Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations

Abstract

The hippocampus (HPP) plays a known role in learning novel spatial information. More specifically, the dentate gyrus (DG) hippocampal subregion is thought to support pattern separation, a mechanism for encoding and separating spatially similar events into distinct representations. Several studies have shown that lesions of the dorsal DG (dDG) in rodents result in inefficient spatial pattern separation for working memory; however, it is unclear whether selective dDG lesions disrupt spatial pattern separation for reference memory. Therefore, the current study investigated the role of the dDG in pattern separation using a spatial reference memory paradigm to determine whether the dDG is necessary for acquiring spatial discriminations for adjacent locations. Male Long-Evans rats were randomly assigned to receive bilateral intracranial infusions of colchicine or saline (control) into the dDG. Following recovery from surgery, each rat was pseudo-randomly assigned to an adjacent arm or separate arm condition and subsequently tested on a place-learning task using an eight-arm radial maze. Rats were trained to discriminate between a rewarded arm and a nonrewarded arm that were either adjacent to one another or separated by a distance of two arm positions. Each rat received 10 trials per day and was tested until the animal reached a criterion of nine correct choices out of 10 consecutive trials across 2 consecutive days of testing. Both groups acquired spatial discriminations for the separate condition at similar rates. However, in the adjacent condition, dDG lesioned animals required significantly more trials to reach the learning criterion than controls. The results suggest that dDG lesions decrease efficiency in pattern separation resulting in impairments in the adjacent condition involving greater overlap among the distal cues. Conversely, in the separate condition, there was less overlap among distal cues during encoding and less need for pattern separation. These findings provide further support for a critical role for the dDG in spatial pattern separation by demonstrating the importance of a processing mechanism that is capable of reducing interference among overlapping spatial inputs across a variety of memory demands.

Introduction

The hippocampus (HPP) plays a known role in learning and memory processes. As discussed in detail below, research suggests that a primary mnemonic function of the HPP is to reduce interference among similar inputs during learning, allowing for more accurate encoding and subsequent retrieval. A potential process for reducing interference is referred to as pattern separation, which may serve to encode highly overlapping spatial information into separate representations so that one place can be remembered as distinct from another (Gilbert and Brushfield, 2009, Rolls and Kesner, 2006). Computational models of hippocampal function suggest that the HPP may support pattern separation (Marr, 1971, McNaughton and Nadel, 1990, Myers and Scharfman, 2009, O’Reilly and McClelland, 1994, O’Reilly and Rudy, 2001, Rolls, 2010, Rolls and Kesner, 2006, Shapiro and Olton, 1994). Pattern separation has been suggested to be supported by sparse but powerful connections between dentate gyrus (DG) granule cells and CA3 pyramidal cells coupled with the low probability that the same set of CA3 cells will receive inputs from a similar set of DG granule cells (Jung and McNaughton, 1993, Rolls and Kesner, 2006). The DG receives its major cortical input from the entorhinal cortex (EC) via the perforant pathway. Information is then fed forward to CA3 along the mossy fiber projection system (Amaral and Witter, 1995, Johnston and Amaral, 2004) and there is evidence to suggest that this pathway may play a prominent role during encoding of spatial information, thereby facilitating the formation of distinct memory representations (Eldridge et al., 2005, Jerman et al., 2006, Lee and Kesner, 2004, Rolls, 2010).

Electrophysiological recording data and evidence from behavioral studies provide additional support for hippocampal involvement in pattern separation (Fyhn et al., 2007, Gilbert et al., 1998, Jung and McNaughton, 1993, Leutgeb et al., 2005, Renaudineau et al., 2007, Tanila, 1999). The aforementioned behavioral pattern separation studies have been conducted in both humans and rodents (Bakker et al., 2008, Gilbert et al., 1998, Kirwan and Stark, 2007, Lacy et al., 2010, McHugh et al., 2007, McTighe et al., 2009). For example, a functional magnetic resonance imaging (fMRI) study conducted by Kirwan and Stark (2007) tested participants on a continuous recognition task that required pattern separation to differentiate between similar visual stimuli. Participants were shown a series of pictures of everyday objects and were asked to make “new, old, or similar” judgments when each visual object was presented. The results showed that HPP activity accurately differentiated between objects that were previously seen (old), and objects that were similar to previously seen objects. Further, there is evidence to suggest that damage to the rodent HPP results in an inability to distinguish between spatial locations with a high degree of similarity among proximal and distal cues (Gilbert et al., 1998). Taken together, findings from these studies suggest that the HPP is important for reducing interference among memory representations with a high degree of similarity.

