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, 15 (12), 899-908

Environmental Novelty Is Associated With a Selective Increase in Fos Expression in the Output Elements of the Hippocampal Formation and the Perirhinal Cortex

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Environmental Novelty Is Associated With a Selective Increase in Fos Expression in the Output Elements of the Hippocampal Formation and the Perirhinal Cortex

Michael VanElzakker et al. Learn Mem.

Abstract

If the hippocampus plays a role in the detection of novel environmental features, then novelty should be associated with altered hippocampal neural activity and perhaps also measures of neuroplasticity. We examined Fos protein expression within subregions of rat hippocampal formation as an indicator of recent increases in neuronal excitation and cellular processes that support neuroplasticity. Environmental novelty, but not environmental complexity, led to a selective increase of Fos induction in the final "output" subregion of the dorsal hippocampal trisynaptic circuit (CA1) and a primary projection site (layer five of the lateral entorhinal cortex, ERC), as well as in the perirhinal cortex. There was no selective effect of novelty on Fos expression within "input" elements of the trisynaptic circuit (ERC layer two, the dentate gyrus or CA3) or other comparison brain regions that may be responsive to overall motor-sensory activity or anxiety levels (primary somatosensory and motor cortex or hypothalamic paraventricular nucleus). Test session ambulatory behavior increased with both novelty and environmental complexity and was not significantly correlated with Fos expression patterns in any of the brain regions examined. In contrast, the extent of manipulated environmental novelty was strongly correlated with Fos expression in CA1. These results support the prospect that a novelty-associated signal is generated within hippocampal neurocircuitry, is relayed to cortical projection sites, and specifically up-regulates neuroplasticity-supporting processes with dorsal hippocampal CA1 and ERC layer five. Whether novelty-dependent Fos induction in perirhinal cortex depends on this hippocampal output or reflects an independent process remains to be determined.

Figures

Figure 1.
Figure 1.
Diagram of approximate regions of interest (ROI) that were selected for determination of the number of Fos immunoreactive cells present in brains after exposure to various treatment conditions. (A) Coronal section (∼1.8 mm posterior to bregma); labeled ROI are (1) primary motor cortex, (2) primary somatosensory cortex (barrel fields), and (3) hypothalamic paraventricular nucleus. (B) Coronal section (∼3.6 mm posterior to bregma); labeled ROI are (1) CA3, (2) CA1, (3) dentate gyrus, suprapyramidal blade, (4) dentate gyrus, infrapyramidal blade, (5) CA4, (6) CA2, (7) lateral entorhinal cortex, layer two, (8) lateral entorhinal cortex, layer five, and (9) perirhinal cortex.
Figure 2.
Figure 2.
Effect of first time placement in an arena with varying environmental complexity on relative Fos expression within hippocampal subregions. Rats were placed for the first time in a circular arena that contained zero, one, or five objects on its floor. After arena exposure (30 min) rats were returned to their home cage for an additional 120 min. Control rats remained in their home cage. * P < 0.01, compared to home-cage control treatment group (N–K test).
Figure 3.
Figure 3.
Effect of first time placement in arena or fifth time placement in arena (with zero, one, or five novel objects) on ambulatory behavior. Rats were placed for the first time in a circular arena that contained zero objects on its floor (“Naïve” group), or fifth time in the arena with zero, one, or five novel objects on the floor. Ambulatory behavior (see Materials and Methods) was scored for the first and second 10-min intervals while in the arena. * P < 0.05, compared to rats placed in the arena for the fifth time with zero objects (“Arena” group) during the same time interval (N–K test); † P < 0.05, compared to the other three treatment groups during the same time interval (Fisher’s least significant difference test).
Figure 4.
Figure 4.
Effect of first time placement in arena or fifth time placement in arena (with zero, one, or five novel objects) on relative Fos expression within hippocampus, entorhinal cortex, and perirhinal cortex. Rats were placed for the first time in a circular arena that contained zero objects on its floor (“Naïve” group), or fifth time in the arena with zero, one, or five novel objects on the floor. After arena exposure (30 min) rats were returned to their home cage for an additional 120 min. Control rats remained in their home cage. The relative Fos expression in the various subregions is presented in the order left to right that approximates the serial order of neural connections between these subregions, ending with perirhinal cortex that has reciprocal connections with entorhinal cortex (ERC = lateral entorhinal cortex, DG = dentate gyrus). * P < 0.05, compared to home-cage control treatment group (N–K test). †, # P < 0.05, compared to rats placed in the arena for the fifth time with zero objects (“Arena” group); (†, N–K test; #, Fisher’s least significant difference test).
Figure 5.
Figure 5.
Representative photomicrographs of Fos immunoreactivity within the CA3 and CA1 hippocampal subregions of individual rats exposed to varying amounts of novelty. Note the increased number of Fos immunoreactive cells in the CA1, but not CA3, hippocampal subregion of rats placed in an arena for the first time (Naïve) or fifth time with five novel objects (Arena + five objects) compared to rats placed in an arena for the fifth time with zero or one novel object (Arena, Arena + one object, respectively).
Figure 6.
Figure 6.
Representative photomicrographs of Fos immunoreactivity within the perirhinal cortex and outer (layer two) and inner (layer five) layers of entorhinal cortex (ERC) of individual rats exposed to varying amounts of novelty. Note the increased number of Fos immunoreactive cells in the inner layer of ERC and perirhinal cortex, but not in the outer layer of ERC of rats placed in an arena for the first time (Naïve) compared to rats placed in an arena for the fifth time (Arena).
Figure 7.
Figure 7.
Effect of first time placement in arena or fifth time placement in arena (with zero, one, or five novel objects) on relative Fos expression in select brain regions outside the hippocampal formation. Rats were placed for the first time in a circular arena that contained zero objects on its floor (“Naïve” group), or fifth time in the arena with zero, one, or five novel objects on the floor. After arena exposure (30 min) rats were returned to their home cage for an additional 120 min. Control rats remained in their home cage. Relative Fos expression was examined within a subregion of primary somatosensory cortex (Barrel Fields), primary motor cortex, and the paraventricular nucleus of the hypothalamus (PVN). *P < 0.01, compared to home-cage control treatment group (N–K test).

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