A stable hippocampal representation of a space requires its direct experience

Abstract

In humans and other mammals, the hippocampus is critical for episodic memory, the autobiographical record of events, including where and when they happen. When one records from hippocampal pyramidal neurons in awake, behaving rodents, their most obvious firing correlate is the animal's position within a particular environment, earning them the name "place cells." When an animal explores a novel environment, its pyramidal neurons form their spatial receptive fields over a matter of minutes and are generally stable thereafter. This experience-dependent stabilization of place fields is therefore an attractive candidate neural correlate of the formation of hippocampal memory. However, precisely how the animal's experience of a context translates into stable place fields remains largely unclear. For instance, we still do not know whether observation of a space is sufficient to generate a stable hippocampal representation of that space because the animal must physically visit a spot to demonstrate which cells fire there. We circumvented this problem by comparing the relative stability of place fields of directly experienced space from merely observed space following blockade of NMDA receptors, which preferentially destabilizes newly generated place fields. This allowed us to determine whether place cells stably represent parts of the environment the animal sees, but does not actually occupy. We found that the formation of stable place fields clearly requires direct experience with a space. This suggests that place cells are part of an autobiographical record of events and their spatial context, consistent with providing the "where" information in episodic memory.

Fig. 1.

Experimental design. The recording environment consisted of two concentric boxes: a clear inner box with no asymmetric cues and an opaque outer box with geometric shapes on its sides to provide spatial cues. The rats were extensively familiarized to the inner box of the environment (I1), after which the outer box was rotated (R1). Following injection and another inner box session (I2), an inner wall was removed, allowing exploration of the entire environment (O1). After a delay the animal was reintroduced to the open configuration (O2) and then back into the closed inner box (I3). Gray portions indicate regions explored by the rat; the red bar indicates cue orientation.

Fig. 2.

Place fields of seven simultaneously recorded hippocampal pyramidal neurons across the entire behavioral sequence from a saline-injected rat (with the rotation session omitted for clarity). Rows are cells and columns are sessions. Color bar shows the cell's firing rate values for the entire set of sessions; unvisited pixels are white. Note that all place fields are stable throughout the experiment, with the exception of those inner box cells that remapped in response to wall removal (e.g., cell 4). Whole-environment correlation scores for the O1–O2 comparison are shown to the Right of the ratemaps.

Fig. 3.

Place fields from seven identified pyramidal neurons across the entire behavioral sequence from a CPP-injected rat. Format is the same as in Fig. 2. Note that most neurons with fields in the inner box (e.g., cells 1–3) maintained firing position throughout the experiment, whereas cell 4, which remapped in response to barrier removal in O1, remapped again in O2, consistent with the known effects of CPP on remapping. All outer box firing fields remapped between sessions O1 and O2, even those of cells (2 and 3) with stable inner box fields, which resulted in midrange stability scores for the entire environment.

Fig. 4.

CPP preferentially destabilizes outer box place fields. Mean stability scores for the O1–O2 comparison when broken out into inner and outer box areas (Materials and Methods), error bars are SEM. An ANOVA revealed a significant difference between the four groups (F = 36.4373, P < 0.001). Post hoc comparisons showed that this difference came entirely from the CPP outer box group, which significantly differed from all three other groups (CPP inner, and saline inner and outer; *P < 0.01).