Differential Arc expression in the hippocampus and striatum during the transition from attentive to automatic navigation on a plus maze

Abstract

The strategies utilized to effectively perform a given task change with practice and experience. During a spatial navigation task, with relatively little training, performance is typically attentive enabling an individual to locate the position of a goal by relying on spatial landmarks. These (place) strategies require an intact hippocampus. With task repetition, performance becomes automatic; the same goal is reached using a fixed response or sequence of actions. These (response) strategies require an intact striatum. The current work aims to understand the activation patterns across these neural structures during this experience-dependent strategy transition. This was accomplished by region-specific measurement of activity-dependent immediate early gene expression among rats trained to different degrees on a dual-solution task (i.e., a task that can be solved using either place or response navigation). As expected, rats increased their reliance on response navigation with extended task experience. In addition, dorsal hippocampal expression of the immediate early gene Arc was considerably reduced in rats that used a response strategy late in training (as compared with hippocampal expression in rats that used a place strategy early in training). In line with these data, vicarious trial and error, a behavior linked to hippocampal function, also decreased with task repetition. Although Arc mRNA expression in dorsal medial or lateral striatum alone did not correlate with training stage, the ratio of expression in the medial striatum to that in the lateral striatum was relatively high among rats that used a place strategy early in training as compared with the ratio among over-trained response rats. Altogether, these results identify specific changes in the activation of dissociated neural systems that may underlie the experience-dependent emergence of response-based automatic navigation.

Keywords: Activity-regulated gene expression; Hippocampus; Place and response navigation; Spatial memory; Striatum; Vicarious trial and error.

Fig. 1

Behavioral testing and experimental time line. (A) Rats were trained from a consistent starting position (e.g., south) to find a food reward (e.g., west; filled circles indicate rewarded food cups) in a room with a heterogeneous extra-maze environment. (B) To probe the dominant strategy (place or response) at various training stages, the rat was started from the opposite (e.g., north) arm. A place strategy was identified as entry into the arm previously rewarded (e.g., west). A response strategy was identified as the use of the previously rewarded turn (e.g., left). (C) The experimental time line is illustrated. Prior to training, rats were food-restricted, habituated to the experimenter, shaped to approach and consume Froot Loop cereal from reward cups, and given two days to explore the maze. To identify the changing reliance on place and response navigation with task repetition, a probe trial was administered after task acquisition, and subsequently every seventh day. ^*Training was terminated either after the first or fifth probe trial. The brains of a subset of rats were processed for in situ hybridization experiments targeting the immediate early gene Arc (see Section 2 for full detail).

Fig. 2

In situ hybridization targeting the immediate early gene Arc. Arc mRNA expression was measured from tissue sections of (A) dorsal hippocampus (between −2.5 mm and −4.5 mm from bregma along the anterior–posterior axis) and (B) dorsal striatum (between 1.0 mm and −1.0 mm from bregma along the anterior–posterior axis). Typical colorimetric ISH (relying on the AP-BCIP/NBT system; see Section 2) results are presented for antisense and sense riboprobe application and together demonstrate the specificity of the experimental technique. Neuronal sub-fields measured include CA1, CA3 and dentate gyrus (DG) of the hippocampus and medial (DMS) and lateral (DLS) striatum.

Fig. 3

Hippocampal and striatal regions of interest. (A) Dorsal hippocampal Arc mRNA expression was measured in the pyramidal cell layer of CA1 and CA3, and in the granule cell layer of dentate gyrus (DG). (B) Dorsal striatal Arc mRNA expression was measured in medial (DMS) and lateral (DLS) sub-fields. (A–B) Exemplar regions of interest (shaded) and background regions (selected in areas that contained little to no punctate staining) are illustrated.

Fig. 4

Dual-solution task performance. Rats reduced their latency to find the goal (A–C) and arm entry errors (D–F) across days of training. (A–B, D–E) Equivalent learning curves between rats that used place strategies compared with those that used response strategies on the first probe suggest strategy reliance did not influence task performance. (C, F) High levels of performance were maintained with continued training. Rats that utilized place navigation on the first probe: n = 33; Rats that utilized response navigation on the first probe: n = 31. Error bars indicate ± one standard error of the mean.

Fig. 5

Strategy reliance and vicarious trial and error across training sessions. (A) On the first probe, about half (52%) of rats relied on spatial (place) navigation. With continued training, response navigation dominated, as shown by an almost exclusive reliance on response strategies (93%) by the fifth and final probe. (B) Similar to the transition from place to response navigation, vicarious trial and error (VTE) decreased from the first to last probe trial. (B inset) However, this experience-dependent reduction in VTE may be modulated by strategy engagement. Notably, place and response strategies were equivalent relatively early in training; a modest difference in VTE between strategies increased after extended training. Error bars indicate ± one standard error of the mean.

Fig. 6

Distinct patterns of Arc expression within hippocampus and striatum correlate with the experience-dependent emergence of response navigation. Arc mRNA expression in the dorsal hippocampus (CA1; CA3; dentate gyrus: DG) and dorsal striatum (medial: DMS; lateral: DLS) was quantified as the mean grayscale intensity (corrected for background; see Section 2; Figs. 2 and 3). Expression among neural structures from rats that used a place strategy on the first probe and from those that used a response strategy on the fifth probe is displayed. (A) Hippocampal Arc mRNA expression is high early in training when attentive performance dominates, and declines with task repetition which coincides with the emergence of response navigation. In contrast, Arc mRNA expression in medial and lateral striatal fields remains relatively stable across testing. (C–E) However, on an individual level, the ratio of expression in hippocampus to DLS (C), but not to DMS (E), and (D) the ratio of expression in medial to lateral striatal sub-fields discriminate training stage; this latter result stems from modest (non-significant) and opposing effects on Arc of training duration/strategy engagement in medial and lateral striatum. Bars indicate mean; circles represent individual data points; ^*p < 0.05.