Subregional accounts of hippocampal function suggest that the DG plays a critical role in pattern separation (Bakker et al., 2008, Clelland et al., 2009, Gilbert et al., 2001, Kesner, 2007, Kesner et al., 2004, Koehl and Abrous, 2011, Lacy et al., 2010, Leutgeb et al., 2007, McHugh et al., 2007, Rolls and Kesner, 2006, Sahay et al., 2011, Schmidt et al., 2012, Tronel et al., 2010, Yassa and Stark, 2011). In support of this mnemonic processing role, several studies have shown that disruptions of the DG in rats are capable of producing functional alterations in pattern separation on spatial working memory tasks, or tasks that require use of information that is trial unique (Emerich and Walsh, 1989, Gilbert et al., 2001, Olton, 1978, Talpos et al., 2010). For example, Gilbert and colleagues (2001) tested rats with selective dorsal DG (dDG) lesions on a delayed-match-to-sample (DMTS) for spatial location task that was designed to measure the ability to discriminate between spatial locations that varied in spatial similarity. On each trial, animals were given a choice between two identical objects that were separated by one of five spatial separations (15–105 cm). The results showed that rats with dDG lesions were impaired at short separations (high degree of overlap among distal cues); however, their performance increased as the distance between the two objects increased (lessening degree of overlap among distal cues). Goodrich-Hunsaker, Hunsaker, and Kesner (2008) obtained similar results using a spontaneous recognition task and showed that rats with dDG lesions were incapable of detecting a change in metric distance between two objects on a cheeseboard maze as evidenced by a reduction in exploration for the displaced objects compared to control rats. Taken together, results from these studies suggest that the dDG hippocampal subregion is important for reducing interference among representations with a high degree of spatial similarity. The results also indicate that the dDG may be particularly sensitive to manipulations in metric distance (Kesner, 2007).

The HPP was previously thought to support spatial working memory but not spatial reference memory, or memory for information that remains constant across time (Olton, Becker, & Handelman, 1979). However, several studies have shown that HPP damage in rats produces acquisition impairments on spatial reference memory tasks (McDonald and White, 1995, McTighe et al., 2009, Morris et al., 1982). For example, McDonald and White (1995) tested rats with fimbria-fornix lesions on an active place-learning paradigm that required animals to distinguish between spatial locations on an eight-arm radial maze with a high degree of similarity among extra-maze cues. The results showed that lesioned animals were impaired in acquiring spatial discriminations when spatial locations were adjacent to each other; however, their performance matched normal control animals when the spatial locations were widely separated. The findings from this study suggest that the HPP is necessary for acquiring spatial discriminations for spatial locations that are close together. In addition, several studies have shown that selective lesions of the DG in rodents disrupt performance on spatial reference memory tasks (McLamb et al., 1988, Nanry et al., 1989, Okada and Okaichi, 2009, Xavier et al., 1999). There also is evidence to suggest that disruption of neurogenesis in mice disrupts performance on tasks that require animals to discriminate between similar contexts (Tronel et al., 2010). However, the distance between spatial locations was not directly manipulated in these studies and did not assess spatial pattern separation.

Therefore, the present study directly examined the role of the dDG in spatial pattern separation for reference memory using an active place-learning paradigm described by McDonald and White (1995). The primary aim of the study was to determine whether an intact dDG is necessary for spatial discriminations involving adjacent locations, but not locations with a high degree of spatial separation. Impairments on a reference memory task involving close spatial locations in dDG lesion rats would provide further support for a critical role for the dDG in separating spatial memories into distinct representations. The present findings may demonstrate the importance of a processing dDG dependent mechanism that is capable of reducing interference among overlapping inputs across a variety of different memory demands.