the RSC in cue learning that is intimately tied to contextual learning and memory.
Section snippets
Connectivity of the retrosplenial cortex
Here we summarize the connections of the RSC that make it well-suited to contribute to cue-specific learning and memory. We note that many of these connections are likely also important for spatial navigation and contextual learning and memory. For example, projections from the visual cortex to the RSC might be involved in cue learning, as well as aspects of spatial and contextual processing. Thus, we do not suggest that the anatomy described here is exclusively important for cue-specific
Retrosplenial cortex contributions to cue-specific learning and memory
A growing body of evidence for the involvement of RSC in cue-specific learning and memory has emerged from studies that have tested the effects of various perturbations of RSC on behavior. In addition, Michael Gabriel and colleagues have examined the contribution of RSC to discriminative avoidance learning, using a combination of lesion and neural recording methods. In this review, we will focus on behavioral experiments that have manipulated the RSC in an effort to causally link RSC function
RSC function: the many influences of context
The preceding sections have provided evidence that the RSC contributes to learning and memory for auditory and visual cues in putatively non-spatial paradigms. Damage to the RSC produces deficits in a range of conditioning paradigms. However, when considering the most selective manipulations (e.g., neurotoxic lesions, temporary inactivation), the RSC has been found to consistently impair trace fear conditioning (acquisition, retrieval, and extinction), the retrieval of remotely acquired
Is RSC function selective or shared?
The majority of experiments examining RSC contributions to cue-specific learning and memory have focused the RSC itself, and have not examined connections between the RSC and other regions (cf. Todd et al., 2018). However, assessment of hippocampal and cortical contributions to RSC-dependent forms of cue-specific learning and memory may shed light on the larger networks supporting these functions.
Evidence from human imaging studies
In their review, Vann et al. (2009) noted that human imaging studies have found RSC modulation in a “bewildering array of tasks or procedures” (pg. 797). Indeed, human imaging studies have suggested a role for the RSC in mental imagery, self-referential processing, imagining and planning for the future (for reviews see Chrastil, 2018; Vann et al., 2009). In particular, the RSC is consistently active during episodic memory retrieval (Chrastil, 2018; Vann et al., 2009). Ranganath and Ritchey
Where does this leave us, and where do we go from here?
We have reviewed and assessed experiments examining the role of the RSC in Pavlovian and instrumental conditioning, and based on this review, we suggest the following summary points. First, a significant number of studies have consistently reported that the RSC is not necessary for the acquisition, retrieval, or extinction of Pavlovian delay conditioning when a single cue is paired with a single outcome and tested shortly after conditioning. Second, manipulations of the RSC consistently impair
Acknowledgements
This work was supported by National Science Foundation grant IOS1353137 (D.J.B.) and National Institute of Drug Abuse grant T32DA037202 (D.I.F.). T.P.T was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number K01MH116158. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. The authors thank Drs. Robert Leaton, Byron Nelson, and Eric Thrailkill
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