Social odors drive hippocampal CA2 place cell responses to social stimuli

Abstract

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

Keywords: CA2; Hippocampus; Place cells; Social cognition; Social memory; Social odor.

Figure 1.

Behavioral task. Rats freely explored a familiar open field arena for four 20-minute sessions per day. A stimulus cage, a standard rat housing cage, was placed in a corner of the arena. In the first (A) and final (A’) sessions of experimental conditions (i.e., Social Odor, Visual + Odor, Visual, Mirror, and Non-social Odor), and in all four sessions of the Control condition, the cage contained only clean bedding. In the middle two sessions (B and B’) of experimental conditions, a cage containing stimuli (“stimulus cage”) was presented. In the Social Odor condition, a stimulus cage containing soiled bedding of a familiar rat or rats was presented. In the Visual + Odor condition, a stimulus cage containing a familiar rat and the rat’s soiled bedding was presented. In the Visual condition, a familiar rat was placed in the stimulus cage with clean bedding and a filter-top lid to minimize social odors. In the Mirror condition, a familiar rat was placed in the stimulus cage with clean bedding, and the cage was lined with a one-way mirror attachment. This prevented the stimulus rat from seeing the implanted rat, thereby limiting reciprocal social interactions. In the Non-social Odor condition, a wooden block infused with hexyl acetate, a fruity-smelling odorant, was placed in the stimulus cage under clean bedding.

Figure 2.

CA2 Histology. An example hippocampal section showing immunohistological identification of a tetrode track in CA2. To identify CA2, hippocampal sections were immunostained with a CA2 marker, Purkinje cell protein 4 (PCP4, red). DAPI nuclear staining is shown in blue. Scale bar, 200 μm.

Figure 3.

Example CA2 place cell firing rate maps across the four recording sessions for all conditions. Color-coded firing rate maps are shown for all place cells recorded on a single example tetrode in each condition for one example rat. Rate maps are shown scaled to the maximal firing rate (shown inset) of each cell across all sessions. White pixels indicate places that were not visited by the rat during a session.

Figure 4.

Remapping in CA2 in response to social stimuli. A-B. The estimated means of spatial correlation coefficients from our generalized linear mixed model are shown across each condition and session pair (A). The estimated means of spatial correlation coefficients from our generalized linear mixed model are shown across each condition for all session pairs combined (B). Error bars represent 95% confidence intervals. Statistics and associated p-values for specific pairwise comparisons of spatial correlations are shown in Table 3. C-G. Spatial correlation measures are shown for the entire sample of CA2 place cells for all pairs of sessions across all conditions. Each marker represents a spatial correlation value for an individual place cell. Different symbols are used for CA2 place cells recorded from different rats.

Figure 5.

Exploration of stimuli across conditions. A. Heat maps show mean exploration times of different locations in the arena, with the stimulus cage shown in the top right corner of the arena. Time spent was calculated for the first 2 minutes of each session individually and then averaged within each rat. Heat maps shown are averaged across rats. B. Time spent exploring locations close to the cage (within 12 cm) was calculated for each session and then averaged within a rat. Individual dots represent the mean exploration time for each rat, and error bars represent 95% confidence intervals across all sessions within a rat. Rats increased their exploration time of the stimulus cage in session B for the Social Odor, Visual, and Mirror conditions compared to the Control condition (* indicates p-values < 0.05 and ** indicates p-values < 0.01).

Figure 6.

CA2 place cells that responded to a social odor preferentially fired during sharp wave-ripples. A. The difference between firing rates of CA2 place cells during sharp wave-ripples in the rest periods following sessions A and B were positively correlated to the selectivity index for the Social Odor condition (B) but not the Control condition (A). The selectivity index indicates a cell’s preference for session A (value of −1 for maximum selectivity in session A) or session B (value of 1 for maximum selectivity in session B).