Fig 1.
Schematic representation of the “spatial” (green) and the “non-spatial” (red) hippocampal subnetworks and conceptual schemas of models of spatial and non-spatial information processing in the medial temporal lobe.
(A) The LEC and MEC project to CA1 at different proximodistal levels. Proximal CA3 projects preferentially to distal CA1, and distal CA3 projects preferentially to proximal CA1. Proximal CA3 is less connected to the enclosed blade of the DG than distal CA3. Of note, this diagram is not quantitative. For the sake of clarity, projections were drawn as reaching distinct neurons. However, the model does not imply this to be mandatory. (B–D) Schemas of models of information processing in the medial temporal lobe. According to the “segregated” view of information processing in the hippocampus [24,25], only the “spatial” subnetwork (proximal CA1 and distal CA3) would be recruited if the salient dimension of the memory was spatial (panel B), while only the “non-spatial” subnetwork (distal CA1 and proximal CA3) would be engaged if the salient dimension was non-spatial (panel C).Within the frame of the “two-streams model” [1,2], the spatial and non-spatial dimensions of an episode are integrated at the level of the hippocampus. In other words, both the “spatial” (i.e., distal CA3–proximal CA1) and the “non-spatial” (i.e., proximal CA3–distal CA1) hippocampal subnetworks would be recruited in this case (panel D). DG, dentate gyrus; dist., distal; LEC, lateral entorhinal cortex; MEC, medial entorhinal cortex; prox., proximal.
Fig 2.
Memory task and location of the imaging frames.
(A) Behavioral protocol. The animals were placed into an open field with 4 identical objects during the 10-min study phase 1, followed by a 50-min delay phase. After the first delay phase, animals returned to the same open field with a new set of 4 identical objects during the 10-min study phase 2. Following the second 50-min delay phase, memory for the spatial arrangement of the objects (where the objects were originally placed) and the temporal aspect of the task (when the objects were presented) was assessed by returning animals to the open field for a third time, with 2 copies of the objects from study phase 2 (recent stationary objects) and 2 copies of the objects from study phase 1 (“old” objects: one stationary and one displaced), and by measuring the time mice explored each object that was used to calculate discrimination ratios during the test phase. (B) Location of the imaging frames [49]. Black frames define the level at which images were taken with a 40× objective. Three images were taken per target area on nonconsecutive sections that covered approximately 400 microns. Counting was performed only on neurons as described in [43] and totaled approximately 270 neurons per area.
Fig 3.
Examples of Arc labeling in CA1 and CA3.
DAPI-stained neuronal nuclei are shown in blue. Arc intranuclear labeling in red. Red arrows show examples of Arc-positive cells, and green arrowheads show examples of Arc-negative cells. Example of Arc expression in (A) distal CA1, (B) proximal CA1, (C) proximal CA3, and (D) distal CA3. Scale bars: 20 μm. SO, stratum oriens [44]; SR, stratum radiatum [49].
Fig 4.
Arc expression varies with temporal and spatial discrimination in a distinct manner in the distal and proximal parts of CA1 and CA3.
Scatter plots of Arc expression as a function of both temporal and spatial D2 ratios. Overlaid are contour lines predicted by the linear mixed model that estimates each area’s level of Arc activity based on both D2 ratios concurrently. Distal CA1 shows the strongest increase in activity with increasing retrieval of temporary information (i.e., contour lines are more vertical), while Arc expression increases more with retrieval of spatial information in all other areas (i.e., contour lines are more horizontal). The arrow indicates the preferred direction of Arc variation (underlying data in Supporting Information S2 and S3 Data).
Fig 5.
Arc expression correlates with memory performance (D2 ratios).
Arc expression in (A) distal CA1—the area hypothesized to primarily process temporal information—strongly correlates with the temporal D2 scores, whereas no other hippocampal region does. In contrast, (B) proximal CA1 and (C and D) both parts of CA3—candidate areas for spatial information processing—correlate with the spatial discrimination index (spatial D2), whereas distal CA1 does not (S2 Fig for nonsignificant correlations; underlying data in Supporting Information S2 and S3 Data).